Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])[CH3:7].[I-].[CH3:20][N:21]1[C:29]2[C:24](=[C:25]([CH3:30])[CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:31][N+](C)(C)C)=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:31][CH:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[N:21]([CH3:20])[CH2:22]2)[C:9]1=[O:17])[CH3:7]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)CCC(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a mixture of 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid methyl ester (85 mg, 0.34 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (175 mg, 0.51 mmol) in DMF (2.5 mL) was added K2CO3 (95 mg, 0.69 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 25% EtOAc in Hexane as the eluent to afford the desired 4-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester (120 mg, 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 200 ml tetrahydrofuran were added dropwise 35 ml (315 mmol) 1-methylpiperazine within 10 min. The reaction mixture was refluxed for additional 1.5 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.9 g (quantitative) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C>O1CCCC1>[C:29]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:12]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])=[N:13]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.41 g) in tetrahydrofuran (10 mL) were added acetic acid (0.11 mL) and acetic anhydride (0.18 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The resulting precipitated crystal was collected by filtration to give 1-acetyl-4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.36 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][C:22]=1[CH3:23]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:26])[CH2:25][C:10]([C:4]2[CH:3]=[C:2]([Br:1])[C:7]([F:8])=[C:6]([Br:9])[CH:5]=2)([OH:15])[C:11]([F:14])([F:12])[F:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: CC(=O)c1ccc(C)c(Cl)c1
Reactant: O=C(c1cc(Br)c(F)c(Br)c1)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)CC(O)(c2cc(Br)c(F)c(Br)c2)C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(3,5-dibromo-4-fluorophenyl)-2,2,2-trifluoroethanone (0.99 g) and 1-(3-chloro-4-methylphenyl)ethanone (0.48 g) in ethyl acetate (3 mL) was added dithylamine (0.062 g). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by liquid chromatography (medium pressure collection apparatus: Purif-α2 manufactured by Moritex Corporation) eluted with ethyl acetate-hexane (1:10) to afford the title compound as a pale yellow oil (1.40 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:10][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60% dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. After about 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After about 16 h, the reaction mixture was poured onto ice-cold water (120 mL) and the precipitate was collected by vacuum filtration. The crude solid was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with DCM. The product-containing fractions were concentrated under reduced pressure to give 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 2, Method d) Rt=1.58 min; MS m/z: 352/354 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.O[C:7]12[CH2:16]C3CC([CH2:15][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)[CH2:14]2.[H-].[K+].CI>CCOC(C)=O>[CH3:3][O:4][C:5]12[CH2:1][CH:2]3[CH2:16][CH:7]([CH2:8][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]1)[CH2:14]2
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(O)(C3)C2
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5-hydroxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-6 (0.15 g, 0.5 mmol). Potassium hydride (47 mg, 1.1 mmol) was added to this mixture at 0° C., under N2 atm. The reaction mixture was then stirred at room temperature for 30 minutes. Methyl iodide was slowly added (0.12 g, 0.8 mmol) at 0° C. and the resulting reaction mass was refluxed at 60° C. under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with ethyl acetate (25 ml×3). The organic layer was washed with sodium chloride solution, was dried over anhydrous sodium sulfate and was concentrated to give crude Intermediate-17, which was subjected to column chromatogram (22% EtOAc in PE) to obtain an oily mass (0.1 g, yield=70%).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C(O)C.O>[CH:1]1([CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
A solution comprised of diethyl 2-cyclohexylmethylmalonate (12.817 g, 50 mmol) in ethanol (100 mL) was treated with a solution of comprised of lithium hydroxide (1.198 g, 50 mmol) in water (50 mL) and the mixture was stirred for approximately 12 hours at ambient temperature. Solvent was removed by evaporation and the residue was diluted with water (50 mL). The dilution was extracted with diethyl ether (2×). The aqueous layer was cooled to 0° C., acidified to pH 1.5 with 1N hydrochloric acid (50 mL), saturated with solid sodium chloride and then extracted with ethyl acetate (2×). The combined ethyl acetate extracts were dried (MgSO4) and concentrated. The residue was dried to provide 3-cyclohexyl-2-ethoxycarbonylpropionic acid (8.52 g, 37 mmol) as an oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:39][O:40][C:41]1[N:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=1>C1COCC1>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:45][N:46]=1
Reactant: COc1ccc(CO)cn1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
According to Scheme 16 Method A: Phenol (1.5 eq, 2.80 mmol, 0.26 g), PPh3 (2 eq, 3.70 mmol, 1.20 g) and DEAD (2 eq, 3.70 mmol, 1.60 g) were added to a solution of (6-methoxypyridin-3-yl)methanol (1 eq, 1.87 mmol, 0.26 g) in THF (6 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the reaction mixture was diluted with water. The organic layer washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 85/15 to afford 2-methoxy-5-(phenoxymethyl)pyridine (0.93 mmol, 0.20 g, 49%) as a pale oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][C:16](C)([O-:18])C.[Na+].C(OCC)(=O)C.Cl>C(OC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:16]([CH3:15])=[O:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccccc1OC
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)c1ccccc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 2-methoxyphenyiacetate (11.6 g), sodium tert-butoxide (12.7 g) and ethyl acetate (15.8 g) in diisopropylether was heated at 70° C. for 2.5 hours and stirred at room temperature overnight. Ethyl acetate and hydrochloric acid (2M) were added and the organic phase dried (magnesium sulphate) and evaporated. The residue was distilled in vacuo to give ethyl 2-(2-methoxyphenyl)acetoacetate as a liquid (8.5 g), NMR 1.15 and 1.13(t,3h), 1.8 and 2.2(s,3H), 3.75 and 3.85(s,3H), 4.1-4.3(2q,2H), 5.15(s,1H), 6.9-7.3(m,4H), 13.1(s,1H).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([NH:15][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCC2OC2C1
Reactant: NCc1ccccc1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1NCc1ccccc1

