Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.[H-].[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>O1CCCC1>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:3]2[C:4](=[O:7])[O:5][CH2:6][C:2]=2[OH:1])=[O:20])=[CH:16][CH:17]=1
Reactant: O=C1C=C(O)CO1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxy-2(5H)-furanone (1.47 g, 14.7 mmol) in tetrahydrofuran (30 ml) was slowly added at 0° C. to a suspension of sodium hydride (80% oil dispersion) (530 mg, 14.7 mmol) in tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 15 minutes, then a solution of 4-trifluoromethylphenyl isocyanate (2.75 g, 14.7 mmol) in tetrahydrofuran (20 ml) was added and the mixture stirred overnight at room temperature. At the end of the reaction, the insoluble product was filtered off and the solvent removed under reduced pressure. Crude product was suspended in water (60 ml) and methanol (6 ml) and the mixture acidified to pH 2 with concentrated HCl; the solid thus obtained was filtered and crystallised from acetone giving 1.75 g (41%) of pure N-(4-trifluoromethylphenyl)-4-hydroxy-2-oxo-(5H)-furan-3-carboxamide as a white solid. m.p.204-206° C. (dec.)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][O:19]C(=O)C)[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:23]=[N+:24]=[N-:25])(=[O:3])[CH3:2].CC(O)=O.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CO>[C:1]([O:4][C@H:5]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([CH2:18][O:19][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:11][C@H:7]([S:8][CH2:9][CH3:10])[C@H:6]1[N:23]=[N+:24]=[N-:25])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCS[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: CCS[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 22 (3.71 g, 9.88 mmol) in MeOH (30 mL) NaOMe (1 M) was added. The mixture was neutralized with AcOH after 1 h and concentrated. The dry residue was dissolved in pyridine (15 mL) and tert-butyldimethylsilyl chloride (1.94 g, 12.87 mmol) was added. The reaction mixture was stirred at rt overnight. Acetylation with acetic anhydride, dilution with toluene, filtration (silica), concentration and purification by chromatography (1:0→1:1 toluene-EtOAc) gave 23 (4.357 g, 9.73 mmol, 99%); [α]D+109° (c 1.0, CHCl3); 13C NMR δ −5.33, −5.28 (CH3Si), 14.7 (SCH2CH3), 18.4 ((CH3)3CSi), 20.7, 20.9 (CH3CO), 25.0 (SCH2CH3), 25.9 ((CH3)3CSi), 62.6, 62.9, 67.0, 71.7, 71.9 (C-2-6), 81.5 (C-1), 169.7, 170.1 (CH3CO); 1H NMR δ 0.05 (s, 3H), 0.05 (s, 3H), 0.90 (s, 9H), 1.30 (t, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.55-2.75 (m, 2H), 3.60-3.75 (m, 2H), 4.10 (m, 1H), 4.15-4.20 (m, 1H), 5.20-5.25 (m, 1H), 5.30-5.35 (m, 1H); HRMS calcd for C18H33N3NaO6SSi [M+Na]+ 470.1757, found 470.1750.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=O.[CH3:30][NH2:31]>CCO>[CH3:30][NH:31][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:2]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (15 mg, 0.039 mmol) and methylamine (1 mL, 2 M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. Solvent was evaporated in vacuo, and the residue was chromatographed (0-5% MeOH/CH2Cl2) to give 4.9 mg of the title compound as a pale yellow solid. MS: (+) m/z 386.21 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:22])[C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:22])[C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)=[O:18]
Reactant: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
A mixture of 120 mg of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoic acid, 87 mg of 4-nitrobenzyl bromide and 139 mg of potassium carbonate in 3 ml of dimethylformamide was stirred at 0° C. for 4 hours. The solvent was evaporated in vacuo, and the residue was triturated with a mixture of methylene chloride and saturated sodium bicarbonate solution. The unsoluble material was isolated by filtration to yield 190 mg of p-nitrobenzyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-hydroxy-2-methylbenzoate, m.p. 210°-244° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C(#N)C>[CH3:21][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1)=[O:33])[CH3:20]
Reactant: CCCCCCCCCCCCc1cc(N)on1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Product: CCCCCCCCCCCCc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)on1
Temperature: -20 °C
Yield: 20.4 %

