Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH:22]=[C:21]([CH3:35])[N:20]=3)[S:17][CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:35][C:21]1[N:20]=[C:19]([C:16]2[S:17][CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=2)[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=2)[CH:22]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)cs2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(S(N)(=O)=O)s3)cs2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To 5-{2-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-thiazol-4-yl}-thiophene-2-sulfonic acid tert-butylamide (example 324) (0.100 g, 0.186 mmol) was added TFA (10 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.075 g, 83%). MS (ISP) 482.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:7]=1.[N:19]1([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:24][CH2:23]2)[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=1
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: COc1ccccc1-c1nc(Cl)c2sccc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)c2sccc2n1
Yield: 47.8 %

Procedure:
A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperazine-1-carboxylate (0.10 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.11 g, 55% yield). LC/MS: m/z 427.5 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]#[N:18])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+].[H][H]>[Co].O1CCCC1>[NH2:18][CH2:17][C:6]1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: [H][H]
Reactant: CC(C)Cn1c(C#N)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: [Co]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of 6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (16.0 g), sponge cobalt (manufactured by Kawaken Fine Chemicals Co., Ltd.; trademark: ODHT-60) (4 ml), 25% ammonium hydroxide (2 ml) and tetrahydrofuran. (80 ml) was stirred at 60° C. at a 1 MPa hydrogen pressure for 4 h and the catalyst was filtered off. The solvent was evaporated and acetonitrile (48 ml) was added to the residue. The mixture was heated to about 70° C. The obtained solution was cooled to 25° C. to give crystals, and water (80 ml) was added dropwise. The obtained mixture was cooled to around 5° C. and the mixture was stirred for 1 h. The precipitated crystals were collected by filtration to give the title compound (14.8 g, yield 91.4%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.C(N(CC)CC)C.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:2][CH:1]=1
Reactant: Nc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of p-phenylenediamine (16.2 g) and triethylamine (20.8 ml) in DMF (80 ml) was added di-tert-butyl carbonate (34.4 ml). The reaction mixture was stirred at room temperature for 8 hr and diluted with ethyl acetate. The ethyl acetate solution was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=4/1 to ethyl acetate), and the resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (29.2 g, 95%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][C@:14]1([C:30]([O:32][CH3:33])=[O:31])[CH2:24][C@@H:23]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C@@H:17]2[O:18]C(C)(C)[O:20][C@@H:16]2[CH2:15]1>CO>[OH:13][C@:14]1([C:30]([O:32][CH3:33])=[O:31])[CH2:24][C@@H:23]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])[C@H:17]([OH:18])[C@H:16]([OH:20])[CH2:15]1
Reactant: COC(=O)[C@]1(O)C[C@H]2OC(C)(C)O[C@H]2[C@H](OS(C)(=O)=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](OS(C)(=O)=O)C1
Reaction time: 8 h
Yield: 78 %

Procedure:
Para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) was added to a room temperature solution of Example 17A in methanol (50 mL). After stirring overnight, the reaction mixture was concentrated and the concentrate was purified by flash column chromatography using ethyl acetate to afford 3.96 g (78%) of the desired product as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]([OH:18])=[O:17].[CH3:19]O>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 98 %

Procedure:
Concentrated sulfuric acid (1 mL) was added to a suspension of 5-bromo-1H-indazole-3-carboxylic acid (CXV) (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The solution was cooled to room temperature and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) as a white solid (1.35 g, 5.29 mmol, 98% yield). 1H NMR (DMSO-d6) δ ppm 14.13 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.59 (dd, J=7.2, 1.2 Hz, 1H), 3.92 (s, 3H); ESIMS found for C9H7BrN2O2 m/z 256.0 (M+H).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:12][CH:13]=1)([O-:7])=[O:6].[CH3:21][C:22]([CH3:24])=O.C([BH3-])#N.[Na+]>CO>[CH:22]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=2)[CH2:16][CH2:17]1)([CH3:24])[CH3:21]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10% acetic acid in methanol was added 5-nitro-2-(piperidin-4-yloxy)pyridine (1 eq) and anhydrous acetone (5 eq). The solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. on an ice bath and sodium cyanoborohydride (1.5 eq) was added. The reaction mixture was then warmed to room temperature and stirred for 5 hours. The solvent was evaporated, the residue brought to pH=10 with sodium carbonate and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, and evaporated to give the crude material. Purification by silica gel column chromatography using 2% methanol/dichloromethane afforded the product as a yellow solid. LC/MS (m/z): 266.3 (MH+), Rt 1.85 minutes.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([NH:29]C(=O)C)([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH2:12]1)C(OCC)=O)C.Cl>CO>[NH2:29][CH:5]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH2:12]1)[C:4]([OH:33])=[O:3]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Agent: Cl
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CCC(C(N)C(=O)O)C2
Reaction time: 2 h

