Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OCC(F)(F)F
Yield: 61.5 %

Procedure:
To a refluxing mixture of acetone (20 mL), methyl 5-cyano-2-hydroxybenzoate (2.0 g, 11.3 mmol, Astatech) and potassium carbonate (3.1 g, 22.6 mmol) in a 40 mL sealed vial was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.9 g, 16.9 mmol, TCI). The mixture was stirred at reflux overnight and then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and dichloromethane (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 1.8 g of crude methyl 5-cyano-2-(2,2,2-trifluoroethoxy)benzoate that was suspended in methanol/water (1:1, 100 mL) and treated with an aqueous solution of 5N sodium hydroxide (2.8 mL, 13.9 mmol). After stirring at 40° C. for 16 h, the reaction mixture was concentrated and then washed with methylene chloride. The aqueous layer was acidified to pH˜2 with aqueous 2N HCl solution to precipitate the product. The precipitate was filtered and dried under reduced pressure to afford 1.1 g of a product mixture of the title compound with unreacted 5-cyano-2-hydroxybenzoic acid (5:2 ratio). MS (ESI+) m/z 263 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([N:11]2[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][O:13][C:12]2([CH3:21])[CH3:20])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]([N:11]2[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][O:13][C:12]2([CH3:21])[CH3:20])=[O:10])=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
(5-Bromo-6-chloro-pyridin-3-yl)-((R)-4-isobutyl-2,2-dimethyl-oxazolidin-3-yl)-methanone (2.0 g, 5.5 mmol) was dissolved in toluene (10 mL). To this solution was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro-methane complex (226 mg), 4-chlorophenyl-boronic acid (1.34 g, 8.3 mmol), and 2 N sodium carbonate solution (8.3 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature (RT) and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 0.81 g of the title compound as off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][N:5]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]=[C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[N:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:28][C:15]2=3)[CH2:7]1.O.[OH-].[Li+]>C1COCC1.O>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:5]([CH2:4][C:3]([OH:41])=[O:2])[CH:6]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[N:24][C:19]=4[CH2:18][O:17][C:16]4[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:28][C:15]3=4)[CH2:7]2)=[CH:39][CH:38]=1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(=O)O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2

Procedure:
To a solution of [(4-Chloro-benzyl)-(1-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-pyrrolidin-3-yl)-amino]-acetic acid methyl ester (116 mg, 0.2 mmol) in THF:H2O (4:1, 10 mL total volume) was added lithium hydroxide monohydrate (17 mg, 0.4 mmol). The resultant solution was stirred at rt for 3 h. The reaction solution was quenched with 1N HCl and extracted with ethyl ether, dried over MgSO4, filtered and concentrated. The final product was filtered through filter paper and re-concentrated. This product was submitted without further purification. LCMS (retention time=1.72, ES+562); 1H NMR (CD3OD): δ 8.48 (1H, d), 7.78 (1H, d), 7.48 (2H, m), 7.31 (5H, m), 6.76 (1H, d), 6.15 (1H, t), 3.85 (2H, dd), 3.60 (2H, m), 3.30 (7H, m), 3.24 (1H, s), 3.18 (1H, m), 3.06 (1H, m), 2.58 (1H, m), 2.48 (1H, t), 2.06 (2H, m), 1.50 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C([C@H]1C[C@@H]1c1ccc(Br)cc1)N1CCOCC1
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2C[C@@H]2CN2CCOCC2)cc1

Procedure:
Following the general procedure, reaction of 6e (4.20 g assayed, 13.55 mmol) with 1 M BH3 in THF (47.4 mL, 47.4 mmol) afforded 7e in an assay yield of 2.68 g (9.05 mmol, 67% assay yield, 100% peak area). A sample was concentrated in vacuo to an oil to provide the standard.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=O)[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:30]>P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:28][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:22]([Cl:23])[C:17]=1[N:5]1[C:6](=[N:8][CH:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[Cl:30])[CH:7]=[C:3]([C:1]#[N:2])[NH:4]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc(NC(=O)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: Cc1ccccc1
Product: N#Cc1cc(=NC(Cl)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 139 g (0.33 mol) of N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-5-yl]pyrazine-2-carboxamide, 72.6 g (0.35 mol) of phosphorus pentachloride, and 300 ml of toluene was heated under reflux for 2 hours. Further, 5 g of phosphorus pentachloride was added thereto, followed by heating under reflux for 1 hour. The mixture was cooled to room temperature and allowed to stand overnight. After stirring for 30 minutes, crystals were filtrated and washed with toluene. The crystals were dissolved in 1 L of chloroform and the solution was extracted after the addition of water. The organic layer was washed twice with water, and with saturated saline, and then, dried over anhydrous sodium sulfate. The solvent was removed by distillation and the resulting crystals were washed with hexane to obtain 112.3 g (yield 79%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylchloromethylimino)pyrazole-3-carbonitrile.
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18][CH:2]=[C:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: N#CCC(C#N)C=O
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Product: N#CCC(C#N)=CNC(c1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (7.26 g, 49.7 mmol) and 1-(4-fluorophenyl)-1-phenylmethaneamine (11.0 g, 54.7 mmol) in water-(20 ml) was added acetic acid (20 ml) at room temperature, the mixture was stirred at 100° C. for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic by adding potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc[nH]c(=O)c1C#N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 316.2 %

