Access and modulation of substituted
pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones

Abdelaziz Ejjoummany, Jonathan Elie, Ahmed El Hakmaoui, Mohamed

Akssira, Sylvain Routier, Frédéric Buron

► To cite this version:

Abdelaziz Ejjoummany, Jonathan Elie, Ahmed El Hakmaoui, Mohamed Akssira, Sylvain Routier, et al.. Access and modulation of substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. Molecules, 2023, 28 (15), pp.5811. 10.3390/molecules28155811. hal-04451336

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Access and modulation of substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones

Abdelaziz Ejjoummany, Jonathan Elie, Ahmed El Hakmaoui, Mohamed

Akssira, Sylvain Routier, Frédéric Buron

► To cite this version:

Abdelaziz Ejjoummany, Jonathan Elie, Ahmed El Hakmaoui, Mohamed Akssira, Sylvain Routier, et al.. Access and modulation of substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. Molecules, 2023, 28 (15), pp.5811. 10.3390/molecules28155811. hal-04451336

HAL Id: hal-04451336

https://hal.science/hal-04451336v1

Submitted on 4 Apr 2024

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entific research documents, whether they are pub-
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abroad, or from public or private research centers.

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Article

# Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones

Abdelaziz Ejjoummany<sup>1,2</sup>, Jonathan Elie<sup>1</sup>, Ahmed El Hakmaoui<sup>2</sup>, Mohamed Akssira<sup>2 ID</sup>, Sylvain Routier<sup>1,*</sup> and Frédéric Buron<sup>1,* ID</sup>

**Abstract:** The first access to polyfunctionnalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione derivatives is reported. The series were generated from diethyl acetylenedicarboxylate and arylhydrazines, which afforded the key intermediates bearing two functional positions. The annellation to generate the maleimide moiety of the bicycle was studied. Moreover, an efficient palladium-catalyzed C-C and C-N bond formation via Suzuki–Miyaura or Buchwald–Hartwig coupling reactions in C-6 position was investigated from 6-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. This method provides novel access to various 1,6 di-substituted pyrrolo[3,4-c] pyrazole-4,6-(2H,5H)-diones.

**Keywords:** pyrrolo[3,4-c] pyrazole; cross-coupling; fused [5,5] ring systems

## 1. Introduction

Pyrazole derivatives are an important class of five-membered heterocyclic compounds, which are widely encountered as the central core in a large panel of products used in various therapeutic areas such as antibacterial and antifungal agents, antibiotics and pesticides [1–9]. For example, the pyrazole ring is present in a variety of drugs such as Celebrex, Sildenafil (Viagra), Rimonabant and Difenamizole (Figure 1). For these reasons, their use as pharma-cophores in medicinal chemistry programs has grown, in particular with a view to increasing molecular diversity and exploring innovative chemical spaces.

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Some examples of pyrazole-based commercial drugs.</figcaption></figure>

In contrast, bicyclic heterocycles containing a pyrazole moiety are relatively rare in nature but nonetheless prevalent in the pharmaceutical industry. Such a class is well represented by ring-contracted [5,5] bicyclic aromatic rings [10–16]. Among this heterocyclic family, the pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione nucleus stands out through the little attention it has been given, despite previous reports of interesting biological activities as a phosphatase inhibitor [16–18]. The classic and main method available to date to access this bicyclic system involves building the maleimide moiety using the appropriate functionalized pyrazole moiety [19,20]. Despite the apparent efficiency of this step, molecular diversity cannot be easily managed under this synthetic pathway due to the limitation in terms of access or commercial availability of pyrazole derivatives. In order to introduce

<figure><img src="image_3.png" /></figure>

### check for updates

**Citation:** Ejjoummany, A.; Elie, J.; El Hakmaoui, A.; Akssira, M.; Routier, S.; Buron, F. Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. *Molecules* **2023**, *28*, 5811. https://doi.org/10.3390/molecules28155811

Academic Editor: Lucia Veltri

Received: 6 July 2023

Revised: 27 July 2023

Accepted: 28 July 2023

Published: 1 August 2023

<figure><img src="image_4.png" /></figure>

**Copyright:** © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

<footnote n="1"><sup>1</sup> Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, BP 6759, CEDEX 2, F-45067 Orléans, France</footnote>

<footnote n="2"><sup>2</sup> Faculté des Sciences et Technique, Université Hassan II-Casablanca, BP 146, Mohammedia 28800, Morocco</footnote>

<footnote>* Correspondence: sylvain.routier@univ-orleans.fr (S.R.); frederic.buron@univ-orleans.fr (F.B.)</footnote>
<figure><img src="image_2.png" /></figure>

Article

# Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones

Abdelaziz Ejjoummany<sup>1,2</sup>, Jonathan Elie<sup>1</sup>, Ahmed El Hakmaoui<sup>2</sup>, Mohamed Akssira<sup>2 ID</sup>, Sylvain Routier<sup>1,*</sup> and Frédéric Buron<sup>1,* ID</sup>

**Abstract:** The first access to polyfunctionnalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione derivatives is reported. The series were generated from diethyl acetylenedicarboxylate and arylhydrazines, which afforded the key intermediates bearing two functional positions. The annellation to generate the maleimide moiety of the bicycle was studied. Moreover, an efficient palladium-catalyzed C-C and C-N bond formation via Suzuki–Miyaura or Buchwald–Hartwig coupling reactions in C-6 position was investigated from 6-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. This method provides novel access to various 1,6 di-substituted pyrrolo[3,4-c] pyrazole-4,6-(2H,5H)-diones.

**Keywords:** pyrrolo[3,4-c] pyrazole; cross-coupling; fused [5,5] ring systems

## 1. Introduction

Pyrazole derivatives are an important class of five-membered heterocyclic compounds, which are widely encountered as the central core in a large panel of products used in various therapeutic areas such as antibacterial and antifungal agents, antibiotics and pesticides [1–9]. For example, the pyrazole ring is present in a variety of drugs such as Celebrex, Sildenafil (Viagra), Rimonabant and Difenamizole (Figure 1). For these reasons, their use as pharma-cophores in medicinal chemistry programs has grown, in particular with a view to increasing molecular diversity and exploring innovative chemical spaces.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Some examples of pyrazole-based commercial drugs.</figcaption></figure>

In contrast, bicyclic heterocycles containing a pyrazole moiety are relatively rare in nature but nonetheless prevalent in the pharmaceutical industry. Such a class is well represented by ring-contracted [5,5] bicyclic aromatic rings [10–16]. Among this heterocyclic family, the pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione nucleus stands out through the little attention it has been given, despite previous reports of interesting biological activities as a phosphatase inhibitor [16–18]. The classic and main method available to date to access this bicyclic system involves building the maleimide moiety using the appropriate functionalized pyrazole moiety [19,20]. Despite the apparent efficiency of this step, molecular diversity cannot be easily managed under this synthetic pathway due to the limitation in terms of access or commercial availability of pyrazole derivatives. In order to introduce

<figure><img src="image_4.png" /></figure>

### check for updates

**Citation:** Ejjoummany, A.; Elie, J.; El Hakmaoui, A.; Akssira, M.; Routier, S.; Buron, F. Access and Modulation of Substituted Pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones. *Molecules* **2023**, *28*, 5811. https://doi.org/10.3390/molecules28155811

Academic Editor: Lucia Veltri

Received: 6 July 2023

Revised: 27 July 2023

Accepted: 28 July 2023

Published: 1 August 2023

<figure><img src="image_5.png" /></figure>

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

<footnote n="1"><sup>1</sup> Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, BP 6759, CEDEX 2, F-45067 Orléans, France</footnote>

<footnote n="2"><sup>2</sup> Faculté des Sciences et Technique, Université Hassan II-Casablanca, BP 146, Mohammedia 28800, Morocco</footnote>

<footnote>* Correspondence: sylvain.routier@univ-orleans.fr (S.R.); frederic.buron@univ-orleans.fr (F.B.)</footnote>
a wide range of functional groups and to explore its multiple substitutions, a promising solution is to find an efficient method to selectively functionalize polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones at the C-3 position, an indispensable step to designing future original bioactive molecules (Figure 2).

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Access to polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones.</figcaption></figure>

## 2. Results

Based on diethyl acetylenedicarboxylate (DEAD) reactivity with arylhydrazine, new pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones were prepared in a few steps (Scheme 1) [21]. Condensation of the substituted phenylhydrazine chlorhydrate and diethyl acetylenedicarboxylate in ethanol led to 5-hydroxypyrazols **1** and **2** in 65 and 70% yields, respectively. In the next step, treatment of the derivatives **1** and **2** with POCl₃ and DMF in DCE led to 4-formyl-5-chloropyrazoles **3** and **4** in yields of over 85%. A Pinnick oxidation using sodium chlorite under mild acidic conditions afforded the corresponding acids **5** and **6** in good yields [22–24]. An amide bond formation with HOBt and EDCI as peptide coupling reagents [25] was performed in the presence of several amines such as methylamine, aniline or PMBNH₂ to afford the expected amides **7–10**. Saponification of the ester function with KOH furnished acids **11–14** in good yields. Finally, the formation of the maleimide moiety was carried out from amines **11–14** in the presence of 1,1'-carbonyldiimidazole to access 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones **15–17** in yields of 80–86% [26]. Only the aromatic N-aryl derivative **18** was never observed, which is a limitation of this annellation method.

With these three compounds in hand, we then achieved the chlorine displacement by Suzuki–Miyaura cross-coupling to explore their reactivity and also access C-3 substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones [27]. This prompted us to propose to the community a general and efficient catalytic system by optimizing the main reaction parameters (Table 1). First, we used **15** as starting material, Pd(OAc)₂ as the palladium source, Xantphos as a ligand, K₂CO₃ as a base and 1,4-dioxane as the solvent under microwave irradiation at 130 °C for 1.5 h [28]. With these conditions, the desired product **19** was isolated in a low but encouraging yield (20%, entry 2), in contrast with PdCl₂(PPh₃)₂ as a catalytic system, which totally inhibited reactivity (entry 1). When the palladium system
a wide range of functional groups and to explore its multiple substitutions, a promising solution is to find an efficient method to selectively functionalize polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones at the C-3 position, an indispensable step to designing future original bioactive molecules (Figure 2).

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Access to polyfunctionalized pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones.</figcaption></figure>

## 2. Results

Based on diethyl acetylenedicarboxylate (DEAD) reactivity with arylhydrazine, new pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones were prepared in a few steps (Scheme 1) [21]. Condensation of the substituted phenylhydrazine chlorhydrate and diethyl acetylenedicarboxylate in ethanol led to 5-hydroxypyrazols **1** and **2** in 65 and 70% yields, respectively. In the next step, treatment of the derivatives **1** and **2** with POCl₃ and DMF in DCE led to 4-formyl-5-chloropyrazoles **3** and **4** in yields of over 85%. A Pinnick oxidation using sodium chlorite under mild acidic conditions afforded the corresponding acids **5** and **6** in good yields [22–24]. An amide bond formation with HOBt and EDCI as peptide coupling reagents [25] was performed in the presence of several amines such as methylamine, aniline or PMBNH₂ to afford the expected amides **7–10**. Saponification of the ester function with KOH furnished acids **11–14** in good yields. Finally, the formation of the maleimide moiety was carried out from amines **11–14** in the presence of 1,1'-carbonyldiimidazole to access 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones **15–17** in yields of 80–86% [26]. Only the aromatic N-aryl derivative **18** was never observed, which is a limitation of this annellation method.

With these three compounds in hand, we then achieved the chlorine displacement by Suzuki–Miyaura cross-coupling to explore their reactivity and also access C-3 substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones [27]. This prompted us to propose to the community a general and efficient catalytic system by optimizing the main reaction parameters (Table 1). First, we used **15** as starting material, Pd(OAc)₂ as the palladium source, Xantphos as a ligand, K₂CO₃ as a base and 1,4-dioxane as the solvent under microwave irradiation at 130 °C for 1.5 h [28]. With these conditions, the desired product **19** was isolated in a low but encouraging yield (20%, entry 2), in contrast with PdCl₂(PPh₃)₂ as a catalytic system, which totally inhibited reactivity (entry 1). When the palladium system
was switched for Pd(PPh₃)₄, the reactivity was improved, and the desired compound **19** was obtained in 65% yield. A fine adjustment of the temperature coupled with an increase in the reaction time improved the reactivity, and the compound was isolated in 85% yield. In the following experiment, we used Cs₂CO₃ as a base, which induced a slight decrease in yield. Finally, the nature of the solvent was investigated, showing that toluene induced a drastic inhibition of the reactivity.

<figure><img src="image_6.png" /><figcaption>**Scheme 1.** Steps in the synthesis of 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H, 5H)-diones **15–17**.</figcaption></figure>

<table><caption>**Table 1.** Optimization of Suzuki–Miyaura cross-coupling reaction.</caption><thead><tr><th>Entry</th><th>Catalyst System<br>(10 mol %)</th><th>Base<br>(3.0 eq.)</th><th>T (°C)</th><th>Solvent</th><th>Time (h)</th><th>19, Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>PdCl<sub>2</sub>(PPh<sub>3</sub>)<sub>2</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>0</td></tr><tr><td>2</td><td>Pd(OAc)<sub>2</sub>/Xantphos (0.2 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>20</td></tr><tr><td>3</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>65</td></tr><tr><td>4</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>1.5</td><td>80</td></tr><tr><td>5</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>2.0</td><td>85</td></tr><tr><td>7</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>2.0</td><td>79</td></tr><tr><td>6</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Toluene</td><td>2.0</td><td>0</td></tr></tbody></table>

Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives (Table 2). The use of electron-donating substituents as a methoxy group was well tolerated and afforded the derivative **20** in 79% yield. In contrast, the presence of electron-withdrawing substituents slightly decreased the efficiency of the reaction, and compounds **23** and **24** were isolated in 65% and 60% yields, respectively. Next, we investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of **22** were observed), the meta orientation led to the desired compound **21** in 67% yield. The introduction of electron-rich heterocycles was also studied with 2- or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products **25–27** were isolated in satisfactory yields. The only identified limit concerned the use of a π-electron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound **29**

<footnote><sup>a</sup> Isolated yield.</footnote>
was switched for Pd(PPh₃)₄, the reactivity was improved, and the desired compound **19** was obtained in 65% yield. A fine adjustment of the temperature coupled with an increase in the reaction time improved the reactivity, and the compound was isolated in 85% yield. In the following experiment, we used Cs₂CO₃ as a base, which induced a slight decrease in yield. Finally, the nature of the solvent was investigated, showing that toluene induced a drastic inhibition of the reactivity.

<figure><img src="image_7.png" /><figcaption>**Scheme 1.** Steps in the synthesis of 2-aryl-3-chloropyrrolo[3,4-c]pyrazole-4,6-(2H, 5H)-diones **15–17**.</figcaption></figure>

<table><caption>**Table 1.** Optimization of Suzuki–Miyaura cross-coupling reaction.</caption><thead><tr><th>Entry</th><th>Catalyst System<br>(10 mol %)</th><th>Base<br>(3.0 eq.)</th><th>T (°C)</th><th>Solvent</th><th>Time (h)</th><th>19, Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>PdCl<sub>2</sub>(PPh<sub>3</sub>)<sub>2</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>0</td></tr><tr><td>2</td><td>Pd(OAc)<sub>2</sub>/Xantphos (0.2 eq.)</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>20</td></tr><tr><td>3</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1.5</td><td>65</td></tr><tr><td>4</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>1.5</td><td>80</td></tr><tr><td>5</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>2.0</td><td>85</td></tr><tr><td>7</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Dioxane</td><td>2.0</td><td>79</td></tr><tr><td>6</td><td>Pd(PPh<sub>3</sub>)<sub>4</sub></td><td>K<sub>2</sub>CO<sub>3</sub></td><td>150</td><td>Toluene</td><td>2.0</td><td>0</td></tr></tbody></table>

Next, the scope and potential limitations of the Pd-coupling step were investigated by modulation of the boron derivatives (Table 2). The use of electron-donating substituents as a methoxy group was well tolerated and afforded the derivative **20** in 79% yield. In contrast, the presence of electron-withdrawing substituents slightly decreased the efficiency of the reaction, and compounds **23** and **24** were isolated in 65% and 60% yields, respectively. Next, we investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a dramatic decrease in yield (only traces of **22** were observed), the meta orientation led to the desired compound **21** in 67% yield. The introduction of electron-rich heterocycles was also studied with 2- or 3-furanyl boronic acids and 2-thienyl boronic acid, and the desired products **25–27** were isolated in satisfactory yields. The only identified limit concerned the use of a π-electron-deficient heterocycle such as 4-pyridinyl boronic acid, which drastically inhibited the reaction. Lastly, we evaluated the influence of the nature of the substituent in N-2 and N-5 positions. Remarkably, the presence of PMB substituent in N-5 position preserved the efficiency, and compound **29**

<footnote><sup>a</sup> Isolated yield.</footnote>
was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded **30** in 84% yield.

