Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.C[Si]([N:37]=[C:38]=[O:39])(C)C>CN(C)C=O>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:38]([NH2:37])=[O:39])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A solution of 250 mg (0.74 mmol) of (RS)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 1f)] in 2 ml of N,N-dimethylformamide is cooled to 0° C. and successively treated with 386 μl (2.2 mmol) of N-ethyl-diisopropylamine and 307 μl (2.2 mmol) of trimethylsilylisocyanate. The mixture is left to warm to RT and stirred for 4 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The red residue is dissolved in dichloromethane and the organic phase washed with water. After separation of the organic layer and drying over sodium sulfate, it is evaporated to give a red oil. For purification, the crude product is chromatographed on silica gel using a gradient of a 95:5- to 90:10-mixture of dichloromethane and methanol as the eluent. After the chromatography, in addition, the product is triturated in ethyl acetate and sodium hydrogencarbonate at RT. There are obtained 153 mg (60% of theory) of (RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-urea as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN1CCCC1=O>[CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCn1c(Nc2ccccc2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 150 °C
Yield: 48 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-pyrrolidone (1 ml) was added aniline (0.20 g, 2.14 mmol) and the mixture was heated at 150° C. overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 5% methanol in dichloromethane to give the product (0.034 g, 47%) as a brown solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=3[N:12]=[CH:11]2)[CH2:6][CH2:5]1)(=O)C.[ClH:20]>C(O)C>[ClH:20].[ClH:20].[NH:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:18]3[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=3[N:12]=[CH:11]2)[CH2:8][CH2:9]1
Reactant: CC(=O)N1CCC(n2cnc3c(=O)[nH]ccc32)CC1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ccc2c1ncn2C1CCNCC1

Procedure:
To a solution of 1-(1-acetyl-piperidin-4-yl)-1,5-dihydro-imidazo[4,5-c]pyridin-4-one (6.00 g, 23.05 mmol) in ethanol (48 mL) was added conc. HCl (24 mL) and the reaction mixture heated to reflux for 16 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 219.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3].[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(O)(C)C>[CH2:1]([N:4]1[C:8]([OH:9])=[C:7]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=2[Cl:14])[C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C=CCN1N=C(C)CC1=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCn1nc(C)c(C(=O)c2ccc(Cl)cc2Cl)c1O
Reaction time: 1.5 h
Yield: 40.7 %

Procedure:
A suspension of 1.4 g. of 1-allyl-3-methyl-2-pyrazolin-5-one and 0.74 g. of calcium hydroxide in 20 ml. of isopropanol is heated under reflux with stirring for 1.5 hours. After cooling, to the resulting mixture is added dropwise 2.3 g. of 2,4-dichlorobenzoyl chloride. After completion of the dropwise addition, the resulting mixture is heated under reflux for 5.5 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture and to the residue is added 3 ml. of 2 N hydrochloric acid to adjust pH to 3.0. Then, the mixture is extracted with chloroform and the extract solvent is distilled off from the extract. The residue is dissolved in a small amount of benzene and the solution is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting residue is recrystallized from isopropyl ether containing a small amount of methylene chloride to give 1.18 g. of the desired product as white crystals melting at 161°-163° C. Yield 40.7%.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH:24]=O)([CH3:23])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH2:23][NH:4][CH:1]1[CH2:3][CH2:2]1)([CH3:24])[CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14]
Reactant: NC1CC1
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.3 %

