Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH3:20])=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([N:19]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:15][C:14]=2[CH3:20])=[CH:10][C:9]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc(N)cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-5-methyl-pyridin-3-ylamine (0.6 g) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 1:2 (v:v) gives 0.52 g of the compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[K+].[I:16]I.C(OCC)(=O)C>CN(C=O)C>[I:16][C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A mixture of 6-(trifluoromethyl)-1H-indazole (0.5 g, 2.69 mmol), KOH (0.45 g, 8.1 mmol) and I2 (1.37 g, 5.38 mmol) in dry DMF (20 mL) was stirred for 16 hours at room temperature. Ethyl acetate (100 mL) was added and the mixture was washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was then washed with ether (2 mL) and filtered to afford 3-iodo-6-(trifluoromethyl)-1H-indazole (688 mg, crude) as a yellow solid. LCMS: (M+H)+=313.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37].[ClH:38]>O1CCOCC1.CCOCC>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCNCC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The tert-butyl 4-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.713 g, 1.36 mmol) was dissolved in 15 ml of dioxane and treated with 7.5 ml of anhydrous 4N HCl in dioxane at room temperature (RT). The reaction mixture was stirred at room temperature for two hours. The mixture was then diluted with 25 ml of ether and stirred until product separated as a solid. Solid product was filtered and washed with ether. The solid was dissolved in MeOH (20 ml) and concentrated to dryness twice. The product was dried at high vacuum to yield 0.652g of yellow solid (bis HCl salt) (96%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.32 (br. s, 1H), 8.10 (d, J=4.7 Hz, 1H), 7.61 (d, J=4.3 Hz, 1H), 7.39 (dd, J=8.2, 2.0 Hz, 1H), 7.33 (dd, J=11.3, 8.2 Hz, 1H), 7.19 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.56 (d, J=6.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.86 (s, 3H), 3.40-3.32 (m, 2H), 3.12-2.96 (m, 2H), 2.22-2.12 (m, 2H), 1.99-1.86(m, 2H). LCMS: 425 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[CH3:21][C:19]([C:18]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:18]([C:19]([CH3:21])=[CH2:20])=[O:22])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)=[O:22])=[CH2:20]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Product: C=C(C)C(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C(=C)C)cc2)cc1

Procedure:
adduct of 1 mol of bisphenol A with 2 mol of glycidyl methacrylate
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22].C([O-])([O-])=O.[K+].[K+].CO>O>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22]
Reactant: COc1nc2c(c(Cl)c1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(c(Cl)c1Br)C(C)CNCC2
Temperature: 57.5 °C
Yield: 98.2 %

Procedure:
To a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (303 mg, 1.00 mmol) in MeCN (6 ml) was added a solution of NCS (134 mg, 1.00 mmol) in MeCN (6 ml). The resulting mixture was stirred for 2 h at 50° C. and then quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 165 mg (49%) of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.28 (0.5H), 3.95 (2.5H), 3.88 (3H), 3.71 (2H), 3.61 (1H), 3.34 (1H), 3.16 (1H), 2.99 (1H), 1.13 (3H) ppm. To a solution of CuBr2 (43.0 mg, 0.19 mmol) and nBuNO2 (28.0 μl, 0.24 mmol) in MeCN (2.7 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (54.0 mg, 0.16 mmol) in MeCN (2 ml) at room temperature. After leaving the mixture for 16 h at room temperature, it was heated at 50° C. for 4 h. After removal of MeCN under reduced pressure, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 45 mg (70%) of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H NMR (CDCl3) δ 4.29 (0.5H), 4.00 (0.5H), 3.90 (3H), 3.85 (1H), 3.75 (1H), 3.40 (1H), 3.30 (1H), 3.20 (1H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (60 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 1 h. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give 45 mg (98%) of 3-bromo-4-chloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.58 (m, 1H), 3.22 (m, 2H), 3.09 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.24 (d, 3H) ppm.
Reaction SMILES: [OH:1][C@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: CON(C)C(=O)[C@](C)(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CON(C)C(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
(R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol) and 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added and stirred at ambient temperature overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (R)—N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (22.9 g, 113 mmol, 57.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=2)=[O:31])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (110 mg) and commercially available 4-nitrobenzoic acid (100 mg) were dissolved in N,N-dimethylformamide (4 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (176 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 50 to obtain 126 mg of the title compound (yield: 77%).
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[C:7]([O-:10])(=[O:9])[CH3:8].[K+].CN(C)C=O>O>[C:7]([O:10][CH2:2][C:3](=[O:6])[CH2:4][CH3:5])(=[O:9])[CH3:8]
Reactant: CCC(=O)CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 95.6 %