<table><caption>**Table 2.** Synthesis of **19–30**.</caption><thead><tr><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td><img src="image_19.png" alt="19-17 product structure"></td><td>85%</td><td>7</td><td><img src="image_19.png" alt="19-30 product structure"></td><td>76%</td></tr><tr><td>2</td><td><img src="image_20.png" alt="20-19 product structure"></td><td>79%</td><td>8</td><td><img src="image_26.png" alt="26-19 product structure"></td><td>56%</td></tr><tr><td>3</td><td><img src="image_21.png" alt="21-19 product structure"></td><td>67%</td><td>9</td><td><img src="image_27.png" alt="27-19 product structure"></td><td>45%</td></tr><tr><td>4</td><td><img src="image_22.png" alt="22-19 product structure"></td><td>Traces</td><td>10</td><td><img src="image_28.png" alt="28-19 product structure"></td><td>-</td></tr><tr><td>5</td><td><img src="image_23.png" alt="23-19 product structure"></td><td>65%</td><td>11</td><td><img src="image_29.png" alt="29-19 product structure"></td><td>70%</td></tr><tr><td>6</td><td><img src="image_24.png" alt="24-19 product structure"></td><td>60%</td><td>12</td><td><img src="image_30.png" alt="30-19 product structure"></td><td>84%</td></tr></tbody></table>

<footnote><sup>a</sup> Isolated yield.</footnote>
was isolated in good yield. The same behavior was observed with a 4-nitrophenyl moiety in N-2 position and afforded **30** in 84% yield.

<table><caption>**Table 2.** Synthesis of **19–30**.</caption><thead><tr><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td><img src="image_19.png" alt="19-17 Product"></td><td>85%</td><td>7</td><td><img src="image_19-30.png" alt="19-30 Product"></td><td>76%</td></tr><tr><td>2</td><td><img src="image_20.png" alt="20-1 Product"></td><td>79%</td><td>8</td><td><img src="image_20.png" alt="20-2 Product"></td><td>56%</td></tr><tr><td>3</td><td><img src="image_21.png" alt="21-1 Product"></td><td>67%</td><td>9</td><td><img src="image_21.png" alt="21-2 Product"></td><td>45%</td></tr><tr><td>4</td><td><img src="image_22.png" alt="22-1 Product"></td><td>Traces</td><td>10</td><td><img src="image_22.png" alt="22-2 Product"></td><td>-</td></tr><tr><td>5</td><td><img src="image_23.png" alt="23-1 Product"></td><td>65%</td><td>11</td><td><img src="image_23.png" alt="23-2 Product"></td><td>70%</td></tr><tr><td>6</td><td><img src="image_24.png" alt="24-1 Product"></td><td>60%</td><td>12</td><td><img src="image_24.png" alt="24-2 Product"></td><td>84%</td></tr></tbody></table>

<footnote><sup>a</sup> Isolated yield.</footnote>
We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc)₂/Xantphos as a catalytic system, Cs₂CO₃ as a base and dioxane at 130 °C under microwave irradiation. However, in this case, with aniline as a partner, the desired product **31** was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd₂dba₃, the reactivity was improved, and the desired compound **31** was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h at 100 °C was the best condition, and **31** was isolated in 83% of yield (entry 4). Modifications of the nature of other parameters, such as the base or solvent, did not improve the efficiency of the reaction. Finally, to show that the amination follows a palladium-assisted mechanism without a concomitant S<sub>N</sub>Ar reaction, we carried out the transformation without any catalyst (Table 3, Entry 7), and, as expected, no reaction occurred.

<table><caption>**Table 3.** Optimization of the conditions for the formation of **31**.</caption><thead><tr><th>Entry</th><th>Catalyst<br>(10 mol %)</th><th>Ligand<br>(20 mol %)</th><th>Base<br>(3.0 eq.)</th><th>T (°C)<br>M.W.</th><th>Solvent</th><th>Time (h)</th><th>31, Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>Pd(OAc)<sub>2</sub></td><td>Xantphos</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>0.5</td><td>8</td></tr><tr><td>2</td><td>Pd<sub>2</sub>dba<sub>3</sub></td><td>Xantphos</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>0.5</td><td>56</td></tr><tr><td>3</td><td>Pd<sub>2</sub>dba<sub>3</sub></td><td>Xantphos</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>130</td><td>Dioxane</td><td>1</td><td>50</td></tr><tr><td>4</td><td>Pd<sub>2</sub>dba<sub>3</sub></td><td>Xantphos</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>100</td><td>Dioxane</td><td>1</td><td>83</td></tr><tr><td>5</td><td>Pd<sub>2</sub>dba<sub>3</sub></td><td>Xantphos</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>100</td><td>Dioxane</td><td>1</td><td>76</td></tr><tr><td>6</td><td>Pd<sub>2</sub>dba<sub>3</sub></td><td>Xantphos</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>100</td><td>Toluene</td><td>1</td><td>N.D.<sup>b</sup></td></tr><tr><td>7</td><td>-</td><td>Xantphos</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>100</td><td>Dioxane</td><td>1</td><td>0</td></tr></tbody></table>

<sup>a</sup> Isolated yield. <sup>b</sup> Not detected.

Next, the scope and limitations of the amination were investigated by modulating the nature of the amines (Table 4). The use of electron-rich anilines was well tolerated and afforded derivative **32** in good yields (entries 2). In contrast, the presence of electron-withdrawing substituents such as trifluoromethyl slightly decreased the efficiency of the reaction, and compound **35** was isolated in 41% of yield. We next investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a slight decrease in yield (34, 65% versus 32, 88%), the meta orientation did not alter the efficiency of the cross-coupling reaction, as product **33** was isolated in high yield. The only identified limit concerned the nature of the amine. The use of poorly nucleophilic lactams or morpholine as well as secondary alkylamines or 3-aminopyridine was prohibited.

Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds **39** and **40** were isolated in 68% and 51% of yields, respectively.
We next focused our attention on creating a C-N bond instead of a C-C bond under palladium catalysis by chlorine displacement [29]. We started with conditions that had proved their efficiency in the imidazodiazole series [30,31], namely Pd(OAc)₂/Xantphos as a catalytic system, Cs₂CO₃ as a base and dioxane at 130 °C under microwave irradiation. However, in this case, with aniline as a partner, the desired product **31** was isolated in only 8% of yield (Table 3, entry 1). When the catalyst was switched for Pd₂dba₃, the reactivity was improved, and the desired compound **31** was obtained in an encouraging 56% yield (entry 2). The fine adjustment of the temperature and reaction time showed that 1h at 100 °C was the best condition, and **31** was isolated in 83% of yield (entry 4). Modifications of the nature of other parameters, such as the base or solvent, did not improve the efficiency of the reaction. Finally, to show that the amination follows a palladium-assisted mechanism without a concomitant S<sub>N</sub>Ar reaction, we carried out the transformation without any catalyst (Table 3, Entry 7), and, as expected, no reaction occurred.

<table><caption>**Table 3.** Optimization of the conditions for the formation of **31**.</caption><thead><tr><th>Entry</th><th>Catalyst<br>(10 mol %)</th><th>Ligand<br>(20 mol %)</th><th>Base<br>(3.0 eq.)</th><th>T (°C)<br>M.W.</th><th>Solvent</th><th>Time (h)</th><th>31, Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>Pd(OAc)₂</td><td>Xantphos</td><td>Cs₂CO₃</td><td>130</td><td>Dioxane</td><td>0.5</td><td>8</td></tr><tr><td>2</td><td>Pd₂dba₃</td><td>Xantphos</td><td>Cs₂CO₃</td><td>130</td><td>Dioxane</td><td>0.5</td><td>56</td></tr><tr><td>3</td><td>Pd₂dba₃</td><td>Xantphos</td><td>Cs₂CO₃</td><td>130</td><td>Dioxane</td><td>1</td><td>50</td></tr><tr><td>4</td><td>Pd₂dba₃</td><td>Xantphos</td><td>Cs₂CO₃</td><td>100</td><td>Dioxane</td><td>1</td><td>83</td></tr><tr><td>5</td><td>Pd₂dba₃</td><td>Xantphos</td><td>K₂CO₃</td><td>100</td><td>Dioxane</td><td>1</td><td>76</td></tr><tr><td>6</td><td>Pd₂dba₃</td><td>Xantphos</td><td>Cs₂CO₃</td><td>100</td><td>Toluene</td><td>1</td><td>N.D.<sup>b</sup></td></tr><tr><td>7</td><td>-</td><td>Xantphos</td><td>K₂CO₃</td><td>100</td><td>Dioxane</td><td>1</td><td>0</td></tr></tbody></table>

Next, the scope and limitations of the amination were investigated by modulating the nature of the amines (Table 4). The use of electron-rich anilines was well tolerated and afforded derivative **32** in good yields (entries 2). In contrast, the presence of electron-withdrawing substituents such as trifluoromethyl slightly decreased the efficiency of the reaction, and compound **35** was isolated in 41% of yield. We next investigated the influence of steric hindrance using the methoxy position switch on the phenyl ring. While the ortho orientation induced a slight decrease in yield (34, 65% versus 32, 88%), the meta orientation did not alter the efficiency of the cross-coupling reaction, as product **33** was isolated in high yield. The only identified limit concerned the nature of the amine. The use of poorly nucleophilic lactams or morpholine as well as secondary alkylamines or 3-aminopyridine was prohibited.

Lastly, the influence of the nature of the substituent in N-2 and N-5 positions was explored. Remarkably, the presence of the PMB substituent in N-5 position or the 4-nitrophenyl moiety in N-1 position led to the same observation, i.e., a slight decrease in the reactivity, and compounds **39** and **40** were isolated in 68% and 51% of yields, respectively.

<footnote><sup>a</sup> Isolated yield. <sup>b</sup> Not detected.</footnote>
<table><caption>**Table 4.** Synthesis of 31–40.</caption><thead><tr><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td><img src="image_0_1.png" alt="15-17: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>83%</td><td>6</td><td><img src="image_0_2.png" alt="31-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>-</td></tr><tr><td>2</td><td><img src="image_0_3.png" alt="31-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>88%</td><td>7</td><td><img src="image_0_4.png" alt="36-37: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>-</td></tr><tr><td>3</td><td><img src="image_0_5.png" alt="31-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>84%</td><td>8</td><td><img src="image_0_6.png" alt="37-38: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>-</td></tr><tr><td>4</td><td><img src="image_0_7.png" alt="31-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>65%</td><td>9</td><td><img src="image_0_8.png" alt="38-39: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>68%</td></tr><tr><td>5</td><td><img src="image_0_9.png" alt="31-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>41%</td><td>10</td><td><img src="image_0_10.png" alt="39-40: 2,4-dichloro-4-(naphthalen-1-yl)-1,3,5-triazin-2-ol"></td><td>51%</td></tr></tbody></table>

### 3. Materials and Methods

#### 3.1. *General Information*

¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl₃ and DMSO-d₆. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by ¹H NMR, and ¹³C NMR, which are consistent with those reported in the literature (Supplementary Materials). Melting points are uncorrected. IR absorption spectra were obtained on a PerkinElmer PARAGON 1000 PC, and the values are reported in inverse centimeters. HRMS spectra were acquired in positive mode with an ESI source on a Q-TOF mass by the "Fédération de Recherche" ICOA/CBM (FR2708) platform, and NMR data were generated on the Salsa platform. Monitoring of the reactions was performed using silica gel TLC plates (silica Merck 60 F 254). Spots were visualized by using UV light (254 nm and 356 nm). Column chromatography was performed using silica gel 60

<footnote><sup>a</sup> Isolated yield.</footnote>
<table><caption>**Table 4.** Synthesis of 31–40.</caption><thead><tr><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th><th>Entry</th><th>Product</th><th>Yield (%) <sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td><img src="image_0_0_1.png" alt="15-17: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>83%</td><td>6</td><td><img src="image_0_0_2.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>-</td></tr><tr><td>2</td><td><img src="image_0_0_3.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>88%</td><td>7</td><td><img src="image_0_0_4.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>-</td></tr><tr><td>3</td><td><img src="image_0_0_5.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>84%</td><td>8</td><td><img src="image_0_0_6.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>-</td></tr><tr><td>4</td><td><img src="image_0_0_7.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>65%</td><td>9</td><td><img src="image_0_0_8.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>68%</td></tr><tr><td>5</td><td><img src="image_0_0_9.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>41%</td><td>10</td><td><img src="image_0_0_10.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>51%</td></tr><tr><td>6</td><td><img src="image_0_0_11.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>41%</td><td>10</td><td><img src="image_0_0_12.png" alt="31-40: 1,2,3,4-tetrahydro-1H-imidazole-4-carboxylic acid anhydride"></td><td>51%</td></tr></tbody></table>

### 3. Materials and Methods

#### 3.1. *General Information*

¹H NMR and ¹³C NMR spectra were recorded on a Bruker DPX 400 Mhz instrument using CDCl₃ and DMSO-d₆. The chemical shifts are reported in parts per million (δ scale), and all coupling constant (J) values are reported in hertz. The following abbreviations were used for the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), p (pentuplet), m (multiplet), sext (sextuplet) and dd (doublet of doublets). All compounds were characterized by ¹H NMR, and ¹³C NMR, which are consistent with those reported in the literature (Supplementary Materials). Melting points are uncorrected. IR absorption spectra were obtained on a PerkinElmer PARAGON 1000 PC, and the values are reported in inverse centimeters. HRMS spectra were acquired in positive mode with an ESI source on a Q-TOF mass by the "Fédération de Recherche" ICOA/CBM (FR2708) platform, and NMR data were generated on the Salsa platform. Monitoring of the reactions was performed using silica gel TLC plates (silica Merck 60 F 254). Spots were visualized by using UV light (254 nm and 356 nm). Column chromatography was performed using silica gel 60

<footnote><sup>a</sup> Isolated yield.</footnote>
(0.063–0.200 mm, Merck, Darmstadt, Germany). Microwave irradiation was carried out in sealed vessels placed in a Biotage Initiator or Biotage Initiator + system (400 W maximum power). The temperatures were measured externally by using IR. Pressure was measured by using a non-invasive sensor integrated into the cavity lid. All reagents were purchased from commercial suppliers and were used without further purification.

## 3.2. Synthesis and Characterization

### 3.2.1. Ethyl 5-Hydroxy-1-(p-tolyl)-1H-pyrazole-3-carboxylate (1)

To a suspension of *p*-tolylphenylhydrazine hydrochloride (5.0 g, 31.5 mmol, 1.0 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (6.05 mL, 37.83 mmol, 1.2 eq.) and then slowly Et<sub>3</sub>N (8.72 mL, 63.05 mmol, 2.0 eq.). The mixture was stirred for 20 h at room temperature. The solvent was removed, the residue was taken in EtOAc, and the organic layer was washed with aqueous HCl 6 M. The aqueous layer was extracted twice with EtOAc; organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated; and the residue was precipitated and washed with Et<sub>2</sub>O to give the title product **1** (2.99 g, 65%) as a white solid. R.f = 0.3 (EtOAc:PE, 8:2). Mp: 194–196 °C. <sup>1</sup>H NMR (250 MHz, DMSO-d<sub>6</sub>) δ 10.36 (s, OH), 7.19 (s, 4H), 6.20 (s, 1H), 4.10 (q, *J* = 7.1 Hz, 2H), 2.31 (s, 3H), 1.11 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, DMSO-d<sub>6</sub>) δ 161.3 (CO), 158.9 (CO), 138.1 (Cq), 137.6 (Cq), 133.4 (Cq), 129.3 (2 × CH), 125.7 (2 × CH), 97.8 (CH), 61.2 (CH<sub>2</sub>), 21.1 (CH<sub>3</sub>), 14.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2985, 1722, 1557, 1462, 813, 764, 514. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>13</sub>H<sub>15</sub>N<sub>2</sub>O<sub>3</sub>: 247.1074, found: 247.1077.

### 3.2.2. Ethyl 5-Hydroxy-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (2)

To a suspension of 4-nitrophenylhydrazine (4.5 g, 29.40 mmol, 1.00 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (3.07 mL, 35.28 mmol, 1.2 eq.) and then slowly Et<sub>3</sub>N (8.15 mL, 58.80 mmol, 2.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, the residue was taken in EtOAc, and the organic layer was washed with aqueous HCl 6 M. The aqueous layer was extracted twice with EtOAc; organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated; and the residue was precipitated and washed with Et<sub>2</sub>O to give the title product **2** (5.11 g, 70%) as a white solid. Mp: 246–248 °C. <sup>1</sup>H NMR (400 MHz, DMSO-d<sub>6</sub>) δ 8.30 (d, *J* = 8.9 Hz, 2H), 8.08 (d, *J* = 8.9 Hz, 2H), 5.96 (s, 1H), 4.28 (q, *J* = 7.1 Hz, 2H), 1.29 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, DMSO-d<sub>6</sub>) δ 161.9 (CO), 155.1 (Cq), 145.3 (Cq), 144.1 (Cq), 143.6 (Cq), 125.2 (2 × CH), 121.7 (2 × CH), 90.1 (CH), 60.9 (CH<sub>2</sub>), 14.6 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2955, 1724, 1595, 1421, 1155, 1023, 854, 767. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>12</sub>H<sub>12</sub>N<sub>3</sub>O<sub>5</sub>: 278.0768, found: 278.0771.