Procedure:
Cyclopropylamine (1.00 mL, 14.4 mmol), glacial acetic acid (1.0 mL), and sodium cyanoborohydride (1.82 g, 29.0 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (2.90 g, 14.5 mmol) in ethanol (40 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclopropylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.33 g, 5.51 mmol, 38%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.04 (2H, m), 0.12-0.16 (2H, m), 0.62 (6H, d, J=6.4 Hz), 0.76-0.86 (1H, m), 0.88 (3H, s), 1.00 (3H, t, J=6.9 Hz), 1.12-1.25 (2H, m), 1.30-1.38 (2H, m), 1.82-1.87 (1H, m), 2.38 (1H, d, J=11.7 Hz), 2.67 (1H, d, J=11.9 Hz), 3.86 (2H, q, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[C:2]([F:1])=[CH:7][C:6]([OH:8])=[CH:5][C:4]=3[F:9])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(F)c(-c2ccc3cc(O)ccc3c2)c(F)c1
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol (510 mg, 1.86 mmol) and NCS (301 mg, 2.25 mmol) in THF (30 mL) according to Method C to yield 440 mg (77%) of yellowish solid: mp 213–214° C.; 1H NMR (acetone-d6): δ 6.71–6.78 (2H, m), 7.47 (1H, d, J=8.85 Hz), 7.76 (1H, dd, J=8.12 Hz, J=1.52 Hz), 7.97 (1H, d, J=8.90 Hz), 8.04 (1H, s), 8.29 (1H, d, J=8.80 Hz), 9.26 (1H, s), 9.60 (1H, s); MS (ESI) m/z 305/307 (M−H)−; HRMS: calcd for C16H9ClF2O2, 306.0259; found (ESI−), 306.01991 Anal. for C16H9ClF2O2.0.25 H2O:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[NH:12][C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:22])=[C:16]([O:20][CH3:21])[C:17]=2[Br:19])[N:12]([CH2:33][CH:32]=[CH2:31])[C:11]=1[Br:23])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)c(Br)c12)NC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(Br)c(C[C@H](NC(C)=O)C(=O)OC)c2c(Br)c(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 39.8 mg (0.08 mmol) of (S)-(+)-N-acetyl-2,4,6-tribromo-5-methoxytryptophan methyl ester (4) dissolved in 2.5 mL of N,N-dimethylformamide was charged with 36.5 mg (0.26 mmol) of potassium carbonate and subsequently with 0.13 mL (d=1.398, 1.51 mmol) of allyl bromide. The mixture was stirred at room temperature for 30 minutes. The reaction solution was charged with water and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain yellow oil. Purification by column chromatography using silica gel as a carrier and chloroform as an elution solvent was performed to obtain the substance of interest (6) at a yield of 42.4 mg (99%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][CH:2]=[CH:10][CH:9]=3)=[O:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Yield: 97.8 %

Procedure:
Treat 1H-indole-2-carboxylic acid 3 (X═H, 1.0 mg, 6.21 mmol) with N-(tert-butoxycarbonyl)piperazine (1.10 equiv., 1.3 g, 6.83 mmol) as described in General Synthetic Procedure VIa to afford 4-(1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester 8 (X═H, R4=piperazin-4-yl-1-carboxylic acid tert-butyl ester; 2.0 g, 99%) as a white solid, mp 205-206° C. 1H NMR (DMSO-d6) δ 11.6 (brs, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 7.2 (t, 1H), 7.1 (t, 1H0, 6.8 (s, 1H), 3.8-3.7 (m, 4H), 3.5-3.4 (m, 4H), 1.4 (s, 9H); m/z=330 (M+1). Treat 4-(1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (329 g, 1.0 mmol) with phenyldisulfide (283 mg, 1.3 equiv., 1.3 mmol) as described in General Synthetic Procedure VIIa and then treat with trifluoroacetic acid (4 mL) in HOAc, to remove the Boc protecting group, to afford (3-phenylsulfanyl-1H-indol-2-yl)-piperazin-1-yl-methanone. Dissolve (3-phenylsulfanyl-1H-indol-2-yl)-piperazin-1-yl-methanone in EtOAc and treat with 1N HCl/Et2O to provide the title compound Iae (103 mg, 29%) as a tan solid, mp 240° C. (dec); m/z=338 (M+1).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2Cl)CN1C(=O)Cn1nccn1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 56, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (70 mg, 55%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.25 (m, 2H), 7.23-7.15 (m, 2H), 7.06-6.91, (m, 4H), 5.50 (q, 2H), 4.56-4.48 (m, 1H), 3.92-3.81 (m, 1H), 3.44-3.36 (m, 1H), 2.94-2.73 (m, 3H), 2.28-1.86 (m, 2H). MS (EI) for C28H25ClFN5O3. found 533.9 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.[O-:12][C:13]#[N:14].[Na+]>O>[NH:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[C:13]([NH2:14])=[O:12]
Reactant: N#C[O-]
Reactant: NCc1csc2cncn12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1csc2cncn12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 14.8 %