Procedure:
Compound 6 (300 mg, 0.65 mmol) was added to 12 M HCl (10 ml). The mixture was heated to reflux and MeOH (5 ml) was added until the mixture became homogenous. Reflux was continued for 2 hours until the starting material was consumed as determined by thin layer chromatography (TLC). The reaction mixture was concentrated under reduced pressure and co-evaporated with MeOH and diethyl ether multiple times. The desired compound 8 was recrystallized from diethyl ether and hexanes to provide a light brown solid and used directly for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromo-2-methoxybenzaldehyde (1.90 g, 8.84 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.0 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.66 g (86% yield) of tert-butyl 4-[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 385 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:16])[CH2:6][CH2:5]2
Reactant: COCCN
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 370 mg CDI (2.28 mmol) and 165.2 mg 2-methoxyethylamine (2.20 mmol) produced 6-hydroxy-N-(2-methoxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[CH3:33]OC(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)S(C1C=CC(F)=CC=1/C=C\CO)(=O)=O)=O.N1CCC1>>[N:3]1([CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:33][CH2:2][CH2:1]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: C1CNC1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCC2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and azetidine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)(=[O:33])=[O:32])[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: CC1(C)C=Cc2cc(CNc3ccccc3)cnc2O1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2cnc3c(c2)C=CC(C)(C)O3)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 19a (20 mg, 0.075 mmol) in DCM (1 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (36 mg, 0.150 mmol) and triethylamine (0.021 mL, 0.150 mmol). The reaction was stirred for 24 hours at room temperature. The reaction mixture was washed with water (×2) and the organic layer dried over MgSO4 and concentrated in vacuo. Column chromatography (2:1 hexane/EtOAc) gave a white solid (?? g). Yield: 43%. 1H NMR (CDCl3): δ 1.47 (s, 6H), 3.76 (s, 3H), 3.97 (s, 3H), 4.60 (s, 2H), 5.66 (d, 1H, J=9.6), 6.26 (d, 1H, J=10), 6.93-6.99 (m, 4H), 7.23-7.25 (m, 3H), 7.32-7.36 (m, 2H), 7.63 ppm (d, 1H, J=2.4). HRMS (ESI) m/z calcd for C25H25N2O5S [M+H)+] 467.1641. found: 467.1636. HPLC: ret. time=7.5 min, 99.0%
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>C(Cl)Cl>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:3]1
Reactant: OC1CCNC1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC(O)C1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 3-hydroxypyrrolidine (0.35 g, 4.02 mmol) and Et3N (1.16 mL, 8.04 mmol) in CH2Cl2 (20 mL) was added allyl chloroformate (0.47 mL, 4.43 mmol) at 0° C. The mixture was kept at 0° C. for 0.5 hr and more CH2Cl2 was added. It was then washed with 5% NaHCO3, water and brine, dried over Na2SO4 and concentrated to give the product (0.34 g) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:46][CH:47]([F:50])[CH2:48][NH2:49]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:49][CH2:48][CH:47]([F:50])[F:46])=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: NCC(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NCC(F)F)c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-2,5-difluorobenzoic acid (1.28 g, 6.64 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.07 g, 8.07 mmol) in 1,2-dichloroethane (20 mL) was stirred for 10 min. at room temperature prior to the addition of a solution of 2,2-difluoroethanamine (538 mg, 6.64 mmol) in dichloroethane (2 mL). The resulting solution was stirred for 1 h. at room temperature. LCMS data indicated that the major reaction component was the desired product. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=256.0.
Reaction SMILES: [N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:23]=[CH:22][C:10]3[NH:11][C:12]([CH:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[OH:15])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(O)(=O)C.[OH-].[NH4+]>O>[N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:23]=[CH:22][C:10]3[NH:11][C:12]([C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:15])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(c1ccccc1)c1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)c1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
A mixture of 1.5 parts of 5-[(1H-imidazol-1-yl)phenylmethyl]-α-phenyl-1H-benzimidazole-2-methanol, 1.4 parts of potassium dichromate and 25 parts of acetic acid was stirred for 45 minutes at room temperature. Water was added to the mixture and the whole was made alkaline with concentrated ammonium hydroxide. The product was extracted with a mixture of trichloromethane and methanol (95:5 by volume). The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 63 parts of ethyl acetate. The product was filtered off and dried in vacuo at 100° C. during 17 hours, yielding 0.8 parts (54%) of [5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazol-2-yl] phenylmethanone; mp. 223.3° C. (compound 264).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH2:11]1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCC(N2CCCC2)CC1
Agent: Cl
Product: O=C(CN1CCC(N2CCCC2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(pyrrolidin-1-yl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 43, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(pyrrolidin-1-yl)piperidin-1-yl)acetamido)propanamide (22.1 mg, 48.1%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.96 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (m, 2H), 7.01 (m, 4H), 4.68 (m, 1H), 4.52 (s, 2H), 3.75 (m, 2H), 3.25 (m, 2H), 2.95 (s, 2H), 2.83 (m, 2H), 2.09 (t, 2H), 2.00 (m, 1H), 1.79 (m, 2H), 1.68 (m, 5H), 1.44 (m, 2H). MS (EI) for C33H39FN4O4: 575.8 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13]([F:19])[C:12]=1[Cl:20])C1C=CC=CC=1>[Pd].C1COCC1>[Cl:20][C:12]1[C:13]([F:19])=[N:14][C:15]([F:18])=[C:16]([F:17])[C:11]=1[CH2:10][C:9]([OH:21])=[O:8]
Reactant: O=C(Cc1c(F)c(F)nc(F)c1Cl)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)Cc1c(F)c(F)nc(F)c1Cl
Reaction time: 4 h
Yield: 78.2 %