### 3.2.3. Ethyl 5-Chloro-4-formyl-1-(p-tolyl)-1H-pyrazole-3-carboxylate (3)

To a suspension of compound **1** (2.20 g, 9.01 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.13 mL, 34.8 mmol, 3.0 eq.) and POCl<sub>3</sub> (1.51 mL, 15.76 mmol, 1.75 eq.). The mixture was stirred and refluxed for 1.5 h. After cooling, POCl<sub>3</sub> (3.8 mL, 39.64 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly, and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated to give the title product **3** (2.63 g, 85%) as a white solid. Mp: 168–170 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 10.51 (s, 1H<sub>Ald</sub>), 7.41 (d, *J* = 8.4 Hz, 2H), 7.32 (d, *J* = 8.4 Hz, 2H), 4.49 (q, *J* = 7.1 Hz, 2H), 2.43 (s, 3H), 1.43 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 185.2 (CH<sub>Ald</sub>), 160.9 (CO), 144.1 (Cq), 140.4 (Cq), 134.0 (Cq), 131.8 (Cq), 129.9 (2 × CH), 125.6 (2 × CH), 119.4 (Cq), 62.1 (CH<sub>2</sub>), 21.3 (CH<sub>3</sub>), 14.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2982, 2928, 1740, 1516, 1422, 1259, 1028, 827. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>14</sub>H<sub>14</sub>ClN<sub>2</sub>O<sub>3</sub>: 293.0685, found: 293.0687.

### 3.2.4. Ethyl 5-Chloro-4-formyl-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (4)

To a suspension of compound **2** (3.00 g, 10.13 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.4 mL, 30.39 mmol, 3.0 eq.) and POCl<sub>3</sub> (1.71 mL, 17.72 mmol, 1.75 eq.). The mixture
(0.063–0.200 mm, Merck, Darmstadt, Germany). Microwave irradiation was carried out in sealed vessels placed in a Biotage Initiator or Biotage Initiator + system (400 W maximum power). The temperatures were measured externally by using IR. Pressure was measured by using a non-invasive sensor integrated into the cavity lid. All reagents were purchased from commercial suppliers and were used without further purification.

## 3.2. Synthesis and Characterization

### 3.2.1. Ethyl 5-Hydroxy-1-(p-tolyl)-1H-pyrazole-3-carboxylate (1)

To a suspension of *p*-tolylphenylhydrazine hydrochloride (5.0 g, 31.5 mmol, 1.0 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (6.05 mL, 37.83 mmol, 1.2 eq.) and then slowly Et<sub>3</sub>N (8.72 mL, 63.05 mmol, 2.0 eq.). The mixture was stirred for 20 h at room temperature. The solvent was removed, the residue was taken in EtOAc, and the organic layer was washed with aqueous HCl 6 M. The aqueous layer was extracted twice with EtOAc; organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated; and the residue was precipitated and washed with Et<sub>2</sub>O to give the title product **1** (2.99 g, 65%) as a white solid. R.f = 0.3 (EtOAc:PE, 8:2). Mp: 194–196 °C. <sup>1</sup>H NMR (250 MHz, DMSO-d<sub>6</sub>) δ 10.36 (s, OH), 7.19 (s, 4H), 6.20 (s, 1H), 4.10 (q, *J* = 7.1 Hz, 2H), 2.31 (s, 3H), 1.11 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, DMSO-d<sub>6</sub>) δ 161.3 (CO), 158.9 (CO), 138.1 (Cq), 137.6 (Cq), 133.4 (Cq), 129.3 (2 × CH), 125.7 (2 × CH), 97.8 (CH), 61.2 (CH<sub>2</sub>), 21.1 (CH<sub>3</sub>), 14.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2985, 1722, 1557, 1462, 813, 764, 514. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>13</sub>H<sub>15</sub>N<sub>2</sub>O<sub>3</sub>: 247.1074, found: 247.1077.

### 3.2.2. Ethyl 5-Hydroxy-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (2)

To a suspension of 4-nitrophenylhydrazine (4.5 g, 29.40 mmol, 1.00 eq.) in EtOH (50 mL) was added diethyl acetylenedicarboxylate (3.07 mL, 35.28 mmol, 1.2 eq.) and then slowly Et<sub>3</sub>N (8.15 mL, 58.80 mmol, 2.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, the residue was taken in EtOAc, and the organic layer was washed with aqueous HCl 6 M. The aqueous layer was extracted twice with EtOAc; organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated; and the residue was precipitated and washed with Et<sub>2</sub>O to give the title product **2** (5.11 g, 70%) as a white solid. Mp: 246–248 °C. <sup>1</sup>H NMR (400 MHz, DMSO-d<sub>6</sub>) δ 8.30 (d, *J* = 8.9 Hz, 2H), 8.08 (d, *J* = 8.9 Hz, 2H), 5.96 (s, 1H), 4.28 (q, *J* = 7.1 Hz, 2H), 1.29 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, DMSO-d<sub>6</sub>) δ 161.9 (CO), 155.1 (Cq), 145.3 (Cq), 144.1 (Cq), 143.6 (Cq), 125.2 (2 × CH), 121.7 (2 × CH), 90.1 (CH), 60.9 (CH<sub>2</sub>), 14.6 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2955, 1724, 1595, 1421, 1155, 1023, 854, 767. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>12</sub>H<sub>12</sub>N<sub>3</sub>O<sub>5</sub>: 278.0768, found: 278.0771.

### 3.2.3. Ethyl 5-Chloro-4-formyl-1-(p-tolyl)-1H-pyrazole-3-carboxylate (3)

To a suspension of compound **1** (2.20 g, 9.01 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.13 mL, 34.8 mmol, 3.0 eq.) and POCl<sub>3</sub> (1.51 mL, 15.76 mmol, 1.75 eq.). The mixture was stirred and refluxed for 1.5 h. After cooling, POCl<sub>3</sub> (3.8 mL, 39.64 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly, and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO<sub>4</sub>, filtrated and concentrated to give the title product **3** (2.63 g, 85%) as a white solid. Mp: 168–170 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 10.51 (s, 1H<sub>Ald</sub>), 7.41 (d, *J* = 8.4 Hz, 2H), 7.32 (d, *J* = 8.4 Hz, 2H), 4.49 (q, *J* = 7.1 Hz, 2H), 2.43 (s, 3H), 1.43 (t, *J* = 7.1 Hz, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 185.2 (CH<sub>Ald</sub>), 160.9 (CO), 144.1 (Cq), 140.4 (Cq), 134.0 (Cq), 131.8 (Cq), 129.9 (2 × CH), 125.6 (2 × CH), 119.4 (Cq), 62.1 (CH<sub>2</sub>), 21.3 (CH<sub>3</sub>), 14.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2982, 2928, 1740, 1516, 1422, 1259, 1028, 827. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>14</sub>H<sub>14</sub>ClN<sub>2</sub>O<sub>3</sub>: 293.0685, found: 293.0687.

### 3.2.4. Ethyl 5-Chloro-4-formyl-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (4)

To a suspension of compound **2** (3.00 g, 10.13 mmol, 1.0 eq.) in DCE (60 mL) was added DMF (2.4 mL, 30.39 mmol, 3.0 eq.) and POCl<sub>3</sub> (1.71 mL, 17.72 mmol, 1.75 eq.). The mixture
was stirred and refluxed for 1.5 h. After cooling, POCl₃ (4.27 mL, 44.57 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO₄, filtrated and concentrated to give the title product **4** (2.63 g, 86%) as a white solid. Mp: 174–176 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, Hₐld), 8.47 (d, *J* = 8.5 Hz, 2H), 8.01 (d, *J* = 8.5 Hz, 2H), 4.42 (q, *J* = 7.1 Hz, 2H), 1.35 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 185.4 (CHₐld), 160.8 (CO), 148.3 (Cq), 145.0 (Cq), 141.3 (Cq), 132.1 (Cq), 127.7 (2 × CH), 125.4 (2 × CH), 119.7 (Cq), 62.3 (CH₂), 14.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3115, 2988, 1723, 1535, 1321, 1025, 860, 687. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₅: 324.0378, found: 324.0381.

### 3.2.5. 5-Chloro-3-(ethoxycarbonyl)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid (5)

To a suspension of **3** (2.63 g, 9.01 mmol, 1.0 eq.) in a mixture of *t*-BuOH/H₂O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH₂PO₄ (6.48 g, 54.06 mmol, 6.0 eq.) and NaClO₂ (4.89 g, 54.06 mmol, 6.0 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et₂O. Organics layers were combined, dried over MgSO₄ and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound **5** (2.77 g, 88%) as a white solid. Mp: 172–174 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (d, *J* = 8.4 Hz, 2H), 7.38 (d, *J* = 8.4 Hz, 2H), 4.26 (q, *J* = 7.1 Hz, 2H), 2.40 (s, 3H), 1.27 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.4 (CO), 163.1 (CO), 144.1 (Cq), 139.4 (Cq), 135.4 (Cq), 130.2 (2 × CH), 126.6 (Cq), 125.9 (2 × CH), 121.4 (Cq), 61.2 (CH₂), 21.2 (CH₃), 14.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3011, 2752, 1734, 1452, 1300, 1223, 1027, 826, 763. HRMS: *m/z* [M + H]⁺ calculated for C₁₄H₁₄ClN₂O₄: 309.0999, found: 309.1000.

### 3.2.6. 5-Chloro-3-(ethoxycarbonyl)-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic acid (6)

To a suspension of **4** (2.00 g, 6.22 mmol, 1.00 eq.) in a mixture of *t*-BuOH/H₂O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH₂PO₄ (4.48 g, 37.37 mmol, 6.00 eq.) and NaClO₂ (3.38 g, 37.37 mmol, 6.00 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et₂O. Organic layers were combined, dried over MgSO₄ and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound **6** (1.04 g, 81%) as a white solid. Mp: 174–176 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.44 (d, *J* = 8.9 Hz, 2H), 7.99 (d, *J* = 8.9 Hz, 2H), 4.34 (q, *J* = 7.1 Hz, 2H), 1.29 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9 (CO), 161.5 (CO), 148.1 (Cq), 145.5 (Cq), 141.8 (Cq), 131.1 (Cq), 127.4 (2 × CH), 125.3 (2 × CH), 114.2 (Cq), 62.2 (CH₂), 14.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3086, 2662, 1746, 1414, 1302, 1234, 852, 753. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₆: 340.0331, found: 340.0330.

### 3.2.7. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (7)

To a suspension of **5** (2.00 g, 6.49 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (1.043 g, 7.78 mmol, 1.20 eq.), methylamine (3.4 mL, 6.81 mmol, 1.05 eq.) and then EDCI (1.19, 7.13 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 7 (1.66 g, 80%) as a white solid. Mp: 190–192 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.02 (q, *J* = 4.7 Hz, 1H), 7.37 (d, *J* = 8.2 Hz, 2H), 7.30 (d, *J* = 8.2 Hz, 2H), 4.47 (q, *J* = 7.1 Hz, 2H), 2.99 (d, *J* = 4.7 Hz, 3H), 2.43 (s, 3H), 1.43 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.8 (CO), 160.9 (CO), 140.2 (Cq), 139.9 (Cq), 134.6 (Cq), 133.6 (Cq),
was stirred and refluxed for 1.5 h. After cooling, POCl₃ (4.27 mL, 44.57 mmol, 4.4 eq.) was added a second time and stirred and refluxed for 18 h. After cooling, water was added slowly and then the aqueous layer was extracted three times with DCM. Organic layers were combined, dried over MgSO₄, filtrated and concentrated to give the title product **4** (2.63 g, 86%) as a white solid. Mp: 174–176 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, Hₐld), 8.47 (d, *J* = 8.5 Hz, 2H), 8.01 (d, *J* = 8.5 Hz, 2H), 4.42 (q, *J* = 7.1 Hz, 2H), 1.35 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 185.4 (CHₐld), 160.8 (CO), 148.3 (Cq), 145.0 (Cq), 141.3 (Cq), 132.1 (Cq), 127.7 (2 × CH), 125.4 (2 × CH), 119.7 (Cq), 62.3 (CH₂), 14.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3115, 2988, 1723, 1535, 1321, 1025, 860, 687. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₅: 324.0378, found: 324.0381.

### 3.2.5. 5-Chloro-3-(ethoxycarbonyl)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid (5)

To a suspension of **3** (2.63 g, 9.01 mmol, 1.0 eq.) in a mixture of *t*-BuOH/H₂O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH₂PO₄ (6.48 g, 54.06 mmol, 6.0 eq.) and NaClO₂ (4.89 g, 54.06 mmol, 6.0 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et₂O. Organics layers were combined, dried over MgSO₄ and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound **5** (2.77 g, 88%) as a white solid. Mp: 172–174 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (d, *J* = 8.4 Hz, 2H), 7.38 (d, *J* = 8.4 Hz, 2H), 4.26 (q, *J* = 7.1 Hz, 2H), 2.40 (s, 3H), 1.27 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.4 (CO), 163.1 (CO), 144.1 (Cq), 139.4 (Cq), 135.4 (Cq), 130.2 (2 × CH), 126.6 (Cq), 125.9 (2 × CH), 121.4 (Cq), 61.2 (CH₂), 21.2 (CH₃), 14.5 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3011, 2752, 1734, 1452, 1300, 1223, 1027, 826, 763. HRMS: *m/z* [M + H]⁺ calculated for C₁₄H₁₄ClN₂O₄: 309.0999, found: 309.1000.

### 3.2.6. 5-Chloro-3-(ethoxycarbonyl)-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic acid (6)

To a suspension of **4** (2.00 g, 6.22 mmol, 1.00 eq.) in a mixture of *t*-BuOH/H₂O/2-methyl-2-butene (45 mL/45 mL/27 mL) was added NaH₂PO₄ (4.48 g, 37.37 mmol, 6.00 eq.) and NaClO₂ (3.38 g, 37.37 mmol, 6.00 eq.). The mixture was stirred for 24 h at room temperature. Then, the mixture was poured into a funnel with EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with HCl 12 M, and the precipitate was filtrated, washed with cold water and dried with Et₂O. Organic layers were combined, dried over MgSO₄ and concentrated; the residue was triturated in EtOAc (2 mL); and Petroleum Ether (30 mL) was added. The resulting precipitate was filtrated and combined with the first solid to give the title compound **6** (1.04 g, 81%) as a white solid. Mp: 174–176 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.44 (d, *J* = 8.9 Hz, 2H), 7.99 (d, *J* = 8.9 Hz, 2H), 4.34 (q, *J* = 7.1 Hz, 2H), 1.29 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9 (CO), 161.5 (CO), 148.1 (Cq), 145.5 (Cq), 141.8 (Cq), 131.1 (Cq), 127.4 (2 × CH), 125.3 (2 × CH), 114.2 (Cq), 62.2 (CH₂), 14.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3086, 2662, 1746, 1414, 1302, 1234, 852, 753. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₆: 340.0331, found: 340.0330.

### 3.2.7. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (7)

To a suspension of **5** (2.00 g, 6.49 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (1.043 g, 7.78 mmol, 1.20 eq.), methylamine (3.4 mL, 6.81 mmol, 1.05 eq.) and then EDCI (1.19, 7.13 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 7 (1.66 g, 80%) as a white solid. Mp: 190–192 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.02 (q, *J* = 4.7 Hz, 1H), 7.37 (d, *J* = 8.2 Hz, 2H), 7.30 (d, *J* = 8.2 Hz, 2H), 4.47 (q, *J* = 7.1 Hz, 2H), 2.99 (d, *J* = 4.7 Hz, 3H), 2.43 (s, 3H), 1.43 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.8 (CO), 160.9 (CO), 140.2 (Cq), 139.9 (Cq), 134.6 (Cq), 133.6 (Cq),
129.8 (2 × CH), 125.9 (2 × CH), 116.3 (Cq), 62.6 (CH₂), 26.2 (NCH₃), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3295, 1722, 1642, 1568, 1315, 1230, 1120, 1030, 826. HRMS: *m/z* [M + H]⁺ calculated for C₁₅H₁₇ClN₃O₃: 322.0958, found: 322.0952.