Procedure:
A 1 ml portion of ice-cooled water and 0.5 ml of 5N hydrochloric acid were added to a mixture of 200 mg of 3-aminomethylimidazo[5,1-b]thiazole and 0.5 g of ice, and the mixture was then stirred at 80° C. for 5 minutes. To this solution, 254 mg of sodium cyanate was added, followed by stirring at the same temperature for 1 hour. After cooled to room temperature, the reaction solution was washed once with diethyl ether. Further, potassium carbonate was added to the separated aqueous layer to alkalify the same, and methanol was further added thereto. The solution was sufficiently stirred, and then filtered to remove impurities therefrom. The resulting filtrate was concentrated under reduced pressure, and then allowed to stand at 0° C. overnight. Afterward, the precipitated crystal was collected by filtration to obtain 38 mg of 3-ureidomethylimidazo[5,1-b]thiazole. Furthermore, the mother liquor from which the crystal was collected by the filtration was purified by a column chromatograph of Diaion HP-20 Resin to obtain 49 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[N:26]1([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][S:38]([C:35]4[CH:34]=[CH:33][C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:37][CH:36]=4)(=[O:39])=[O:40])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NS(=O)(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120 mg, 0.485 mmol) in anhydrous methylene chloride (10 mL) were added triethylamine (81 μL, 0.582 mmol) and 4-(4-morpholinyl)benzenesulfonyl chloride (140 mg, 0.534 mmol; described in: Galliani, G. Eur. Pat. Appl. EP 335, 758, 1989, Chem. Abstr. 1990, 112, 98374d [125393-22-8]). The reaction mixture was stirred at room temperature for 4 h, washed with a 2 M NH3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (eluent: chloroform/ethanol, 90:10+0.5% conc. NH3) affording 141 mg (61% yield) of the title compound as a white solid: mp sinters >100° C.; [α]22D +10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 472 (56, M+).
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[F:1][C:2]1[C:17]([F:18])=[C:16]([CH2:19][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: CCCCCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(F)c1F
Reaction time: 2 h
Yield: 83 %

Procedure:
Combine 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol), n-pentylamine (105 mg, 1.20 mmol), and MeOH (3 ml) in a round bottom flask equipped with nitrogen inlet and stir for two hours. Add NaBH4 (57 mg, 1.50 mmol) and stir for an additional two hours before concentrating. Dissolve concentrate in EtOAc and wash with 5% aq. KOH and brine, dry (Na2SO4), and concentrate. Purify on silica gel (5% (1 M NH3/MeOH)/DCM) to give the title compound (290 mg) as a white solid. Mass spectrum (ion spray): m/z=350 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.28 (d, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.22 (d, 1H), 7.15 (m, 1H), 3.73 (s, 2H), 2.48 (t, 2H), 1.41 (m, 2H), 1.25 (m, 4H), 0.84 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]([C:7]#[N:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]=2[C:7]#[N:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To 1.32 g (5.92 mmol)of 4-methoxy-2,6-dinitrobenzonitrile dissolved in 8 mL dimethylformamide was added 2.2 g (2 eq., 11.83 mmol) piperazine-1-carboxylic acid tert-butyl ester. The mixture was heated to 50° C. and stirred overnight, then partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes provided 1.48 g of 4-(2-cyano-5-methoxy-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:39]2C(OC(C)(C)C)=O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[NH:39][CH:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A vial was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (158 mg, 0.31 mmol), tert-butyl 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (176 mg, 0.47 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.0 mg, 0.016 mmol). The vial was evacuated and backfilled with argon then 1,2-dimethoxyethane (1.8 ml) and aqueous 2 M sodium carbonate (0.47 ml, 0.940 mmol) were added. The vial was sealed and the reaction was stirred at 90° C. in an oil bath overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to isolate 93 mg (52%) 2-(6-chloro-1H-indol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light green foam. A minor amount of impure 6-chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indole-1-carboxylic acid tert-butyl ester was also insolated as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C)C=O>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(methoxycarbonyl)picolinic acid (3.33 g, 18.4 mmol) in a mixture of pyridine (20 mL) and N,N-dimethylformamide (35 mL) was treated with 1,1′-carbonyldiimidazole (3.28 g, 20.2 mmol) at 45° C. for 2 hours. After cooling, 2,3-diaminobenzamide (HCl salt) (4.12 g, 18.4 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue used in the next step without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([N:19]([CH:29]([CH3:33])[C:30](=O)[CH3:31])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[CH3:10]>O>[CH3:8][C:9]([N:19]1[CH:29]([CH3:33])[C:30]([CH3:31])=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]1=[O:28])([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[CH3:10]
Reactant: CC(=O)C(C)N(C(=O)Cc1ccccc1)C(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To 15 ml of toluene were added 2.2 g of N-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-phenylacetamide and 3.5 g of 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), followed by stirring at room temperature for 1 hour. After water was added, the solution was extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the solution was subjected to silica gel column chromatography to obtain 1.1 g of the desired 1-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-4,5-dimethyl-3-phenyl-3-pyrroline-2-one.