Procedure:
A mixture of (3-chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl ester (29 g, 91.86 mmol), anhydrous THF (180 ml), and 10% palladium on carbon (1 g) was stirred for 4 hr. at room temperature under hydrogen atmosphere. The reaction mixture was then filtered through celite pad and the pad was washed with ethanol. The combined filtrate was evaporated in vacuo and the residue was recrystallized from dichloromethane to afford 16.2 g (78%) of (3-chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid as a white solid. m.p. 127-129° C.: 1H NMR (200 MHz, CDCl3) δ 3.97 (2H, d, J=1.6 Hz), 8.50 (1H, br. s).
Reaction SMILES: [CH2:1]([N:3]1[C:7](O)=[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5]([CH3:17])=[N:4]1)[CH3:2].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:17])[C:6]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1Cl

Procedure:
A solution of 2.6 g of (1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone in 4 ml of phosphorus oxychloride was stirred at 80° C. for 1.5 h. The mixture was poured into 300 ml of saturated sodium hydrogen carbonate and extracted three times with 70 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40-60° C.) (1:4) for the elution to give 1.74 g of (5-chloro-1-ethyl-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone as a pale yellow liquid. Mass spectrum (ES) m/z 249 [M+H]+, 290 [M+H+CH3CN]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:21])[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:8](=O)[CH3:9])#[N:2].[NH2:22]/[C:23](/[CH3:35])=[CH:24]\[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CCO>[CH2:28]([O:27][C:25]([C:24]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:21])=[C:8]([CH3:9])[NH:22][C:23]=1[CH3:35])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C/C(N)=C/C(=O)OCc1ccccc1
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Solvent: CCO
Product: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester (15.06 g, 52.3 mmol) and benzyl 3-amino-crotonate (10.00 g, 52.3 mmol) in 150 ml of EtOH was refluxed for 36 hrs. After solvent was evaporated, the residue was dissolved in 250 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine was obtained as a yellow oil (23.4 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O-])=[O:11])=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:10][OH:11])=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1
Reactant: CC(C)c1nc(Cl)sc1C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1nc(Cl)sc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a mixture of 8.0 g (0.034 mol) of ethyl, 2-chloro-4-isopropyl-5-thiazolecarboxylate and 20 ml of ethanol was added 1.3 g (0.034 mol) of sodium borohydride in 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was chromatographed on 250 g of silica gel using ether petroleum ether (1:9, v/v) as eluant. The first fraction (2.2 g) was recovered starting material. The second fraction (3.4 g) was Kugelrohr distilled at 0.5 mm (pot temperature 95° C.) go give 2.7 g (40%) of 2-chloro-4-isopropyl-5-thiazolemethanol as a colorless liquid, nD25 1.5425.