Procedure:
A mixture of cyclohexene oxide (1) (19 mL, 0.2 mol, Aldrich cat #C10, 280-4) and benzylamine (27) (21 mL, 0.2 mol, Aldrich cat #407712) in water (5 mL) was refluxed for 3 hours. The cooled reaction mixture was partitioned between 4M aq NaOH (100 mL) and methyl t-butyl ether (150 mL). The aqueous layer was further extracted with methyl t-butyl ether (2×100 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give trans-2-benzylaminocyclohexan-1-ol (28) as a low melting point solid (39.4 g, 96% yield);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:21])[C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2
Reactant: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole (Example 86, 276 mg, 1.12 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (120 mg, 3.0 mmol) and the suspension is stirred for 30 min. Iodomethane (213 mg, 1.5 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Water (2 mL) is added to quench the reaction. The mixture is filtered and purified by HPLC using Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)NC1CCCNCC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCCC(N)CC5)n4)n[nH]c3cn2)cn1
Yield: 47.1 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl azepan-4-ylcarbamate were reacted. The product was deprotected to give 188 as a white solid (47.1% over two steps). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.02-3.86 (m, 4H), 3.85-3.75 (m, 1H), 3.75-3.55 (m, 3H), 2.93-2.85 (s, 1H), 2.10-1.93 (m, 2H), 1.89-1.56 (m, 3H), 1.45-1.31 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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>[OH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Oc1ccccc1
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: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2O)s1
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.12 mmol) is added to a solution of 5-bromothiophene-2-carboxylic acid (850 mg, 4.1 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes and then 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl) phenol (1 g, 4.6 mmol) is added followed by aqueous Na2CO3 (2M, 6.9 mL). The mixture is heated at reflux overnight. The reaction mixture is allowed to cool, poured into water (50 mL), and washed with ether (3×50 mL). The aqueous layer is acidified with concentrated HCl to pH<2. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to yield the desired product (761 mg, 83%). MS for C11H7O3S (ESI) (M−H)+ m/z 219.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].O>C(O)C>[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OCC(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(OCC(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution (2 mL) of the compound (24 mg, 0.058 mmol) obtained in Example 38d in ethanol was added 2N aqueous sodium hydroxide solution (0.12 ml, 0.24 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (11 mg, 49%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:27].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:27][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:41])([F:40])[F:42]
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (100 mg, 0.27 mmol) in anhydrous DMF(15 mL) under a N2 atmosphere containing, at 0° C., sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol) was added. The mixture was allowed to stir at 0° C. for 30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O (1×15 mL), brine (1×15 mL), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to yield {4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone as off-white crystals.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3cccc(F)c3)c2O1

Procedure:
The title compound was prepared (0.38 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 160-163° C.
Reaction SMILES: [CH3:1][C:2]1([C:10]([CH3:12])=[CH2:11])[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]1=[O:9].[CH:13](=[N:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:13]([N:17]1[CH:18]([CH2:19][CH2:20][CH3:21])[CH2:12][C:10]([CH3:11])=[C:2]([CH3:1])[CH2:7][CH2:6][C@H:5]([CH3:8])[CH2:4][C:3]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=NCCCC
Reactant: C=C(C)C1(C)CCC(C)CC1=O
Agent: CCCCN1C(=O)C[C@@H](C)CC/C(C)=C(\C)CC1CCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCN1C(=O)C[C@@H](C)CCC(C)=C(C)CC1CCC

Procedure:
Following the general procedure as described in Example 17, 2,5-dimethyl-2-(prop-1-en-2-yl)cyclohexanone (1.06 g, 6.38 mmol), N-butylidenebutan-1-amine (0.97 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.28 g, 76% yield). 3 isomers in a ratio of 1:2:8.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:30][C:31]=1[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:24][CH2:25][C:26]2[C:31]([CH3:32])=[N:30][C:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[CH:28][CH:27]=2)=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (516 mg, 1.5 mmol), as prepared in step 15 of Example 1, in DMF (8.0 mL) was added N-[5-(aminomethyl)-6-methyl (2-pyridyl)](tert-butoxy) carboxamide (498 mg, 2.1 mmol) (Sanderson, P. E., et al., WO 97/01338 (1997)), BOP (1.06 g, 2.4 mmol), and DIEA (0.78 mL, 4.5 mmol). After stirring for 18 hours, additional amine (107 mg, 450 μmol) was added, and the mixture continued to stir for 18 hours. The solvents were evaporated, and the reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4 (2 times), H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1.5, and 2.5%) to give the title compound (770 mg, 91% yield) as a pale brown foam. 1H-NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.4 Hz, 1H), 7.51-7.41 (m, 6H), 7.23 (bs, 1H), 7.01 (dd, J=8.8, 1.5 Hz, 1H), 6.57 (t, J=9.0 Hz, 1H), 5.64 (br s, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.26-4.22 (m, 1H), 3.79-3.70 (m, 4H), 2.35 (s, 3), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C28H31ClF3N4O3 (M+H): 563.2. Found: 562.9.