Procedure:
A mixture of 1-bromobutan-2-one (10 g, 66.2 mmol), potassium acetate (7.8 g, 79.4 mmol), and N,N-dimethylformamide (50 ml) was stirred at room temperature for 5 days. Water was added to the reaction mixture and extracted with diethyl ether twice. The organic layers were combined and washed with a saturated saline solution, dried over magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound (8.24 g) in the form of a mixture with N,N-dimethylformamide.
Reaction SMILES: [BrH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5]>Br.CC(O)=O>[BrH:1].[NH2:2][CH:3]([CH2:8][CH2:7][Br:1])[C:4]([OH:6])=[O:5]
Reactant: NC1CCOC1=O
Agent: Br
Solvent: CC(=O)O
Product: NC(CCBr)C(=O)O
Temperature: 100 °C
Yield: 64 %

Procedure:
A suspension of α-amino-γ-butyrolactone hydrobromide in 30% HBr in HOAc is heated at 100° C. in a sealed tube for 5 days. The mixture is concentrated to give a white solid that is washed with ether to provide 23.1 g (64%) of 2-amino-4-bromo-butyric acid hydrobromide. Acetyl chloride (61 mL, 860 mmol) is added dropwise to 200 mL of MeOH at 0° C. The mixture is stirred at rt for 30 min before 22.5 g (124 mmol) of 2-amino-4-bromo-butyric acid hydrobromide is added. The mixture is stirred overnight and concentrated. The residue is washed with ether to provide 23.5 g (82%) of methyl 4-bromo-2-amino-butyrate hydrochloride. A solution of 27.7 g (330 mmol) of NaHCO3 in 100 mL of water is slowly added to 19.2 g (82.5 mmol) of this material along with 21.6 g (99.0 mmol) of Boc2O in 140 mL of 1,4-dioxane at 0° C. The mixture is warmed to rt and stirred overnight. N,N-dimethyl propane-1,3-diamine (5 mL) is added to the mixture, and it is stirred for 20 min. The mixture is diluted with water then extracted twice with EtOAc. The extracts are washed with water, 1M NaHSO4, and brine, and then combined, dried with Na2SO4, filtered, and concentrated to provide 21.5 g (88%) of I-042 as a white solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1.Cl[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][N:31]([CH:35]5[CH2:38][O:37][CH2:36]5)[CH2:30][CH2:29]4)[N:23]=3)[C:15]=2[CH:14]=1>CN(C)C(=O)C>[CH3:9][C:5]1[N:4]=[C:3]([C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[N:20][N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH:35]6[CH2:38][O:37][CH2:36]6)[CH2:30][CH2:29]5)[N:23]=4)[C:15]=3[CH:14]=2)[CH:8]=[N:7][CH:6]=1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCN(C3COC3)CC2)n1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCN(C4COC4)CC3)n2)n1
Temperature: 150 °C
Yield: 20.4 %

Procedure:
A mixture of trimethyl-(6-methylpyrazin-2-yl)stannane (0.387 mmol; 99.3 mg), 6-chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-2-pyridyl]pyrazolo[4,3-c]pyridine (0.258 mmol; 99.2 mg), and Palladium(0)tetrakis(triphenylphosphine) (0.0258 mmol; 29.8 mg) in N,N-Dimethylacetamide (3 ml) was purged with argon. The reaction mixture was sealed in a Biotage pressure vial and heated at 150° C. under microwave for 45 min. The mixture filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 10% MeOH in DCM. The material was further purified by reverse phase HPLC to afford 240 as an off-white solid (23.3 mg, 20%). 1H NMR (400 MHz, DMSO) δ 9.66-9.61 (s, 1H), 9.47-9.44 (s, 1H), 9.33-9.30 (s, 1H), 9.06-9.03 (s, OH), 8.67-8.60 (m, 2H), 8.52-8.50 (s, 1H), 7.76-7.68 (td, J=8.1, 3.4 Hz, 2H), 7.25-7.20 (d, J=7.7 Hz, 1H), 7.17-7.13 (d, J=7.7 Hz, 1H), 6.66-6.59 (dd, J=8.3, 6.0 Hz, 2H), 4.55-4.46 (m, 3H), 4.41-4.33 (dt, J=15.0, 6.0 Hz, 3H), 3.98-3.86 (d, J=5.5 Hz, 4H), 3.81-3.73 (m, 2H), 3.67-3.60 (dt, J=11.7, 5.8 Hz, 2H), 2.67-2.63 (s, 2H), 2.62-2.59 (s, 3H), 2.41-2.36 (dd, J=11.3, 6.0 Hz, 3H), 2.05-1.93 (dt, J=18.5, 6.1 Hz, 3H); MS (ESI) m/z: 443.2 [M+H]+
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([C:7](=[O:6])[CH3:8])=[CH:21][CH:22]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(-c2ccccn2)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After 21 ml of a 3M methyl magnesium bromide-diethyl ether solution was added dropwise to a solution of 3.10 g of 4-(2-pyridyl)benzonitrile in 120 ml of dichloromethane under ice-cooling in a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. After the reaction, an aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, followed by stirring of the resulting mixture. The ethyl acetate layer was separated from the reaction mixture, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the crude desired compound as crystals. Further, the crude compound was washed with diisopropyl ether-hexane to obtain 1.56 g of the desired compound.
Reaction SMILES: C[CH2:2][O:3][CH2:4][CH3:5].[CH2:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][NH2:13])=O)[CH3:7]>C(#N)C>[CH2:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]1[N:12]=[C:10]([C:9]2[CH:8]=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:14]=2)[NH:13][N:12]=1)[CH3:7]
Reactant: CCOCC
Reactant: CCc1ccccc1C(=O)NN
Solvent: CC#N
Product: CCc1ccccc1-c1n[nH]c(-c2cccc(OC)c2)n1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of immino ether (85 mg, 0.474 mmoles) and 2-ethyl benzo-hydrazide (164 mg, 1 mmole) in acetonitrile (0.5 mL), was warmed under reflux. After 1 hour stirring, solvent was distilled and substituted by 2-ethoxyethanol (0.6 mL). The reaction mixture was refluxed for 3 hours, the solvent evaporated under vacuum and the residue, re-dissolved in CH2Cl2 (2 mL), was chromatographed on a silica gel column (10 g). As elution solvents, mixtures of CH2Cl2 and CH3COOC2H5 in varying proportion (99:1 to 95:5) were used. Fractions containing the desired product were collected, solvent evaporated to give 96,27 mg (72.6%) of compound (XIII). Of particular interest, was compound (XIV), which, can be synthesised according to the procedure hereafter reported in example 2.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([NH:25][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2scc(-c3ccccc3)c2c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc2scc(-c3ccccc3)c2c(NCc2ccccc2)n1
Temperature: 220 °C
Yield: 61.8 %