### 3.2.8. Ethyl 5-Chloro-4-[(4-methoxyphenyl)methylcarbamoyl]-1-(p-tolyl)-1H-pyrazole-3-carboxylate (8)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.50 g, 3.89 mmol, 1.20 eq.), 4-methoxybenzylamine (0.50 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 8 (0.80 g, 75%) as a white solid. Mp: 168–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.44 (t, *J* = 5.5 Hz, 1H), 7.40 (d, *J* = 8.1 Hz, 2H), 7.37–7.30 (m, 4H), 6.90 (d, *J* = 8.1 Hz, 2H), 4.60 (d, *J* = 5.5 Hz, 2H), 4.46 (q, *J* = 7.1 Hz, 2H), 3.82 (s, 3H), 2.45 (s, 3H), 1.42 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.6 (CO), 160.0 (CO), 158.9 (Cq), 140.2 (Cq), 140.0 (Cq), 134.6 (Cq), 133.8 (Cq), 130.6 (Cq), 129.8 (2 × CH), 129.2 (2 × CH), 125.9 (2 × CH), 116.2 (Cq), 114.0 (2 × CH), 62.6 (CH₂), 55.3 (OCH₃), 43.0 (NCH₂), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3557, 3304, 1721, 1636, 1302, 1255, 1041, 854, 838. HRMS: *m/z* [M + H]⁺ calculated for C₂₂H₂₃ClN₃O₄: 428.1369, found: 428.1371.

### 3.2.9. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (9)

To a suspension of 6 (1.00 g, 3.05 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.55 g, 3.65 mmol, 1.20 eq.), methylamine (1.60 mL, 3.20 mmol, 1.05 eq.) and then EDCI (0.79 mL, 4.42 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 9 (1.902 g, 82%) as a white solid. Mp: 156–158 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.41–8.49 (m, 3H), 7.97 (d, *J* = 8.5 Hz, 2H), 4.31 (q, *J* = 6.8 Hz, 2H), 2.77 (d, *J* = 4.1 Hz, 3H), 1.28 (t, *J* = 6.8 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 160.8 (CO), 160.6 (CO), 147.9 (Cq), 142.3 (Cq), 141.9 (Cq), 128.2 (Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.4 (Cq), 61.7 (CH₂), 26.4 (NCH₃), 14.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3086, 2662, 1746, 1414, 12341, 1157, 1040, 836. HRMS: *m/z* [M + H]⁺ calculated for C₁₄H₁₄ClN₄O₅: 353.0645, found: 353.0647.

### 3.2.10. Ethyl 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (10)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.50 g, 3.89 mmol, 1.20 eq.), phenylamine (0.55 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 10 (1.1 g, 89%) as a white solid. Mp: 176–178 °C. ¹H NMR (400 MHz, CDCl₃) δ 11.41 (s, 1H), 7.78 (d, *J* = 7.9 Hz, 2H), 7.37 (m, 6H), 7.13 (t, *J* = 7.9 Hz, 1H), 4.54 (q, *J* = 7.1 Hz, 2H), 2.45 (s, 3H), 1.46 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.4 (CO), 158.0 (CO), 140.3 (Cq), 139.6 (Cq), 138.4 (Cq), 134.7 (Cq), 134.5 (Cq), 129.9 (2 × CH), 128.9 (2 × CH), 126.0 (2 × CH), 124.2 (CH), 120.1 (2 × CH), 116.5 (Cq), 63.0 (CH₂), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3134, 3274, 1725, 1636, 1354, 1195, 1044, 879, 889. HRMS (EI-MS): *m/z* calculated for C₂₀H₁₉ClN₃O₃: 384.1013 [M + H]⁺, found: 384.1017.

### 3.2.11. 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (11)

To a suspension of 7 (0.56 g, 1.75 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.93 mL, 1.93 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound 11 (0.51 g, 99%) as a white solid. Mp: 228–230 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (q, *J* = 3.9 Hz, 1NH), 7.46 (d, *J* = 8.1 Hz,
129.8 (2 × CH), 125.9 (2 × CH), 116.3 (Cq), 62.6 (CH₂), 26.2 (NCH₃), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3295, 1722, 1642, 1568, 1315, 1230, 1120, 1030, 826. HRMS: *m/z* [M + H]⁺ calculated for C₁₅H₁₇ClN₃O₃: 322.0958, found: 322.0952.

### 3.2.8. Ethyl 5-Chloro-4-[(4-methoxyphenyl)methylcarbamoyl]-1-(p-tolyl)-1H-pyrazole-3-carboxylate (8)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.50 g, 3.89 mmol, 1.20 eq.), 4-methoxybenzylamine (0.50 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 8 (0.80 g, 75%) as a white solid. Mp: 168–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.44 (t, *J* = 5.5 Hz, 1H), 7.40 (d, *J* = 8.1 Hz, 2H), 7.37–7.30 (m, 4H), 6.90 (d, *J* = 8.1 Hz, 2H), 4.60 (d, *J* = 5.5 Hz, 2H), 4.46 (q, *J* = 7.1 Hz, 2H), 3.82 (s, 3H), 2.45 (s, 3H), 1.42 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.6 (CO), 160.0 (CO), 158.9 (Cq), 140.2 (Cq), 140.0 (Cq), 134.6 (Cq), 133.8 (Cq), 130.6 (Cq), 129.8 (2 × CH), 129.2 (2 × CH), 125.9 (2 × CH), 116.2 (Cq), 114.0 (2 × CH), 62.6 (CH₂), 55.3 (OCH₃), 43.0 (NCH₂), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3557, 3304, 1721, 1636, 1302, 1255, 1041, 854, 838. HRMS: *m/z* [M + H]⁺ calculated for C₂₂H₂₃ClN₃O₄: 428.1369, found: 428.1371.

### 3.2.9. Ethyl 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (9)

To a suspension of 6 (1.00 g, 3.05 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.55 g, 3.65 mmol, 1.20 eq.), methylamine (1.60 mL, 3.20 mmol, 1.05 eq.) and then EDCI (0.79 mL, 4.42 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 9 (1.902 g, 82%) as a white solid. Mp: 156–158 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.41–8.49 (m, 3H), 7.97 (d, *J* = 8.5 Hz, 2H), 4.31 (q, *J* = 6.8 Hz, 2H), 2.77 (d, *J* = 4.1 Hz, 3H), 1.28 (t, *J* = 6.8 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 160.8 (CO), 160.6 (CO), 147.9 (Cq), 142.3 (Cq), 141.9 (Cq), 128.2 (Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.4 (Cq), 61.7 (CH₂), 26.4 (NCH₃), 14.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3086, 2662, 1746, 1414, 12341, 1157, 1040, 836. HRMS: *m/z* [M + H]⁺ calculated for C₁₄H₁₄ClN₄O₅: 353.0645, found: 353.0647.

### 3.2.10. Ethyl 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (10)

To a suspension of 5 (1.00 g, 3.25 mmol, 1.00 eq.) in THF (30 mL) was added HOBt·H₂O (0.50 g, 3.89 mmol, 1.20 eq.), phenylamine (0.55 mL, 3.41 mmol, 1.05 eq.) and then EDCI (0.59 mL, 3.36 mmol, 1.10 eq.). The mixture was stirred for 5 h at room temperature. Then, Et₂O (40 mL) was added, and the precipitate was filtered, washed with EtOAc and dried under vacuum to give 10 (1.1 g, 89%) as a white solid. Mp: 176–178 °C. ¹H NMR (400 MHz, CDCl₃) δ 11.41 (s, 1H), 7.78 (d, *J* = 7.9 Hz, 2H), 7.37 (m, 6H), 7.13 (t, *J* = 7.9 Hz, 1H), 4.54 (q, *J* = 7.1 Hz, 2H), 2.45 (s, 3H), 1.46 (t, *J* = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.4 (CO), 158.0 (CO), 140.3 (Cq), 139.6 (Cq), 138.4 (Cq), 134.7 (Cq), 134.5 (Cq), 129.9 (2 × CH), 128.9 (2 × CH), 126.0 (2 × CH), 124.2 (CH), 120.1 (2 × CH), 116.5 (Cq), 63.0 (CH₂), 21.3 (CH₃), 14.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3134, 3274, 1725, 1636, 1354, 1195, 1044, 879, 889. HRMS (EI-MS): *m/z* calculated for C₂₀H₁₉ClN₃O₃: 384.1013 [M + H]⁺, found: 384.1017.

### 3.2.11. 5-Chloro-4-(methylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (11)

To a suspension of 7 (0.56 g, 1.75 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.93 mL, 1.93 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound 11 (0.51 g, 99%) as a white solid. Mp: 228–230 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (q, *J* = 3.9 Hz, 1NH), 7.46 (d, *J* = 8.1 Hz,
2H), 7.40 (d, *J* = 8.1 Hz, 2H), 2.76 (d, *J* = 3.9 Hz, 3H), 2.40 (s, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 162.7 (CO), 161.41 (CO), 142.4 (Cq), 140.0 (Cq), 134.9 (Cq), 130.3 (2 × CH), 128.3 (Cq), 126.0 (2 × CH), 118.6 (Cq), 26.4 (NCH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3368, 1731, 1558, 1257, 1030, 824, 650. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₃ClN₃O₃: 294.0640, found: 294.0639.

### 3.2.12. 5-Chloro-4-((4-methoxybenzyl)carbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (12)

To a suspension of **8** (1.34 g, 3.25 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (2.83 mL, 3.57 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **12** (1.19 g, 90%) as a white solid. Mp: 202–204 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 12.11 (t, *J* = 5.3 Hz, 1NH), 7.30–735 (m, 4H), 7.26 (d, *J* = 8.2 Hz, 2H), 6.89 (d, *J* = 8.2 Hz, 2H), 4.39 (d, *J* = 5.3 Hz, 2H), 3.73 (s, 3H), 2.36 (s, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 164.0 (CO), 160.7 (CO), 158.60 (Cq), 139.7 (Cq), 134.7 (Cq), 134.6 (Cq), 131.9 (Cq), 130.0 (2 × CH), 129.9 (Cq), 129.1 (2 × CH), 126.7 (Cq), 126.6 (2 × CH), 114.2 (2 × CH), 55.5 (OCH₃), 42.1 (NCH₂), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3347, 1752, 1560, 1338, 1176, 1001, 856, 765. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉ClN₃O₄: 400.1059, found: 400.1058.

### 3.2.13. 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylic acid (13)

To a suspension of **9** (0.470 g, 1.38 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.59 mL, 1.51 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12N, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **13** (0.45 g, 90%) as a white solid. Mp: 282–264 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.54 (q, *J* = 4.5 Hz, 1NH), 8.46 (d, *J* = 8.6 Hz, 2H), 7.97 (d, *J* = 8.6 Hz, 2H), 2.77 (d, *J* = 4.5 Hz, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 162.3 (CO), 161.0 (CO), 147.9 (Cq), 143.2 (Cq), 142.0 (Cq), 128.3(Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.0 (Cq), 26.5 (NCH₃). IR (ATR diamond, cm⁻¹) ν: 3128, 2924, 1767, 1606, 1500, 1356, 1005, 606. HRMS: *m/z* [M + H]⁺ calculated for C₁₂H₁₀ClN₄O₅: 325.0332, found: 325.0334.

### 3.2.14. 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (14)

To a suspension of **10** (1.1 g, 2.87 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (3.16 mL, 3.16 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **14** (886 mg, 87%) as a white solid. Mp: 218–220 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.69 (d, *J* = 7.9 Hz, 2H), 7.51 (d, *J* = 8.0 Hz, 2H), 7.43 (d, *J* = 8.0 Hz, 2H), 7.36 (t, *J* = 7.9 Hz, 2H), 7.12 (t, *J* = 7.9 Hz, 1H), 2.42 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.6 (CO), 159.4 (CO), 142.2 (Cq), 140.1 (Cq), 139.5 (Cq), 134.9 (Cq), 130.4 (2 × CH), 129.3 (2 × CH), 128.5 (Cq), 125.9 (2 × CH), 124.2 (CH), 119.7 (2 × CH), 119.3 (Cq), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3145, 1761, 1569, 1588, 1170, 1007, 876, 744. HRMS (EI-MS): *m/z* calculated for C₁₈H₁₅ClN₃O₃: 356.0747 [M + H]⁺, found: 356.0749.

### 3.2.15. 3-Chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (15)

To a suspension of **11** (0.50 g, 1.7 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.830 g, 5.11 mmol, 3.0 eq.). The mixture was stirred for 24 h at
2H), 7.40 (d, *J* = 8.1 Hz, 2H), 2.76 (d, *J* = 3.9 Hz, 3H), 2.40 (s, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 162.7 (CO), 161.41 (CO), 142.4 (Cq), 140.0 (Cq), 134.9 (Cq), 130.3 (2 × CH), 128.3 (Cq), 126.0 (2 × CH), 118.6 (Cq), 26.4 (NCH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3368, 1731, 1558, 1257, 1030, 824, 650. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₃ClN₃O₃: 294.0640, found: 294.0639.

### 3.2.12. 5-Chloro-4-((4-methoxybenzyl)carbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (12)

To a suspension of **8** (1.34 g, 3.25 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (2.83 mL, 3.57 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **12** (1.19 g, 90%) as a white solid. Mp: 202–204 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 12.11 (t, *J* = 5.3 Hz, 1NH), 7.30–735 (m, 4H), 7.26 (d, *J* = 8.2 Hz, 2H), 6.89 (d, *J* = 8.2 Hz, 2H), 4.39 (d, *J* = 5.3 Hz, 2H), 3.73 (s, 3H), 2.36 (s, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 164.0 (CO), 160.7 (CO), 158.60 (Cq), 139.7 (Cq), 134.7 (Cq), 134.6 (Cq), 131.9 (Cq), 130.0 (2 × CH), 129.9 (Cq), 129.1 (2 × CH), 126.7 (Cq), 126.6 (2 × CH), 114.2 (2 × CH), 55.5 (OCH₃), 42.1 (NCH₂), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3347, 1752, 1560, 1338, 1176, 1001, 856, 765. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉ClN₃O₄: 400.1059, found: 400.1058.

### 3.2.13. 5-Chloro-4-(methylcarbamoyl)-1-(4-nitrophenyl)-1H-pyrazole-3-carboxylic acid (13)

To a suspension of **9** (0.470 g, 1.38 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (1.59 mL, 1.51 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12N, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **13** (0.45 g, 90%) as a white solid. Mp: 282–264 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 8.54 (q, *J* = 4.5 Hz, 1NH), 8.46 (d, *J* = 8.6 Hz, 2H), 7.97 (d, *J* = 8.6 Hz, 2H), 2.77 (d, *J* = 4.5 Hz, 3H). ¹³C NMR (400 MHz, DMSO-d₆) δ 162.3 (CO), 161.0 (CO), 147.9 (Cq), 143.2 (Cq), 142.0 (Cq), 128.3(Cq), 126.9 (2 × CH), 125.4 (2 × CH), 120.0 (Cq), 26.5 (NCH₃). IR (ATR diamond, cm⁻¹) ν: 3128, 2924, 1767, 1606, 1500, 1356, 1005, 606. HRMS: *m/z* [M + H]⁺ calculated for C₁₂H₁₀ClN₄O₅: 325.0332, found: 325.0334.

### 3.2.14. 5-Chloro-4-(phenylcarbamoyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylic acid (14)

To a suspension of **10** (1.1 g, 2.87 mmol, 1.0 eq.) in EtOH (10 mL) was added a KOH aqueous solution, 1M (3.16 mL, 3.16 mmol, 1.1 eq.). The mixture was refluxed for 1 h, and after cooling, the solvent was removed partially and then poured into three volumes of cold water. The aqueous mixture was acidified with HCl 12 M, and then the precipitate was filtered off and then solubilized in EtOAc. The organic filtrate was dried over MgSO₄, filtered and concentrated to give the title compound **14** (886 mg, 87%) as a white solid. Mp: 218–220 °C. ¹H NMR (250 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.69 (d, *J* = 7.9 Hz, 2H), 7.51 (d, *J* = 8.0 Hz, 2H), 7.43 (d, *J* = 8.0 Hz, 2H), 7.36 (t, *J* = 7.9 Hz, 2H), 7.12 (t, *J* = 7.9 Hz, 1H), 2.42 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.6 (CO), 159.4 (CO), 142.2 (Cq), 140.1 (Cq), 139.5 (Cq), 134.9 (Cq), 130.4 (2 × CH), 129.3 (2 × CH), 128.5 (Cq), 125.9 (2 × CH), 124.2 (CH), 119.7 (2 × CH), 119.3 (Cq), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3145, 1761, 1569, 1588, 1170, 1007, 876, 744. HRMS (EI-MS): *m/z* calculated for C₁₈H₁₅ClN₃O₃: 356.0747 [M + H]⁺, found: 356.0749.