Procedure:
14 g (104 mmol) of 3-cyano-4-methylpyridone was slowly added to a mixture of 6.52 g (31.3 mmol) of phosphorus pentachloride and 30 ml (48 g, 313 mmol) of phosphorus oxychloride, followed by stirring at room temperature for 70 minutes and then under reflux with heating for 2 hours. After the reaction mixture was left to stand to cool, it was poured into ice water (400 ml) so that the surplus reagent was decomposed, followed by extraction with 100 ml of dichloromethane three times. The dichloromethane solution was washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.1 g of crude crystals of 2-chloro-3-cyano-4-methylpyridine. 1H-NMR (400 MHz, DMSO-d6): δ(ppm) 2.86 (s, 3H), 7.89 (d, J=5.6 Hz, 1H), 8.86 (d, J=5.6 Hz, 1H)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[N:8]([CH2:18][CH3:19])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)[CH3:19]
Reactant: CCOC(=O)c1cn(CC)c2ccc(I)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(I)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 106.4 %

Procedure:
1,4-Dihydro-1-ethyl-6-iodo-4-oxo-quinoline-3-carboxylic acid ethyl ester (7.5 g, 0.02 mol) was suspended in THF (75 mL), NaOH (2 equiv.) solution in water (75 mL) was added and the mixture was stirred at 80° C. for 24 hours. After THF was evaporated, the solution was acidified to pH 5 using HCl. The obtained precipitate was filtrated off and dried under reduced pressure yielding the title compound (7.3 g).
Reaction SMILES: [C:1]([C:3]([CH3:32])([CH3:31])[CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[N:18]=2)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=1)=[O:10])[CH:5]1[CH2:7][CH2:6]1)#[N:2].CC[OH:35]>O.[PtH]1([P](O[H]O[P]1(C)C)(C)C)[P](O)(C)C>[C:1]([C:3]([CH3:32])([CH3:31])[CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[N:18]=2)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:12]=1)=[O:10])[CH:5]1[CH2:6][CH2:7]1)(=[O:35])[NH2:2]
Reactant: CC(C)(C#N)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Reactant: CCO
Solvent: O
Product: CC(C)(C(N)=O)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide (163 mg, 0.36 mmol) in EtOH (9 mL) and H2O (1 mL) was added [PtH(PMe2OH)(PMe2O)2H] (15 mg, 0.036 mmol). The reaction mixture was heated at reflux for 6 h. Additional catalyst (10 mg, 0.023 mmol) was added and heating was continued overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes) to provide 108 mg (64%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide as a viscous colorless oil.
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C(OCC)(=O)C.O>CN(C=O)C>[C:18]([O:21][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])(=[O:20])[CH3:19]
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 86.8 %

Procedure:
A solution of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (1.0 g, 1 equivalent) and potassium acetate (0.6 g, 1.5 equivalents) in 5 mL of DMF was stirred at room temperature for 2 days. The solution was worked up with ethyl acetate and water to give a crude oil. The oil was purified by silica gel flash column chromatography to furnish 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate (0.95 g, 86% yield) as a paste. Compound 1067.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11])[CH3:16]
Reactant: O=C1CCc2ccccc2C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CCc2ccccc21

Procedure:
Heat 8.0 ml of 2-tetralone and 12.0 ml of dimethylformamide dimethyl acetal under reflux at 80° for 11/2 hours. Concentrate the reaction mixture in vacuo. Dissolve the residue in hot methanol, add charcoal, filter, and concentrate the filtrate in vacuo to give the title compound, an amber oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[O:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH:15]=2)[CH:10]=[CH:9]1)#[N:2].[NH3:27]>CO>[NH2:27]/[C:20](/[CH3:21])=[CH:19]\[C:18]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][O:6][C:5]2[CH:24]=[CH:25][CH:26]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(1-((3-cyanophenoxy)methyl)-1H-indol-6-yl)-3-oxobutanamide (1.04 g, 2.99 mmol), MeOH (20 mL) and ammonia (20 mL) was stirred at rt overnight. The mixture was concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.ClCCl>C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:9]([OH:12])[CH2:10][O:11][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 620 mg of tert-butyl[(1R,2R)-2,3-dihydroxy-1-phenylpropyl]carbamate, 0.37 g of tert-butyldimethylchlorosilane, 0.19 g of imidazole, and 9.3 ml of dichloromethane was stirred for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 705 mg of tert-butyl[(1R,2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:2]3[C@H:3]([CH2:7][NH:8][C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[C:15]5[O:19][CH:18]=[CH:17][C:16]=45)=[O:10])[CH2:4][C@H:5]4[C@@H:1]3[CH2:6]4)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1cccc(Cl)c1)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 3′-chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.46 min; [M+H]+=471.1.
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl.[CH3:18][O:19][C:20]1[C:21]([CH2:28]Cl)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>O.C(O)C>[C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:28][C:21]3[C:20]([O:19][CH3:18])=[C:25]([O:26][CH3:27])[CH:24]=[CH:23][N:22]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 6 h
Yield: 61.7 %