Procedure:
A microwave reaction vessel was charged with 4-chloro-6-methyl-3-phenyl-thieno[3,2-c]pyridine (254 mg, 0.982 mmol), benzylamine (642 μl, 5.886 mmol), triethylamine (137 μl, 0.982), solvated in NMP (3 ml), and set to stir in a Biotage microwave reactor. The reaction was heated at 220° C. for 6 h. The crude reaction was next partitioned between ethyl acetate (25 ml) and distilled water (25 ml). The organic phase was dried (MgSO4) and the solvent removed in vacuo. Purification by flash column chromatography (petroleum spirit 40-60° C.:ethyl acetate, 5:1, Rf 0.5) afforded the title compound as a yellow solid (200.4 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:8][N:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[CH:10]=1)[CH3:2].O1CCCC1>[C].[Pd].C(O)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:9]2[CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33])[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn(CCc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A mixture of ethyl(1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl)acetate (800 mg), 5% palladium-carbon (1.50 g), tetrahydrofuran (20 ml), and ethanol (30 ml) was stirred for 3 hours at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-[2-(4-hydroxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (400 mg, yield: 63%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]#[C:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=2)[CH2:19][CH2:18]1
Reactant: COc1cc(C#CCCl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: COc1cc(C#CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 97.3 %

Procedure:
To 4-(3-chloro-1-propyn-1-yl)-2-(methyloxy)-1-nitrobenzene (Example 139, step B) (0.250 g, 1.1 mmol) in 10 mL of dioxane was added, 1-methylpiperazine (0.31 g, 3.1 mmol). The mixture was heated to 110° C. for 3 h. The mixture was purified by flash chromatography to give the title compound of step A (0.309 g, 1.07 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (d, J=8.24 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.33, 1.56 Hz, 1H), 3.94 (s, 3H), 3.55 (s, 2H), 2.64-2.78 (m, 4H), 2.47-2.62 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[C:33]([NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of the compound of Example 20 (100 mg 0.29 mmol) in CHCl3 (8 mL) was added pyridine (0.1 mL) and acetic anhydride (0.1 mL). The reaction was stirred at ambient temperature for 6 h. The reaction was then washed with 2M HCl and saturated NaHCO3, dried (MgSO4), and concentrated under reduced pressure to give the title compound (103 mg) as a yellow solid, m.p. 212-216°. δH 8.69 (1H, s), 8.06 (2H, d, J 8.4 Hz), 7.63-7.60 (2H, m), 7.56 (2H, d, J 8.4 Hz), 7.12-7.08 (2H, m), 5.82 (1H, s), 2.03 (3H, s) and 1.74 (6H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>O>[CH2:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 65 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a flask was added quinoline-2,8-diol (20.0 g, 124.1 mmol), K2CO3 (17.15 g, 124.1 mmol), benzyl bromide (14.76 ml, 124.1 mmol) and DMF (124.1 ml, 124.1 mmol). The resulting mixture was heated to 65° C. overnight. The reaction mixture was poured into 1000 ml water and stirred for 5 hours, filtered solids and then washed with 1000 ml diethyl ether to yield 26.5 g (85% yield) of desired product.
Reaction SMILES: [Cl:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH2:8])[O:3]1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH:8][C:16](=[O:17])[CH:15]([O:14][C:13]2[CH:20]=[C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH:22]=[CH:23][C:12]=2[N+:9]([O-:11])=[O:10])[CH3:19])[O:3]1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1OCC(Cl)O1
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-])C(=O)NCC1OCC(Cl)O1
Temperature: -15 °C

Procedure:
N-(4-Chloro-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-chloro-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(4-trifluoromethylphenoxy)phenoxy]propionamide.