### 3.2.15. 3-Chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (15)

To a suspension of **11** (0.50 g, 1.7 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.830 g, 5.11 mmol, 3.0 eq.). The mixture was stirred for 24 h at
room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (9/1) as eluent to give **15** (0.403 g, 86%) as a white solid. Mp: 208–210 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, *J* = 8.3 Hz, 2H), 7.34 (d, *J* = 8.3 Hz, 2H), 3.15 (s, 3H), 2.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.1 (CO), 160.5 (CO), 152.4 (Cq), 140.4 (Cq), 134.5 (Cq), 130.0 (2 × CH), 125.3 (2 × CH), 125.1 (Cq), 116.7 (Cq), 24.5 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3385, 1715, 1556, 1530, 1357, 1260, 1136, 1177. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₂: 276.0536, found: 276.0534.

### 3.2.16. 3-Chloro-5-(4-methoxybenzyl)-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**16**)

To a suspension of **12** (0.4g, 1.00 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.486 g, 3.00 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (7/3) as eluent to give **16** (0.306 g, 80%) as a white solid. Mp: 158–160 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, *J* = 8.1 Hz, 2H), 7.37 (d, *J* = 8.4 Hz, 2H), 7.32 (d, *J* = 8.1 Hz, 2H), 6.84 (d, *J* = 8.4 Hz, 2H), 4.73 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.5 (CO), 159.9 (CO), 159.1 (Cq), 152.0 (Cq), 140.2 (Cq), 134.2 (Cq), 130.1 (2 × CH), 129.8 (2 × CH), 128.4 (Cq), 125.1 (2 × CH), 125.0 (Cq), 116.4 (Cq), 113.8 (2 × CH), 55.1 (OCH₃), 41.3 (NCH₂), 21.1 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2934, 2838, 1710, 1576, 1241, 1030, 916, 816, 760. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₇ClN₃O₃: 382.0952, found: 382.0952.

### 3.2.17. 3-Chloro-5-methyl-2-(4-nitrophenyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**17**)

To a suspension of **13** (0.5g, 1.54 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.750 g, 4.62 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by flash chromatography with EP/EtOAc (7/3) as eluent to give **17** (0.366 g, 84%) as a white solid. Mp: 206–208 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, *J* = 8.7 Hz, 2H), 7.90 (d, *J* = 8.7 Hz, 2H), 3.20 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.4 (CO), 159.7 (CO), 153.3 (Cq), 148.0 (Cq), 141.6 (Cq), 125.8 (2 × CH), 125.2 (Cq), 124.9 (2 × CH), 117.7 (Cq), 24.7 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3120, 3008, 1731, 1577, 1530, 1350, 982, 733, 674. HRMS: *m/z* [M + H]⁺ calculated for C₁₂H₈ClN₄O₄: 307.6605, found: 307.6610.

### 3.2.18. 5-Methyl-2,3-di-*p*-tolylpyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**19**)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), *p*-tolylboronic acid (0.037 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **19** (0.048 g, 85%) as a white solid. Mp: 170–172 °C. ¹H NMR (400 MHz CDCl₃) δ 7.37 (d, *J* = 8.1 Hz, 2H), 7.27 (d, *J* = 8.1 Hz, 2H), 7.24 (d, *J* = 8.1 Hz, 2H), 7.18 (d, *J* = 8.1 Hz, 2H), 3.17 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.6 (CO), 162.11 (CO), 152.5 (Cq), 141.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 125.6 (2 × CH), 123.7 (Cq), 117.2 (Cq), 24.3 (NCH₃), 21.4 (CH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2922, 2851, 1760, 1703, 1513, 1356, 1019, 851, 793. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₂: 332.1397, found: 332.1393.

### 3.2.19. 3-(4-Methoxyphenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**20**)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 4-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054, mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to
room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (9/1) as eluent to give **15** (0.403 g, 86%) as a white solid. Mp: 208–210 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, *J* = 8.3 Hz, 2H), 7.34 (d, *J* = 8.3 Hz, 2H), 3.15 (s, 3H), 2.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.1 (CO), 160.5 (CO), 152.4 (Cq), 140.4 (Cq), 134.5 (Cq), 130.0 (2 × CH), 125.3 (2 × CH), 125.1 (Cq), 116.7 (Cq), 24.5 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3385, 1715, 1556, 1530, 1357, 1260, 1136, 1177. HRMS: *m/z* [M + H]⁺ calculated for C₁₃H₁₁ClN₃O₂: 276.0536, found: 276.0534.

### 3.2.16. 3-Chloro-5-(4-methoxybenzyl)-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**16**)

To a suspension of **12** (0.4g, 1.00 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.486 g, 3.00 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by using flash chromatography with EP/EtOAc (7/3) as eluent to give **16** (0.306 g, 80%) as a white solid. Mp: 158–160 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, *J* = 8.1 Hz, 2H), 7.37 (d, *J* = 8.4 Hz, 2H), 7.32 (d, *J* = 8.1 Hz, 2H), 6.84 (d, *J* = 8.4 Hz, 2H), 4.73 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.5 (CO), 159.9 (CO), 159.1 (Cq), 152.0 (Cq), 140.2 (Cq), 134.2 (Cq), 130.1 (2 × CH), 129.8 (2 × CH), 128.4 (Cq), 125.1 (2 × CH), 125.0 (Cq), 116.4 (Cq), 113.8 (2 × CH), 55.1 (OCH₃), 41.3 (NCH₂), 21.1 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2934, 2838, 1710, 1576, 1241, 1030, 916, 816, 760. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₇ClN₃O₃: 382.0952, found: 382.0952.

### 3.2.17. 3-Chloro-5-methyl-2-(4-nitrophenyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**17**)

To a suspension of **13** (0.5g, 1.54 mmol, 1.0 eq.) in dry DCM (10 mL) under inert gas was added CDI (0.750 g, 4.62 mmol, 3.0 eq.). The mixture was stirred for 24 h at room temperature. The solvent was removed, and the crude was purified by flash chromatography with EP/EtOAc (7/3) as eluent to give **17** (0.366 g, 84%) as a white solid. Mp: 206–208 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, *J* = 8.7 Hz, 2H), 7.90 (d, *J* = 8.7 Hz, 2H), 3.20 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 160.4 (CO), 159.7 (CO), 153.3 (Cq), 148.0 (Cq), 141.6 (Cq), 125.8 (2 × CH), 125.2 (Cq), 124.9 (2 × CH), 117.7 (Cq), 24.7 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3120, 3008, 1731, 1577, 1530, 1350, 982, 733, 674. HRMS: *m/z* [M + H]⁺ calculated for C₁₂H₈ClN₄O₄: 307.6605, found: 307.6610.

### 3.2.18. 5-Methyl-2,3-di-*p*-tolylpyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**19**)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), *p*-tolylboronic acid (0.037 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **19** (0.048 g, 85%) as a white solid. Mp: 170–172 °C. ¹H NMR (400 MHz CDCl₃) δ 7.37 (d, *J* = 8.1 Hz, 2H), 7.27 (d, *J* = 8.1 Hz, 2H), 7.24 (d, *J* = 8.1 Hz, 2H), 7.18 (d, *J* = 8.1 Hz, 2H), 3.17 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.6 (CO), 162.11 (CO), 152.5 (Cq), 141.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 125.6 (2 × CH), 123.7 (Cq), 117.2 (Cq), 24.3 (NCH₃), 21.4 (CH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2922, 2851, 1760, 1703, 1513, 1356, 1019, 851, 793. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₂: 332.1397, found: 332.1393.

### 3.2.19. 3-(4-Methoxyphenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (**20**)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 4-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054, mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to
give 20 (0.048 g, 79%) as a white solid. M.p: 150–152 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, *J* = 8.8 Hz, 2H), 7.21 (d, *J* = 8.8 Hz, 2H), 7.18 (d, *J* = 8.8 Hz, 2H), 6.81 (d, *J* = 8.8 Hz, 2H), 3.77 (s, 3H), 3.10 (s, 3H), 2.37 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.7 (CO), 162.1 (CO), 161.0 (Cq), 152.5 (Cq), 141.2 (Cq), 139.5 (Cq), 137.1 (Cq), 130.9 (2 × CH), 130.0 (2 × CH), 125.7 (2 × CH), 118.8 (Cq), 116.7 (Cq), 114.2 (2 × CH), 55.35 (OCH₃), 24.3 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2923, 2848, 1763, 1700, 1499, 990, 1180, 803, 517. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₃: 348.1343, found: 348.1342.

### 3.2.20. 3-(3-Methoxyphenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (21)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **21** (0.046 g, 67%) as a white solid. M.p: 168–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.28 (m, 3H), 7.26 (d, *J* = 8.0 Hz, 2H), 7.15 (dd, *J* = 2.6, 1.6 Hz, 1H), 6.99–6.93 (m, 2H), 3.75 (s, 3H), 3.18 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.8 (CO), 162.3 (CO), 159.9 (Cq), 152.8 (Cq), 141.4 (Cq), 140.0 (Cq), 137.3 (Cq), 130.3 (2 × CH), 130.1 (CH), 127.9 (Cq), 126.0 (2 × CH), 121.7 (CH), 117.9 (Cq), 117.2 (CH), 114.5 (CH), 55.6 (OCH₃), 24.6 (NCH₃), 21.6 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2929, 2921, 1758, 1705, 1448, 1360, 962, 787, 547 HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₃: 348.1460, found: 348.1343.

### 3.2.21. 3-(4-Fluorophenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (23)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 4-fluorophenylboronic acid (0.038 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **23** (0.038 g, 65%) as a white solid. M.p: 178–180 °C. ¹H NMR (250 MHz, Chloroform-*d*) δ 7.50–7.41 (m, 2H), 7.22–7.24 (m, 4H), 7.12–6.97 (m, 2H), 3.15 (s, 3H), 2.42 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.49 (d, *J* = 252.5 Hz, Cq), 162.4 (CO), 152.5 (Cq), 140.0 (Cq), 139.8 (Cq), 136.7 (Cq), 131.5 (d, *J* = 8.7 Hz, 2 × CH), 130.1 (2 × CH), 125.6 (2 × CH), **122.7** (d, *J* = 3.5 Hz, Cq), 117.5 (Cq), 116.1 (d, *J* = 22.1 Hz, 2 × CH), 24.3 (NCH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2924, 2920, 1767, 1710, 1448, 1356, 1107, 879, 643, 532. HRMS: *m/z* [M + H]⁺ calculated for C₁₉H₁₅FN₃O₂: 336.1144, found: 336.1142.

### 3.2.22. 3-(4-Cyanophenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (24)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.050 g, 0.18 mmol, 1.00 eq.), 4-cyanophenylboronic acid (0.053 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **24** (0.035 g, 60%) as a white solid. M.p: 178–180 °C. ¹H NMR (250 MHz, CDCl₃) δ 7.65 (d, *J* = 8.5 Hz, 2H), 7.59 (d, *J* = 8.5 Hz, 2H), 7.27 (d, *J* = 8.5 Hz, 2H), 7.22 (d, *J* = 8.5 Hz, 2H), 3.17 (s, 3H), 2.44 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 162.1 (CO), 161.5 (CO), 152.7 (Cq), 140.4 (Cq), 138.6 (Cq), 136.3 (Cq), 132.5 (2 × CH), 130.8 (Cq), 130.4 (2 × CH), 129.8 (2 × CH), 125.6 (2 × CH), 118.7 (Cq), 117.9 (Cq), 113.7 (Cq), 24.5 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2923, 2227, 1764, 1709, 1494, 1352, 1279, 1105, 973, 643, 551. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₅N₄O₂: 343.1192, found: 343.1189.
give 20 (0.048 g, 79%) as a white solid. M.p: 150–152 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, *J* = 8.8 Hz, 2H), 7.21 (d, *J* = 8.8 Hz, 2H), 7.18 (d, *J* = 8.8 Hz, 2H), 6.81 (d, *J* = 8.8 Hz, 2H), 3.77 (s, 3H), 3.10 (s, 3H), 2.37 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.7 (CO), 162.1 (CO), 161.0 (Cq), 152.5 (Cq), 141.2 (Cq), 139.5 (Cq), 137.1 (Cq), 130.9 (2 × CH), 130.0 (2 × CH), 125.7 (2 × CH), 118.8 (Cq), 116.7 (Cq), 114.2 (2 × CH), 55.35 (OCH₃), 24.3 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2923, 2848, 1763, 1700, 1499, 990, 1180, 803, 517. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₃: 348.1343, found: 348.1342.

### 3.2.20. 3-(3-Methoxyphenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (21)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-methoxyphenylboronic acid (0.042 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **21** (0.046 g, 67%) as a white solid. M.p: 168–170 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.28 (m, 3H), 7.26 (d, *J* = 8.0 Hz, 2H), 7.15 (dd, *J* = 2.6, 1.6 Hz, 1H), 6.99–6.93 (m, 2H), 3.75 (s, 3H), 3.18 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.8 (CO), 162.3 (CO), 159.9 (Cq), 152.8 (Cq), 141.4 (Cq), 140.0 (Cq), 137.3 (Cq), 130.3 (2 × CH), 130.1 (CH), 127.9 (Cq), 126.0 (2 × CH), 121.7 (CH), 117.9 (Cq), 117.2 (CH), 114.5 (CH), 55.6 (OCH₃), 24.6 (NCH₃), 21.6 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2929, 2921, 1758, 1705, 1448, 1360, 962, 787, 547 HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₈N₃O₃: 348.1460, found: 348.1343.

### 3.2.21. 3-(4-Fluorophenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (23)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 4-fluorophenylboronic acid (0.038 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **23** (0.038 g, 65%) as a white solid. M.p: 178–180 °C. ¹H NMR (250 MHz, Chloroform-*d*) δ 7.50–7.41 (m, 2H), 7.22–7.24 (m, 4H), 7.12–6.97 (m, 2H), 3.15 (s, 3H), 2.42 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.49 (d, *J* = 252.5 Hz, Cq), 162.4 (CO), 152.5 (Cq), 140.0 (Cq), 139.8 (Cq), 136.7 (Cq), 131.5 (d, *J* = 8.7 Hz, 2 × CH), 130.1 (2 × CH), 125.6 (2 × CH), **122.7** (d, *J* = 3.5 Hz, Cq), 117.5 (Cq), 116.1 (d, *J* = 22.1 Hz, 2 × CH), 24.3 (NCH₃), 21.2 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2924, 2920, 1767, 1710, 1448, 1356, 1107, 879, 643, 532. HRMS: *m/z* [M + H]⁺ calculated for C₁₉H₁₅FN₃O₂: 336.1144, found: 336.1142.

### 3.2.22. 3-(4-Cyanophenyl)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (24)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.050 g, 0.18 mmol, 1.00 eq.), 4-cyanophenylboronic acid (0.053 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **24** (0.035 g, 60%) as a white solid. M.p: 178–180 °C. ¹H NMR (250 MHz, CDCl₃) δ 7.65 (d, *J* = 8.5 Hz, 2H), 7.59 (d, *J* = 8.5 Hz, 2H), 7.27 (d, *J* = 8.5 Hz, 2H), 7.22 (d, *J* = 8.5 Hz, 2H), 3.17 (s, 3H), 2.44 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 162.1 (CO), 161.5 (CO), 152.7 (Cq), 140.4 (Cq), 138.6 (Cq), 136.3 (Cq), 132.5 (2 × CH), 130.8 (Cq), 130.4 (2 × CH), 129.8 (2 × CH), 125.6 (2 × CH), 118.7 (Cq), 117.9 (Cq), 113.7 (Cq), 24.5 (NCH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2923, 2227, 1764, 1709, 1494, 1352, 1279, 1105, 973, 643, 551. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₅N₄O₂: 343.1192, found: 343.1189.
### 3.2.23. 3-(FuraN-2-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (25)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 2-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **25** (0.042 g, 76%) as a white solid. M.p: 172–174 °C. ¹H NMR (400 MHz CDCl₃) δ 7.46 (d, *J* = 1.8 Hz, 1H), 7.38 (d, *J* = 8.2 Hz, 2H), 7.33 (d, *J* = 8.2 Hz, 2H), 6.89 (d, *J* = 3.4 Hz, 1H), 6.49 (dd, *J* = 3.4, 1.8 Hz, 1H), 3.19 (s, 3H), 2.49 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.9 (CO), 161.8 (CO), 152.6 (Cq), 144.7 (CH), 141.7 (Cq), 140.1 (Cq), 137.0 (Cq), 131.5 (Cq), 129.8 (2 × CH), 126.0 (2 × CH), 115.5 (Cq), 115.0 (CH), 112.0 (CH), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2926, 2920, 1770, 1712, 1445, 1355, 1116, 897, 647, 564. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₃: 308.1029, found: 308.1028.