Procedure:
5-Acetyl-6-methyl-2-mercapto-1H-benzimidazole (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H2O (1 ml) were dissolved in 60 ml ethanol. 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H2O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, (3.75 g, 62%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[C:27]([NH2:28])=[CH:26][NH:25][N:24]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]=[C:15]1[C:23]1[C:27]([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:26][NH:25][N:24]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1cccc2cccnc12
Yield: 6.2 %

Procedure:
A mixture of quinoline-8-carboxylic acid (104 mg, 0.60 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) was stirred at room temperature in DMF (1.5 ml) for 20 h. The reaction mixture was purified by preparative LC/MS to give quinoline-8-carboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide (11 mg, 6%) as a brown solid. (LC/MS: Rt 3.85, [M+H]+ 355.11).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[Cl:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Cl:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1Cl)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC([C@H](N)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1Cl)C(F)(F)F
Reaction time: 3 h

Procedure:
3.19 g (5.87 mmol) of tert-butyl 3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorophenyl]propanoate (Example 34A, racemic diastereomer mixture) were dissolved in 50 ml of ethyl acetate. The solution was inertized with argon, and 125 mg of palladium on carbon (5%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen for 3 h. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→3:1) and the diastereomers were separated:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>ClC(Cl)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1
Reactant: Nc1ccncc1N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 98.2 %

Procedure:
A mixture of 3,4-diaminopyridine (1.1 g, 10.1 mmol), 1-benzyl-4-piperidone (3.2 g, 16.9 mmol) sodium triacetoxyborohydride (4.0 g, 18.9 mmol), and acetic acid (10.7 mL) in dichloroethane (10 mL) was stirred for about 6 days at room temperature. The reaction was concentrated to near dryness, and partitioned between chloroform (5×50 mL) and 1N sodium hydroxide (50 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 283 (M+1).
Reaction SMILES: Br[C:2]1[S:19][C:5]2[C:6](=[O:18])[N:7]([CH3:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][N:7]([CH3:17])[C:6](=[O:18])[C:5]3[S:19][C:2]([C:23]4[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=4)=[CH:3][C:4]2=3)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: CN1CC(c2ccc(Cl)cc2)c2cc(Br)sc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc2C1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
2-bromo-4-(4-chlorophenyl)-6-methyl-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.0400 g, 0.112 mmol) and pyridine-4-boronic acid (0.02575 g, 0.2095 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL). Cesium carbonate (0.1096 g, 0.3364 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.0111 g, 0.0134 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10.00 mL) and extracted with EtOAc (10.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified using preparative HPLC to afford the product (0.0080 g, 19.0%) as a white solid. LC/MS (AA) ES+ 355, 357, 358, 359. 1H NMR (DMSO, 400 MHz): δ 8.59-8.58 (2H, m), 7.69-7.67 (2H, m), 7.51 (1H, s), 7.44-7.42 (2H, m), 7.31-7.29 (2H, m), 5.00 (1H, J=6.40, Hz, t), 3.95-3.91 (1H, m), 3.71-3.66 (1H, m), 2.50 (3H, s).
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[S:10](Cl)(Cl)(=[O:12])=[O:11]>CCCCCC>[C:1]([NH:9][S:10]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])(=[O:12])=[O:11])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)NC(C)(C)CC(C)(C)C

Procedure:
The starting N,N'di-t-octylsulfamide is prepared from commercially available t-octylamine and sulfuryl chloride using either the method of Stowell (J. C. Stowell, J. Org. Chem. 32, p.2360, 1967) or of Timberlake (J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral and S. Syilagyi, J. Org. Chem. 46, p.2082-2089, 1981). The reaction is preferably run in hexane and the product isolated as a hexane solution. The hexane solution of the sulfamide can be concentrated prior to oxidizing the sulfamide or it can be concentrated during the oxidation.