### 3.2.24. 3-(FuraN-3-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (26)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **26** (0.039 g, 56%) as a white solid. M.p: 190–192 °C. ¹H NMR (400 MHz CDCl₃) δ 7.61 (s, 1H), 7.35–7.38 (m, 5H), 7.54 (d, *J* = 1.1 Hz, 1H), 3.16 (s, 3H), 2.48 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.5 (CO), 162.1 (CO), 152.6 (Cq), 143.8 (CH), 143.5 (CH), 140.8 (Cq), 136.7 (Cq), 134.5 (Cq), 130.3 (2 × CH), 126.4 (2 × CH), 116.1 (Cq), 113.6 (Cq), 109.6 (CH), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2924, 2921, 1765, 1712, 1447, 1357, 1116, 977, 648, 594. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₃: 308.1029, found: 308.1032.

### 3.2.25. 5-Methyl-3-(thiopheN-3-yl)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (27)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-thienylboronic acid (0.041 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **27** (0.026 g, 45%) as a white solid. M.p: 198–200 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd, *J* = 3.0, 1.3 Hz, 1H), 7.33–7.29 (m, 4H), 7.28 (dd, *J* = 5.2, 3.0 Hz, 1H), 7.21 (dd, *J* = 5.1, 1.3 Hz, 1H), 3.17 (s, 3H), 2.47 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.7 (CO), 162.0 (CO), 152.5 (Cq), 140.5 (CH), 137.0 (CH), 136.9 (Cq), 130.3 (2 × CH), 128.3 (CH), 127.5 (CH), 127.3 (Cq), 126.3 (2 × CH), 126.3 (CH), 116.3 (Cq), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3087, 2923, 2921, 1759, 1700, 1498, 1356, 1116, 971, 792, 509. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₂S: 324.0802, found: 324.0801.

### 3.2.26. 5-(4-Methoxybenzyl)-2,3-di-p-tolylpyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (29)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **16** (0.050 g, 0.114 mmol, 1.00 eq.), *p*-tolylphenylboronic acid (0.026 g, 0.171 mmol, 1.5 eq.), K₂CO₃ (0.047 g, 0.342 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.013 g, 0.011 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (5/5) as eluent to give **29** (0.035 g, 70%) as a white solid. M.p: 160–162 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, *J* = 7.8 Hz, 2H), 7.34 (d, *J* = 7.5 Hz, 2H), 7.22–7.26 (m, 4H), 7.14 (d, *J* = 7.5 Hz, 2H), 6.84 (d, *J* = 7.7 Hz, 2H), 4.75 (s, 2H), 3.77 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 162.3
### 3.2.23. 3-(FuraN-2-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (25)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 2-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **25** (0.042 g, 76%) as a white solid. M.p: 172–174 °C. ¹H NMR (400 MHz CDCl₃) δ 7.46 (d, *J* = 1.8 Hz, 1H), 7.38 (d, *J* = 8.2 Hz, 2H), 7.33 (d, *J* = 8.2 Hz, 2H), 6.89 (d, *J* = 3.4 Hz, 1H), 6.49 (dd, *J* = 3.4, 1.8 Hz, 1H), 3.19 (s, 3H), 2.49 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.9 (CO), 161.8 (CO), 152.6 (Cq), 144.7 (CH), 141.7 (Cq), 140.1 (Cq), 137.0 (Cq), 131.5 (Cq), 129.8 (2 × CH), 126.0 (2 × CH), 115.5 (Cq), 115.0 (CH), 112.0 (CH), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2926, 2920, 1770, 1712, 1445, 1355, 1116, 897, 647, 564. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₃: 308.1029, found: 308.1028.

### 3.2.24. 3-(FuraN-3-yl)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (26)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-furanylboronic acid (0.030 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **26** (0.039 g, 56%) as a white solid. M.p: 190–192 °C. ¹H NMR (400 MHz CDCl₃) δ 7.61 (s, 1H), 7.35–7.38 (m, 5H), 7.54 (d, *J* = 1.1 Hz, 1H), 3.16 (s, 3H), 2.48 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.5 (CO), 162.1 (CO), 152.6 (Cq), 143.8 (CH), 143.5 (CH), 140.8 (Cq), 136.7 (Cq), 134.5 (Cq), 130.3 (2 × CH), 126.4 (2 × CH), 116.1 (Cq), 113.6 (Cq), 109.6 (CH), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 2924, 2921, 1765, 1712, 1447, 1357, 1116, 977, 648, 594. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₃: 308.1029, found: 308.1032.

### 3.2.25. 5-Methyl-3-(thiopheN-3-yl)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (27)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **15** (0.05 g, 0.18 mmol, 1.00 eq.), 3-thienylboronic acid (0.041 g, 0.27 mmol, 1.5 eq.), K₂CO₃ (0.075 g, 0.054 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.021 g, 0.018 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **27** (0.026 g, 45%) as a white solid. M.p: 198–200 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd, *J* = 3.0, 1.3 Hz, 1H), 7.33–7.29 (m, 4H), 7.28 (dd, *J* = 5.2, 3.0 Hz, 1H), 7.21 (dd, *J* = 5.1, 1.3 Hz, 1H), 3.17 (s, 3H), 2.47 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.7 (CO), 162.0 (CO), 152.5 (Cq), 140.5 (CH), 137.0 (CH), 136.9 (Cq), 130.3 (2 × CH), 128.3 (CH), 127.5 (CH), 127.3 (Cq), 126.3 (2 × CH), 126.3 (CH), 116.3 (Cq), 24.3 (NCH₃), 21.4 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3087, 2923, 2921, 1759, 1700, 1498, 1356, 1116, 971, 792, 509. HRMS: *m/z* [M + H]⁺ calculated for C₁₇H₁₄N₃O₂S: 324.0802, found: 324.0801.

### 3.2.26. 5-(4-Methoxybenzyl)-2,3-di-p-tolylpyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (29)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **16** (0.050 g, 0.114 mmol, 1.00 eq.), *p*-tolylphenylboronic acid (0.026 g, 0.171 mmol, 1.5 eq.), K₂CO₃ (0.047 g, 0.342 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min, and then Pd(PPh₃)₄ (0.013 g, 0.011 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (5/5) as eluent to give **29** (0.035 g, 70%) as a white solid. M.p: 160–162 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, *J* = 7.8 Hz, 2H), 7.34 (d, *J* = 7.5 Hz, 2H), 7.22–7.26 (m, 4H), 7.14 (d, *J* = 7.5 Hz, 2H), 6.84 (d, *J* = 7.7 Hz, 2H), 4.75 (s, 2H), 3.77 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 162.3
(CO), 161.7 (CO), 159.1 (Cq), 152.4 (Cq), 144.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.2 (2 × CH), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 129.1 (Cq), 125.6 (2 × CH), 123.6 (Cq), 117.2 (Cq), 114.0 (2 × CH), 55.3 (OCH<sub>3</sub>), 41.3 (CH<sub>2</sub>), 21.2 (CH<sub>3</sub>), 21.2 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2922, 1764, 1707, 1513, 1313, 1150, 916, 845, 775. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>27</sub>H<sub>24</sub>N<sub>3</sub>O<sub>3</sub>: 438.1782, found: 438.1783.

### 3.2.27. 5-Methyl-2-(4-nitrophenyl)-3-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (30)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **17** (0.050 g, 0.16 mmol, 1.00 eq.), *p*-tolylphenylboronic acid (0.033 g, 0.245 mmol, 1.5 eq.), K<sub>2</sub>CO<sub>3</sub> (0.067 g, 0.489 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min and then Pd(PPh<sub>3</sub>)<sub>4</sub> (0.022 g, 0.019 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **30** (0.057 g, 84%) as a white solid. M.p: 222–224 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.31 (d, *J* = 8.8 Hz, 2H), 7.61 (d, *J* = 8.8 Hz, 2H), 7.35 (d, *J* = 7.9 Hz, 2H), 7.26 (d, *J* = 7.9 Hz, 2H), 3.20 (s, 3H), 2.42 (s, 3H). <sup>13</sup>C NMR (63 MHz, CDCl<sub>3</sub>) δ 161.8 (CO), 161.5 (CO), 153.6 (Cq), 147.4 (Cq), 144.1 (Cq), 141.8 (Cq), 141.6 (Cq), 130.0 (2 × CH), 129.2 (2 × CH), 126.1 (2 × CH), 124.8 (2 × CH), 122.9 (Cq), 118.3 (Cq), 24.5 (NCH<sub>3</sub>), 21.5 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3077, 2919, 1764, 1715, 1447, 1343, 1104, 988, 754, 504. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>19</sub>H<sub>15</sub>N<sub>3</sub>O<sub>4</sub>: 363.1083, found: 363.1087.

### 3.2.28. 5-Methyl-3-(phenylamino)-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (31)

A solution of the 3-chloro-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-dione **15** (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the aniline (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd<sub>2</sub>dba<sub>3</sub> (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **31** (0.049 g, 83%) as a yellow solid. M.p: 214–216 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.47 (d, *J* = 8.0 Hz, 2H), 7.43–7.34 (m, 4H), 7.20–7.16 (m, 3H), 6.37 (s, 1H), 3.08 (s, 3H), 2.46 (s, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 162.2 (CO), 161.0 (CO), 153.0 (Cq), 140.1 (Cq), 139.2 (Cq), 138.1 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.3 (2 × CH), 125.2 (2 × CH), 124.6 (CH), 120.0 (2 × CH), 100.7 (Cq), 24.2 (CH<sub>3</sub>), 21.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>19</sub>H<sub>17</sub>N<sub>4</sub>O<sub>2</sub>: 333.1342, found: 333.1346.

### 3.2.29. 3-((4-Methoxyphenyl)amino)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (32)

A solution of the 3-chloro-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-dione **15** (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *p*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd<sub>2</sub>dba<sub>3</sub> (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **32** (0.058 g, 88%) as a white solid. M.p: 204–206 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.46 (d, *J* = 8.3 Hz, 2H), 7.37 (d, *J* = 8.3 Hz, 2H), 7.14 (d, *J* = 8.9 Hz, 2H), 6.92 (d, *J* = 8.9 Hz, 2H), 6.30 (s, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 2.46 (s, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 162.3 (CO), 161.0 (CO), 157.4 (Cq), 152.0 (Cq), 141.0 (Cq), 139.9 (Cq), 134.4 (Cq), 131.1 (Cq), 130.7 (2 × CH), 125.1 (2 × CH), 123.3 (2 × CH), 114.4 (2 × CH), 99.4 (Cq), 55.5 (OCH<sub>3</sub>), 24.1 (CH<sub>3</sub>), 21.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3323, 1760, 1704, 1506, 1361, 1231, 822, 7444. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>20</sub>H<sub>19</sub>N<sub>4</sub>O<sub>3</sub>: 363.1451, found: 363.1452.
(CO), 161.7 (CO), 159.1 (Cq), 152.4 (Cq), 144.3 (Cq), 140.6 (Cq), 139.5 (Cq), 137.0 (Cq), 130.2 (2 × CH), 130.0 (2 × CH), 129.5 (2 × CH), 129.2 (2 × CH), 129.1 (Cq), 125.6 (2 × CH), 123.6 (Cq), 117.2 (Cq), 114.0 (2 × CH), 55.3 (OCH<sub>3</sub>), 41.3 (CH<sub>2</sub>), 21.2 (CH<sub>3</sub>), 21.2 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 2922, 1764, 1707, 1513, 1313, 1150, 916, 845, 775. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>27</sub>H<sub>24</sub>N<sub>3</sub>O<sub>3</sub>: 438.1782, found: 438.1783.

### 3.2.27. 5-Methyl-2-(4-nitrophenyl)-3-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (30)

In a microwave vial, 0.5–2 mL with a stir bar was charged: **17** (0.050 g, 0.16 mmol, 1.00 eq.), *p*-tolylphenylboronic acid (0.033 g, 0.245 mmol, 1.5 eq.), K<sub>2</sub>CO<sub>3</sub> (0.067 g, 0.489 mmol, 3.0 eq.) and dry dioxane (3.0 mL). The mixture was degassed for 15 min and then Pd(PPh<sub>3</sub>)<sub>4</sub> (0.022 g, 0.019 mmol, 0.10 eq.) was added. The vial was sealed and then put in a microwave cavity. After 2 h of irradiation at 150 °C, the mixture was concentrated and purified by using flash chromatography with Petroleum Ether/EtOAc (1/9) as eluent to give **30** (0.057 g, 84%) as a white solid. M.p: 222–224 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.31 (d, *J* = 8.8 Hz, 2H), 7.61 (d, *J* = 8.8 Hz, 2H), 7.35 (d, *J* = 7.9 Hz, 2H), 7.26 (d, *J* = 7.9 Hz, 2H), 3.20 (s, 3H), 2.42 (s, 3H). <sup>13</sup>C NMR (63 MHz, CDCl<sub>3</sub>) δ 161.8 (CO), 161.5 (CO), 153.6 (Cq), 147.4 (Cq), 144.1 (Cq), 141.8 (Cq), 141.6 (Cq), 130.0 (2 × CH), 129.2 (2 × CH), 126.1 (2 × CH), 124.8 (2 × CH), 122.9 (Cq), 118.3 (Cq), 24.5 (NCH<sub>3</sub>), 21.5 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3077, 2919, 1764, 1715, 1447, 1343, 1104, 988, 754, 504. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>19</sub>H<sub>15</sub>N<sub>3</sub>O<sub>4</sub>: 363.1083, found: 363.1087.

### 3.2.28. 5-Methyl-3-(phenylamino)-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (31)

A solution of the 3-chloro-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-dione **15** (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the aniline (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd<sub>2</sub>dba<sub>3</sub> (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **31** (0.049 g, 83%) as a yellow solid. M.p: 214–216 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.47 (d, *J* = 8.0 Hz, 2H), 7.43–7.34 (m, 4H), 7.20–7.16 (m, 3H), 6.37 (s, 1H), 3.08 (s, 3H), 2.46 (s, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 162.2 (CO), 161.0 (CO), 153.0 (Cq), 140.1 (Cq), 139.2 (Cq), 138.1 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.3 (2 × CH), 125.2 (2 × CH), 124.6 (CH), 120.0 (2 × CH), 100.7 (Cq), 24.2 (CH<sub>3</sub>), 21.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>19</sub>H<sub>17</sub>N<sub>4</sub>O<sub>2</sub>: 333.1342, found: 333.1346.

### 3.2.29. 3-((4-Methoxyphenyl)amino)-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-(2*H*,5*H*)-dione (32)

A solution of the 3-chloro-5-methyl-2-(*p*-tolyl)pyrrolo[3,4-*c*]pyrazole-4,6-dione **15** (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *p*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd<sub>2</sub>dba<sub>3</sub> (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **32** (0.058 g, 88%) as a white solid. M.p: 204–206 °C. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.46 (d, *J* = 8.3 Hz, 2H), 7.37 (d, *J* = 8.3 Hz, 2H), 7.14 (d, *J* = 8.9 Hz, 2H), 6.92 (d, *J* = 8.9 Hz, 2H), 6.30 (s, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 2.46 (s, 3H). <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 162.3 (CO), 161.0 (CO), 157.4 (Cq), 152.0 (Cq), 141.0 (Cq), 139.9 (Cq), 134.4 (Cq), 131.1 (Cq), 130.7 (2 × CH), 125.1 (2 × CH), 123.3 (2 × CH), 114.4 (2 × CH), 99.4 (Cq), 55.5 (OCH<sub>3</sub>), 24.1 (CH<sub>3</sub>), 21.3 (CH<sub>3</sub>). IR (ATR diamond, cm<sup>-1</sup>) ν: 3323, 1760, 1704, 1506, 1361, 1231, 822, 7444. HRMS: *m/z* [M + H]<sup>+</sup> calculated for C<sub>20</sub>H<sub>19</sub>N<sub>4</sub>O<sub>3</sub>: 363.1451, found: 363.1452.
### 3.2.30. 3-((3-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (33)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *m*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **33** (0.055 g, 84%) as a white solid. M.p: 180–182 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, *J* = 7.8 Hz, 2H), 7.37 (d, *J* = 7.8 Hz, 2H), 7.26 (t, *J* = 9.8 Hz, 1H), 6.77 (s, 1H), 6.70 (t, *J* = 6.9 Hz, 2H), 6.39 (s, 1H), 3.83 (s, 3H), 3.09 (s, 3H), 2.46 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.2 (CO), 161.0 (CO), 160.5 (Cq), 152.0 (Cq), 140.1 (Cq), 139.3 (Cq), 138.7 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.9 (CH), 125.2 (2 × CH), 111.7 (CH), 109.8 (CH), 105.5 (CH), 101.0 (Cq), 55.4 (OCH₃), 24.2 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3302, 1755, 1699, 1552, 1366, 1199, 966, 764, 743. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉N₄O₃: 363.1451, found: 363.1453.

### 3.2.31. 3-((2-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (34)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *o*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give **34** (0.043 g, 65%) as a white solid. M.p: 218–220 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, *J* = 7.3, 2.1 Hz, 1H), 7.50 (d, *J* = 8.3 Hz, 2H), 7.39 (d, *J* = 8.3 Hz, 2H), 7.15–7.05 (m, 2H), 6.90 (dd, *J* = 7.3, 2.1 Hz, 1H), 6.86 (s, 1H), 3.82 (s, 3H), 3.12 (s, 3H), 2.48 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.2 (CO), 161.4 (CO), 152.0 (Cq), 148.7 (Cq), 139.8 (Cq), 138.6 (Cq), 134.5 (Cq), 130.6 (2 × CH), 127.7 (Cq), 125.0 (2 × CH), 123.9 (CH), 121.1 (CH), 118.7 (CH), 110.2 (CH), 100.7 (Cq), 55.7 (OCH₃), 24.2 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3390, 1757, 1707, 1550, 1357, 1196, 985, 748, 736. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉N₄O₃: 363.1451, found: 363.1452.

### 3.2.32. 5-Methyl-2-(p-tolyl)-3-((4-(trifluoromethyl)phenyl)amino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (35)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *o*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give **35** (0.030 g, 41%) as a blue solid. M.p: 190–192 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, *J* = 8.3 Hz, 2H), 7.41 (d, *J* = 7.9 Hz, 2H), 7.35 (d, *J* = 7.9 Hz, 2H), 7.18 (d, *J* = 8.3 Hz, 2H), 6.51 (s, 1H), 3.09 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.9 (CO), 161.1 (CO), 151.9 (Cq), 141.20 (q, *J* = 1.1 Hz, Cq), 140.5 (Cq), 137.1 (Cq), 134.0 (Cq), 130.8 (2 × CH), 126.6 (q, *J* = 3.7 Hz, 2 × CH), 125.6 (q, *J* = 32.7 Hz, Cq), 125.2 (2 × CH), 123.9 (CH), 118.0 (2 × CH), 102.4 (Cq), 24.3 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3309, 1763, 1713, 1541, 1323, 1108, 1506, 831. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₆F₃N₄O₂: 401.1220, found: 441.1219.

### 3.2.33. 5-(4-Methoxybenzyl)-3-(anilino)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (39)

A solution of the **16** (0.113 mmol, 1.0 eq.), cesium carbonate (0.339 mmol, 3.0 eq.) and the aniline (0.226 mmol, 2.0 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added,
### 3.2.30. 3-((3-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (33)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *m*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give 33 (0.055 g, 84%) as a white solid. M.p: 180–182 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, *J* = 7.8 Hz, 2H), 7.37 (d, *J* = 7.8 Hz, 2H), 7.26 (t, *J* = 9.8 Hz, 1H), 6.77 (s, 1H), 6.70 (t, *J* = 6.9 Hz, 2H), 6.39 (s, 1H), 3.83 (s, 3H), 3.09 (s, 3H), 2.46 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.2 (CO), 161.0 (CO), 160.5 (Cq), 152.0 (Cq), 140.1 (Cq), 139.3 (Cq), 138.7 (Cq), 134.3 (Cq), 130.7 (2 × CH), 129.9 (CH), 125.2 (2 × CH), 111.7 (CH), 109.8 (CH), 105.5 (CH), 101.0 (Cq), 55.4 (OCH₃), 24.2 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3302, 1755, 1699, 1552, 1366, 1199, 966, 764, 743. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉N₄O₃: 363.1451, found: 363.1453.

### 3.2.31. 3-((2-Methoxyphenyl)amino)-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (34)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *o*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give 34 (0.043 g, 65%) as a white solid. M.p: 218–220 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, *J* = 7.3, 2.1 Hz, 1H), 7.50 (d, *J* = 8.3 Hz, 2H), 7.39 (d, *J* = 8.3 Hz, 2H), 7.15–7.05 (m, 2H), 6.90 (dd, *J* = 7.3, 2.1 Hz, 1H), 6.86 (s, 1H), 3.82 (s, 3H), 3.12 (s, 3H), 2.48 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.2 (CO), 161.4 (CO), 152.0 (Cq), 148.7 (Cq), 139.8 (Cq), 138.6 (Cq), 134.5 (Cq), 130.6 (2 × CH), 127.7 (Cq), 125.0 (2 × CH), 123.9 (CH), 121.1 (CH), 118.7 (CH), 110.2 (CH), 100.7 (Cq), 55.7 (OCH₃), 24.2 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3390, 1757, 1707, 1550, 1357, 1196, 985, 748, 736. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₉N₄O₃: 363.1451, found: 363.1452.

### 3.2.32. 5-Methyl-2-(p-tolyl)-3-((4-(trifluoromethyl)phenyl)amino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (35)

A solution of the 3-chloro-5-methyl-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-dione 15 (0.181 mmol, 1.0 eq.), cesium carbonate (0.553 mmol, 3.0 eq.) and the *o*-anisidine (0.273 mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (4/6) as eluent to give 35 (0.030 g, 41%) as a blue solid. M.p: 190–192 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, *J* = 8.3 Hz, 2H), 7.41 (d, *J* = 7.9 Hz, 2H), 7.35 (d, *J* = 7.9 Hz, 2H), 7.18 (d, *J* = 8.3 Hz, 2H), 6.51 (s, 1H), 3.09 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.9 (CO), 161.1 (CO), 151.9 (Cq), 141.20 (q, *J* = 1.1 Hz, Cq), 140.5 (Cq), 137.1 (Cq), 134.0 (Cq), 130.8 (2 × CH), 126.6 (q, *J* = 3.7 Hz, 2 × CH), 125.6 (q, *J* = 32.7 Hz, Cq), 125.2 (2 × CH), 123.9 (CH), 118.0 (2 × CH), 102.4 (Cq), 24.3 (CH₃), 21.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3309, 1763, 1713, 1541, 1323, 1108, 1506, 831. HRMS: *m/z* [M + H]⁺ calculated for C₂₀H₁₆F₃N₄O₂: 401.1220, found: 441.1219.

### 3.2.33. 5-(4-Methoxybenzyl)-3-(anilino)-2-(p-tolyl)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (39)

A solution of the 16 (0.113 mmol, 1.0 eq.), cesium carbonate (0.339 mmol, 3.0 eq.) and the aniline (0.226 mmol, 2.0 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and $Pd_2dba_3$ (0.05 eq.) were then added,
and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **39** (0.034g, 68%) as a yellow solid. M.p: 234–236 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.13 (d, *J* = 8.7 Hz, 2H), 7.93 (d, *J* = 8.6 Hz, 2H), 7.29 (t, *J* = 7.9 Hz, 2H), 7.19 (d, *J* = 8.7 Hz, 2H), 7.15 (d, *J* = 7.6 Hz, 2H), 7.03 (t, *J* = 7.3 Hz, 1H), 6.87 (d, *J* = 8.7 Hz, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.30 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9 (CO), 160.2 (CO), 159.0 (Cq), 152.7 (Cq), 142.3 (Cq), 140.9 (Cq), 140.9 (Cq), 140.2 (Cq), 133.0 (Cq), 129.5 (2 × CH), 129.3 (2 × CH), 129.2 (2 × CH), 129.10, 126.0 (2 × CH), 123.2 (CH), 119.3 (2 × CH), 114.4 (2 × CH), 102.3 (Cq), 55.5 (OCH₃), 43.9 (CH₃), 40.9 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3174, 1786, 1707, 1553, 1356, 1133, 971, 885, 733. HRMS: *m/z* [M + H]⁺ calculated for C₂₆H₂₂N₄O₃: 439.1745, found: 439.1747.

### 3.2.34. 5-Methyl-2-(4-nitrophenyl)-3-(phenylamino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (40)

A solution of the **17** (0.163 mmol, 1.0 eq.), cesium carbonate (0.326 mmol, 3.0 eq.) and the aniline (0.196mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd₂dba₃ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **40** (0.030 g, 51%) as a yellow solid. M.p: 240–242 °C. ¹H NMR (400 MHz, Acetone-d₆) δ 8.56 (s, 1H), 8.43 (d, *J* = 8.6 Hz, 2H), 8.03 (d, *J* = 8.6 Hz, 2H), 7.31 (t, *J* = 7.7 Hz, 2H), 7.20 (d, *J* = 8.1 Hz, 2H), 7.07 (t, *J* = 7.4 Hz, 1H), 2.99 (s, 3H). ¹³C NMR (101 MHz, Acetone-d₆) δ 161.6 (CO), 160.1 (CO) 153.3 (Cq), 147.2 (Cq), 143.3 (Cq), 139.9 (Cq), 139.8 (Cq), 128.9 (2 × CH), 125.7 (2 × CH), 124.9 (2 × CH), 123.1 (CH), 119.0 (2 × CH), 103.1 (Cq), 23.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: *m/z* [M + H]⁺ calculated for C₁₈H₁₄N₅O₄: 364.1033, found: 364.1036.

## 4. Conclusions

In summary, we have described in this work a synthetic pathway for the preparation of an original pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione platform and have developed several arylations/amination at its C-3 position. First, a reactivity study of these derivatives with respect to Suzuki–Miyaura coupling reactions has shown that the reaction is compatible with various arylboronic acids. A strong influence of electronic effect and steric hindrance has also been shown. A study of the Buchwald–Hartwig cross-coupling in C-3 position was also performed. The scope was investigated and showed its limitation to aniline derivatives. Secondly, this work allows access to a novel class of substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones, which will undoubtedly have a major impact on the further synthesis of new bioactive compounds that contain the rare pyrrolo[3,4-c]pyrazole scaffold as the central skeleton. Finally, efforts to achieve these objectives, and particularly to study the reactivity of the maleimide moiety involved in the bicyclic system, are currently in progress.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28155811/s1, Figures S1–S34: ¹H and ¹³C NMR of all synthesized compounds.

**Author Contributions:** F.B., S.R., A.E.H. and M.A. designed research; A.E. and J.E. performed research; A.E., J.E., F.B. and A.E.H. analyzed the data; F.B. and S.R. wrote the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data will be available upon request to the corresponding author.
and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **39** (0.034g, 68%) as a yellow solid. M.p: 234–236 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.13 (d, *J* = 8.7 Hz, 2H), 7.93 (d, *J* = 8.6 Hz, 2H), 7.29 (t, *J* = 7.9 Hz, 2H), 7.19 (d, *J* = 8.7 Hz, 2H), 7.15 (d, *J* = 7.6 Hz, 2H), 7.03 (t, *J* = 7.3 Hz, 1H), 6.87 (d, *J* = 8.7 Hz, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.30 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 161.9 (CO), 160.2 (CO), 159.0 (Cq), 152.7 (Cq), 142.3 (Cq), 140.9 (Cq), 140.9 (Cq), 140.2 (Cq), 133.0 (Cq), 129.5 (2 × CH), 129.3 (2 × CH), 129.2 (2 × CH), 129.10, 126.0 (2 × CH), 123.2 (CH), 119.3 (2 × CH), 114.4 (2 × CH), 102.3 (Cq), 55.5 (OCH₃), 43.9 (CH₃), 40.9 (CH₂). IR (ATR diamond, cm⁻¹) ν: 3174, 1786, 1707, 1553, 1356, 1133, 971, 885, 733. HRMS: *m/z* [M + H]⁺ calculated for C₂₆H₂₂N₄O₃: 439.1745, found: 439.1747.

### 3.2.34. 5-Methyl-2-(4-nitrophenyl)-3-(phenylamino)pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione (40)

A solution of the **17** (0.163 mmol, 1.0 eq.), cesium carbonate (0.326 mmol, 3.0 eq.) and the aniline (0.196mmol, 1.5 eq.) in dry 1,4-dioxane (4 mL) was degassed by bubbling argon through the mixture for 15 min. Xantphos (0.1 eq.) and Pd₂dba₃ (0.05 eq.) were then added, and the mixture was heated at 100 °C for 1 h under microwave irradiation. The mixture was concentrated and purified by using flash chromatography on a silica gel column with Petroleum Ether/EtOAc (3/7) as eluent to give **40** (0.030 g, 51%) as a yellow solid. M.p: 240–242 °C. ¹H NMR (400 MHz, Acetone-d₆) δ 8.56 (s, 1H), 8.43 (d, *J* = 8.6 Hz, 2H), 8.03 (d, *J* = 8.6 Hz, 2H), 7.31 (t, *J* = 7.7 Hz, 2H), 7.20 (d, *J* = 8.1 Hz, 2H), 7.07 (t, *J* = 7.4 Hz, 1H), 2.99 (s, 3H). ¹³C NMR (101 MHz, Acetone-d₆) δ 161.6 (CO), 160.1 (CO) 153.3 (Cq), 147.2 (Cq), 143.3 (Cq), 139.9 (Cq), 139.8 (Cq), 128.9 (2 × CH), 125.7 (2 × CH), 124.9 (2 × CH), 123.1 (CH), 119.0 (2 × CH), 103.1 (Cq), 23.3 (CH₃). IR (ATR diamond, cm⁻¹) ν: 3375, 1781, 1707, 1553, 1341, 1133, 966, 885, 747. HRMS: *m/z* [M + H]⁺ calculated for C₁₈H₁₄N₅O₄: 364.1033, found: 364.1036.

## 4. Conclusions

In summary, we have described in this work a synthetic pathway for the preparation of an original pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-dione platform and have developed several arylations/amination at its C-3 position. First, a reactivity study of these derivatives with respect to Suzuki–Miyaura coupling reactions has shown that the reaction is compatible with various arylboronic acids. A strong influence of electronic effect and steric hindrance has also been shown. A study of the Buchwald–Hartwig cross-coupling in C-3 position was also performed. The scope was investigated and showed its limitation to aniline derivatives. Secondly, this work allows access to a novel class of substituted pyrrolo[3,4-c]pyrazole-4,6-(2H,5H)-diones, which will undoubtedly have a major impact on the further synthesis of new bioactive compounds that contain the rare pyrrolo[3,4-c]pyrazole scaffold as the central skeleton. Finally, efforts to achieve these objectives, and particularly to study the reactivity of the maleimide moiety involved in the bicyclic system, are currently in progress.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28155811/s1, Figures S1–S34: ¹H and ¹³C NMR of all synthesized compounds.

**Author Contributions:** F.B., S.R., A.E.H. and M.A. designed research; A.E. and J.E. performed research; A.E., J.E., F.B. and A.E.H. analyzed the data; F.B. and S.R. wrote the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data will be available upon request to the corresponding author.
**Acknowledgments:** The authors gratefully acknowledge major financial support from the Ligue contre le Cancer du Grand Ouest (comités des Deux Sèvres, du Finistère, de l'Ille-et-Vilaine, du Loir-et-Cher, de Loire-Atlantique, du Loiret, de la Vienne), the Canceropôle Grand Ouest, INCA, Région Centre-Val de Loire, the SFR neuroimagerie (SFR FED 4224), which made this study possible, and also the projects CHER-Bio (FEDER-FSE 2014-2020-EX003677), Techsab (FEDER-FSE 2014-2020-EX011313), Valbiocosm (FEDER-FSE 2014-2020-EX003202), QUALICHIM (APR-IA-PF 2021-00149467) and RTR Motivhealth (2019-00131403) and the Labex programs SYNORG (ANR-11-LABX-0029) and IRON (ANR-11-LABX-0018-01) for their financial support of ICOA, UMR 7311, University of Orléans, CNRS. We also thank the SALSA platform for spectroscopic measurements (IR and UV-Vis) and spectrometric and chromatographic analyses (NMR, HPTLC, HPLC, MS and HRMS).

**Conflicts of Interest:** The authors declare no conflict of interest.

**Sample Availability:** Not applicable.

## References

1. Ebenezer, O.; Shapi, M.; Tuszynski, J.A. A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives. *Biomedicines* **2022**, *10*, 1124. [PubMed]

2. Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman. Review: Biologically active pyrazole derivatives. *New J. Chem.* **2017**, *41*, 16–41.

3. Costa, R.F.; Turones, L.C.; Cavalcante, K.V.N.; Rosa Júnior, I.A.; Xavier, C.H.; Rosseto, L.P.; Napolitano, H.B.; Castro, P.F.d.S.; Neto, M.L.F.; Galvão, G.M.; et al. Heterocyclic Compounds: Pharmacology of Pyrazole Analogs From Rational Structural Considerations. *Front. Pharmacol.* **2021**, *12*, 666725.

4. Rostami, H.; Shiri, L.; Khani, Z. Recent advances in the synthesis of pyrazole scaffolds via nanoparticles: A review. *Tetrahedron* **2022**, *110*, 132688.

5. Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; Al-aizari, F.A.; Ansar, M.h. Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. *Molecules* **2018**, *23*, 134.

6. Sridhar, R.; Perumal, P.T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M.N.; Prabavathy, V.R.; Mathivanan, N. Design, synthesis and anti-microbial activity of 1H-pyrazole carboxylates. *Bioorg. Med. Chem. Lett.* **2004**, *14*, 6035–6040.

7. Alam, R.; Wahi, D.; Singh, R.; Sinha, D.; Tandon, V.; Grover, A.; Rahisuddin. Design, synthesis, cytotoxicity, HuTopoIIα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents. *Bioorg. Chem.* **2016**, *69*, 77–90.

8. Alam, M.; Alam, O.; Alam, P.; Naim, M. A review on pyrazole chemical entity and biological activity. *Int. J. Pharma. Sci. Res.* **2015**, *12*, 1433–1442.

9. Ríos, M.-C.; Portilla, J. Recent Advances in Synthesis and Properties of Pyrazoles. *Chemistry* **2022**, *4*, 940–968.

10. Kumar, V.; Kaur, K.; Gupta, G.K.; Sharma, A.K. Pyrazole containing natural products: Synthetic preview and biological significance. *Eur. J. Med. Chem.* **2013**, *69*, 735–753.

11. Santora, V.J.; Almos, T.A.; Barido, R.; Basinger, J.; Bellows, C.L.; Bookser, B.C.; Breitenbucher, J.G.; Broadbent, N.J.; Cabebe, C.; Chai, C.-K.; et al. Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties. *J. Med. Chem.* **2018**, *61*, 6018–6033.

12. Asproni, B.; Manca, I.; Pinna, G.; Cichero, E.; Fossa, P.; Murineddu, G.; Lazzari, P.; Loriga, G.; Pinna, G.A. Novel pyrrolocycloalkylpyrazole analogues as CB(1) ligands. *Chem. Biol. Drug Des.* **2018**, *91*, 181–193.

13. Tenora, L.; Galeta, J.; Řezníčková, E.; Kryštof, V.; Potáček, M. Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of 5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles that Inhibit ALK5 Kinase. *J. Org. Chem.* **2016**, *81*, 11841–11856.

14. Bai, X.-G.; Yu, D.-K.; Wang, J.-X.; Zhang, H.; He, H.-W.; Shao, R.-G.; Li, X.-M.; Wang, Y.-C. Design, synthesis and anticancer activity of 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives. *Bioorg. Med. Chem. Lett.* **2012**, *22*, 6947–6951.

15. Schöffski, P.; Besse, B.; Gauler, T.; de Jonge, M.J.A.; Scambia, G.; Santoro, A.; Davite, C.; Jannuzzo, M.G.; Petroccione, A.; Delord, J.P. Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: A multi-tumour, multi-institutional phase II study. *Ann. Oncol.* **2015**, *26*, 598–607.

16. Liu, G.-N.; Luo, R.-H.; Zhou, Y.; Zhang, X.-J.; Li, J.; Yang, L.-M.; Zheng, Y.-T.; Liu, H. Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives. *Molecules* **2016**, *21*, 1198.

17. Abunada, N.M.; Hassaneen, H.M.; Kandile, N.G.; Miqdad, O.A. Synthesis and Biological Activity of Some New Pyrazoline and Pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives: Reaction of Nitriliminines with Some Dipolarophiles. *Molecules* **2008**, *13*, 1011–1024.

18. Chen, H.-J.; Liu, Y.; Wang, L.-N.; Shen, Q.; Li, J.; Nan, F.-J. Discovery and structural optimization of pyrazole derivatives as novel inhibitors of Cdc25B. *Bioorg. Med. Chem. Lett.* **2010**, *20*, 2876–2879.

19. Rüger, A.J.; Nieger, M.; Bräse, S. Synthesis of tetra-substituted pyrazoles. *Tetrahedron* **2012**, *68*, 8823–8829.

20. Farina, F.; Fernandez, P.; Teresa Fraile, M.; Martin, M.V.; Martin, M.R. 1,3-Dipolar cycloadditions with methyl 4-oxo- and 4-hydroxy-2-butynoates. Synthesis of functionalized pyrazoles and triazoles. *Heterocycles* **1989**, *29*, 967.

21. Padwa, A.; MacDonald, J.G. Reaction of hydrazonyl chlorides and carboalkoxymethylene triphenylphosphoranes to give 5-alkoxy substituted pyrazoles. *J. Heterocycl. Chem.* **1987**, *24*, 1225–1227.

22. Nicolaou, K.C.; Kang, Q.; Ng, S.Y.; Chen, D.Y.K. Total Synthesis of Englerin A. *J. Am. Chem. Soc.* **2010**, *132*, 8219–8222. [PubMed]
**Acknowledgments:** The authors gratefully acknowledge major financial support from the Ligue contre le Cancer du Grand Ouest (comités des Deux Sèvres, du Finistère, de l'Ille-et-Vilaine, du Loir-et-Cher, de Loire-Atlantique, du Loiret, de la Vienne), the Canceropôle Grand Ouest, INCA, Région Centre-Val de Loire, the SFR neuroimagerie (SFR FED 4224), which made this study possible, and also the projects CChemBio (FEDER-FSE 2014-2020-EX003677), Techsab (FEDER-FSE 2014-2020-EX011313), Valbiocosm (FEDER-FSE 2014-2020-EX003202), QUALICHIM (APR-IA-PF 2021-00149467) and RTR Motivhealth (2019-00131403) and the Labex programs SYNORG (ANR-11-LABX-0029) and IRON (ANR-11-LABX-0018-01) for their financial support of ICOA, UMR 7311, University of Orléans, CNRS. We also thank the SALSA platform for spectroscopic measurements (IR and UV-Vis) and spectrometric and chromatographic analyses (NMR, HPTLC, HPLC, MS and HRMS).

**Conflicts of Interest:** The authors declare no conflict of interest.

**Sample Availability:** Not applicable.

## References

1. Ebenezer, O.; Shapi, M.; Tuszynski, J.A. A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives. *Biomedicines* **2022**, *10*, 1124. [PubMed]

2. Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman. Review: Biologically active pyrazole derivatives. *New J. Chem.* **2017**, *41*, 16–41.

3. Costa, R.F.; Turones, L.C.; Cavalcante, K.V.N.; Rosa Júnior, I.A.; Xavier, C.H.; Rosseto, L.P.; Napolitano, H.B.; Castro, P.F.d.S.; Neto, M.L.F.; Galvão, G.M.; et al. Heterocyclic Compounds: Pharmacology of Pyrazole Analogs From Rational Structural Considerations. *Front. Pharmacol.* **2021**, *12*, 666725.

4. Rostami, H.; Shiri, L.; Khani, Z. Recent advances in the synthesis of pyrazole scaffolds via nanoparticles: A review. *Tetrahedron* **2022**, *110*, 132688.

5. Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; Al-aizari, F.A.; Ansar, M.h. Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. *Molecules* **2018**, *23*, 134.

6. Sridhar, R.; Perumal, P.T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M.N.; Prabavathy, V.R.; Mathivanan, N. Design, synthesis and anti-microbial activity of 1H-pyrazole carboxylates. *Bioorg. Med. Chem. Lett.* **2004**, *14*, 6035–6040.

7. Alam, R.; Wahi, D.; Singh, R.; Sinha, D.; Tandon, V.; Grover, A.; Rahisuddin. Design, synthesis, cytotoxicity, HuTopoIIα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents. *Bioorg. Chem.* **2016**, *69*, 77–90.

8. Alam, M.; Alam, O.; Alam, P.; Naim, M. A review on pyrazole chemical entity and biological activity. *Int. J. Pharma. Sci. Res.* **2015**, *12*, 1433–1442.

9. Ríos, M.-C.; Portilla, J. Recent Advances in Synthesis and Properties of Pyrazoles. *Chemistry* **2022**, *4*, 940–968.

10. Kumar, V.; Kaur, K.; Gupta, G.K.; Sharma, A.K. Pyrazole containing natural products: Synthetic preview and biological significance. *Eur. J. Med. Chem.* **2013**, *69*, 735–753.

11. Santora, V.J.; Almos, T.A.; Barido, R.; Basinger, J.; Bellows, C.L.; Bookser, B.C.; Breitenbucher, J.G.; Broadbent, N.J.; Cabebe, C.; Chai, C.-K.; et al. Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties. *J. Med. Chem.* **2018**, *61*, 6018–6033.

12. Asproni, B.; Manca, I.; Pinna, G.; Cichero, E.; Fossa, P.; Murineddu, G.; Lazzari, P.; Loriga, G.; Pinna, G.A. Novel pyrrolocycloalkylpyrazole analogues as CB(1) ligands. *Chem. Biol. Drug Des.* **2018**, *91*, 181–193.

13. Tenora, L.; Galeta, J.; Řezníčková, E.; Kryštof, V.; Potáček, M. Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of 5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles that Inhibit ALK5 Kinase. *J. Org. Chem.* **2016**, *81*, 11841–11856.

14. Bai, X.-G.; Yu, D.-K.; Wang, J.-X.; Zhang, H.; He, H.-W.; Shao, R.-G.; Li, X.-M.; Wang, Y.-C. Design, synthesis and anticancer activity of 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives. *Bioorg. Med. Chem. Lett.* **2012**, *22*, 6947–6951.

15. Schöffski, P.; Besse, B.; Gauler, T.; de Jonge, M.J.A.; Scambia, G.; Santoro, A.; Davite, C.; Jannuzzo, M.G.; Petroccione, A.; Delord, J.P. Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: A multi-tumour, multi-institutional phase II study. *Ann. Oncol.* **2015**, *26*, 598–607.

16. Liu, G.-N.; Luo, R.-H.; Zhou, Y.; Zhang, X.-J.; Li, J.; Yang, L.-M.; Zheng, Y.-T.; Liu, H. Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives. *Molecules* **2016**, *21*, 1198.

17. Abunada, N.M.; Hassaneen, H.M.; Kandile, N.G.; Miqdad, O.A. Synthesis and Biological Activity of Some New Pyrazoline and Pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives: Reaction of Nitriliminines with Some Dipolarophiles. *Molecules* **2008**, *13*, 1011–1024.

18. Chen, H.-J.; Liu, Y.; Wang, L.-N.; Shen, Q.; Li, J.; Nan, F.-J. Discovery and structural optimization of pyrazole derivatives as novel inhibitors of Cdc25B. *Bioorg. Med. Chem. Lett.* **2010**, *20*, 2876–2879.

19. Rüger, A.J.; Nieger, M.; Bräse, S. Synthesis of tetra-substituted pyrazoles. *Tetrahedron* **2012**, *68*, 8823–8829.

20. Farina, F.; Fernandez, P.; Teresa Fraile, M.; Martin, M.V.; Martin, M.R. 1,3-Dipolar cycloadditions with methyl 4-oxo- and 4-hydroxy-2-butynoates. Synthesis of functionalized pyrazoles and triazoles. *Heterocycles* **1989**, *29*, 967.

21. Padwa, A.; MacDonald, J.G. Reaction of hydrazonyl chlorides and carboalkoxymethylene triphenylphosphoranes to give 5-alkoxy substituted pyrazoles. *J. Heterocycl. Chem.* **1987**, *24*, 1225–1227.

22. Nicolaou, K.C.; Kang, Q.; Ng, S.Y.; Chen, D.Y.K. Total Synthesis of Englerin A. *J. Am. Chem. Soc.* **2010**, *132*, 8219–8222. [PubMed]
23. Hussein, A.A.; Al-Hadedi, A.A.M.; Mahrath, A.J.; Moustafa, G.A.I.; Almalki, F.A.; Alqahtani, A.; Shityakov, S.; Algazally, M.E. Mechanistic investigations on Pinnick oxidation: A density functional theory study. *R. Soc. Open Sci.* **2020**, *7*, 191568. [PubMed]

24. Ball, M.; Gaunt, M.J.; Hook, D.F.; Jessiman, A.S.; Kawahara, S.; Orsini, P.; Scolaro, A.; Talbot, A.C.; Tanner, H.R.; Yamanoi, S.; et al. Total Synthesis of Spongistatin 1: A Synthetic Strategy Exploiting Its Latent Pseudo-Symmetry. *Angew. Chem. Int. Ed.* **2005**, *44*, 5433–5438.

25. Sheehan, J.; Cruickshank, P.; Boshart, G. Notes-A Convenient Synthesis of Water-Soluble Carbodiimides. *J. Org. Chem.* **1961**, *26*, 2525–2528.

26. Patora-Komisarska, K.; Jadwiga Podwysocka, D.; Seebach, D. Preparation of the β2-Homoselenocysteine Derivatives Fmoc-(S)-β2hSec(PMB)-OH and Boc-(S)-β2hSec(PMB)-OH for Solution and Solid-Phase Peptide Synthesis. *Helv. Chim. Acta* **2011**, *94*, 1–17.

27. Beletskaya, I.P.; Alonso, F.; Tyurin, V. The Suzuki-Miyaura reaction after the Nobel prize. *Coord. Chem. Rev.* **2019**, *385*, 137–173.

28. Copin, C.; Henry, N.; Buron, F.; Routier, S. Synthesis of 2,6-Disubstituted Imidazo[2,1-b][1,3,4]thiadiazoles through Cyclization and Suzuki–Miyaura Cross-Coupling Reactions. *Eur. J. Org. Chem.* **2012**, *16*, 3079–3083.

29. Dorel, R.; Grugel, C.P.; Haydl, A.M. The Buchwald–Hartwig Amination After 25 Years. *Angew. Chem. Int. Ed.* **2019**, *58*, 17118–17129.

30. Copin, C.; Massip, S.; Léger, J.-M.; Jarry, C.; Buron, F.; Routier, S. SNAr versus Buchwald-Hartwig Amination/Amidation in the Imidazo[2,1-b][1,3,4]thiadiazole Series. *Eur. J. Org. Chem.* **2015**, *31*, 6932–6942.

31. Buron, F.; Hiebel, M.-A.; Mérour, J.-Y.; Plé, K.; Routier, S. Chapter Four—The Chemistry of Sulfur-Containing [5,5]-Fused Ring Systems With a Bridgehead Nitrogen. In *Advances in Heterocyclic Chemistry*; Scriven, E.F.V., Ramsden, C.A., Eds.; Academic Press: Cambridge, MA, USA, 2018; Volume 125, pp. 301–356.

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
23. Hussein, A.A.; Al-Hadedi, A.A.M.; Mahrath, A.J.; Moustafa, G.A.I.; Almalki, F.A.; Alqahtani, A.; Shityakov, S.; Algazally, M.E. Mechanistic investigations on Pinnick oxidation: A density functional theory study. *R. Soc. Open Sci.* **2020**, *7*, 191568. [PubMed]

24. Ball, M.; Gaunt, M.J.; Hook, D.F.; Jessiman, A.S.; Kawahara, S.; Orsini, P.; Scolaro, A.; Talbot, A.C.; Tanner, H.R.; Yamanoi, S.; et al. Total Synthesis of Spongistatin 1: A Synthetic Strategy Exploiting Its Latent Pseudo-Symmetry. *Angew. Chem. Int. Ed.* **2005**, *44*, 5433–5438.

25. Sheehan, J.; Cruickshank, P.; Boshart, G. Notes-A Convenient Synthesis of Water-Soluble Carbodiimides. *J. Org. Chem.* **1961**, *26*, 2525–2528.

26. Patora-Komisarska, K.; Jadwiga Podwysocka, D.; Seebach, D. Preparation of the β2-Homoselenocysteine Derivatives Fmoc-(S)-β2hSec(PMB)-OH and Boc-(S)-β2hSec(PMB)-OH for Solution and Solid-Phase Peptide Synthesis. *Helv. Chim. Acta* **2011**, *94*, 1–17.

27. Beletskaya, I.P.; Alonso, F.; Tyurin, V. The Suzuki-Miyaura reaction after the Nobel prize. *Coord. Chem. Rev.* **2019**, *385*, 137–173.

28. Copin, C.; Henry, N.; Buron, F.; Routier, S. Synthesis of 2,6-Disubstituted Imidazo[2,1-b][1,3,4]thiadiazoles through Cyclization and Suzuki–Miyaura Cross-Coupling Reactions. *Eur. J. Org. Chem.* **2012**, *16*, 3079–3083.

29. Dorel, R.; Grugel, C.P.; Haydl, A.M. The Buchwald–Hartwig Amination After 25 Years. *Angew. Chem. Int. Ed.* **2019**, *58*, 17118–17129.

30. Copin, C.; Massip, S.; Léger, J.-M.; Jarry, C.; Buron, F.; Routier, S. SNAr versus Buchwald-Hartwig Amination/Amidation in the Imidazo[2,1-b][1,3,4]thiadiazole Series. *Eur. J. Org. Chem.* **2015**, *31*, 6932–6942.

31. Buron, F.; Hiebel, M.-A.; Mérour, J.-Y.; Plé, K.; Routier, S. Chapter Four—The Chemistry of Sulfur-Containing [5,5]-Fused Ring Systems With a Bridgehead Nitrogen. In *Advances in Heterocyclic Chemistry*; Scriven, E.F.V., Ramsden, C.A., Eds.; Academic Press: Cambridge, MA, USA, 2018; Volume 125, pp. 301–356.

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.