Procedure:
A slurry of 5-amino-3-dodecylisoxazole (1.44 g, 5.71 mmol) in acetonitrile (50 mL) was warmed until homogeneous. 2,6-Diisopropylphenylisocyanate (1.22 mL, 5.71 mmol) was then added in one portion and the resulting solution was heated under reflux for 24 hours. The resulting solution was cooled to -20° C. The resulting precipitate was collected by filtration, dissolved in a minimal amount of warm chloroform, and chromatographed on silica (70:30 hexane:ethyl acetate). The product containing fractions were concentrated and the resulting solid was recrystallized from acetonitrile to yield 0.53 g (20.4%) of the title compound as white needles, m.p. 112.5°-114° C.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[O:15])=[O:7])(C)(C)C>C(O)=O>[CH:6]([OH:7])=[O:5].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cc(C(=O)NCCC(=O)O)cc([N+](=O)[O-])c1
Solvent: O=CO
Product: NCCCCCC(=O)Nc1cc(C(=O)NCCC(=O)O)cc([N+](=O)[O-])c1
Yield: 80.3 %

Procedure:
807 mg of N-[3-[6-(1-t-butoxyformamido)hexanamido]-5-nitrobenzoyl]-β-alanine are left to stand at room temperature in 2.7 ml of formic acid for 18 hours. The solvent is evaporated in a vacuum. The residue is dissolved in water and the solution is evaporated in a vacuum. There are obtained 573 mg of N-[3-(6-aminohexanamido)-5-nitrobenzoyl]-β-alanine formate (2:1), MS: 367 (67, M+H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([C@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([C@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnn([C@H]2CCOC2)c1
Product: C[C@@H](c1ccc(-c2cnn([C@H]3CCOC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 37 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(S)-tetrahydro-furan-3-yl]-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 37% of theory; LC (method 3): tR=3.16 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[NH2:10].[CH2:11]([N:13]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1)[CH3:12]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:10]=[C:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:11][CH3:12])[CH:17]=1)[N:8]2[CH3:9]
Reactant: CNc1ncnc(Cl)c1N
Reactant: CCn1cc(C=O)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 103 %

Procedure:
To a solution of 6-chloro-N4-methylpyrimidine-4,5-diamine (300 mg, 1.9 mmol) in anhydrous DMF (8 mL) were added 1-ethyl-1H-pyrazole-4-carbaldehyde (236 mg, 1.9 mmol) and Iron (III) chloride hexahydrate (0.51 g, 1.9 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (20 g). The resulting precipitate was collected by vacuum filtration, and triturated with 10 mL of ethanol at 50° C. for 30 min. The solids were collected by vacuum filtration to give 514 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, 2H), 8.19 (s, 1H), 4.25 (q, 2H), 3.95 (s, 3H), 1.43 (t, 3H); MS (EI) for C11H11ClN6: 263.3 (MH+).
Reaction SMILES: [SH:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([S:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(S)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC(C)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 31.3 %

Procedure:
3-[(3-Mercapto-2-benzylbutanoyl)amino]benzoic acid (compound of Example 194) (1.7 g) is suspended in dichloromethane (17 ml), and thereto is added triethylamine (0.52 g)with stirring under ice cooling. To the mixture are further added dropwise acetyl chloride (0.51 g) and triethylamine (0.52 g) simultaneously, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then dichloromethane is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC=CC=1>O>[CH:9](=[N:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC1C=CCCCC1
Solvent: c1ccccc1
Solvent: O
Product: C1=CC(N=Cc2ccccc2)CCCC1
Yield: 83.8 %

Procedure:
A mixture of 2-cycloheptenylamine (11.1 g, 0.1 mole), benzaldehyde (10.6 g, 0.1 mole) and benzene (50 ml) was heated under reflux, and resulting water was removed by azeotropic distillation. The mixture was concentrated to obtain 16.7 g of N-benzylidene-2-cycloheptenylamine [Compound (280)].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-n2nccn2)c1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A89 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.45 (m, 8H), 4.90-2.70 (m, 5H), 2.35-0.65 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:22]([C:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[S:17][C:13]=1[CH2:11][CH3:12])(=[O:23])=[O:24]
Reactant: CCc1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-ethylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.31 g) and THF (7 ml). Recrystallization from chloroform and hexanes provided 0.24 g (60%) of a tan crystalline solid, m.p. 118.5-120° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(Br)ccc(OC(F)F)c1OC
Temperature: 70 °C
Yield: 45.5 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (500 mg, 1.858 mmol) in acetonitrile (20 mL) was added potassium carbonate (769 mg, 5.57 mmol) and ethyl 2-bromoacetate (568 mg, 3.71 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of Ethyl 2-(6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)acetate as solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:5]=2[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Reactant: OB(O)c1ccccc1F
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1n[nH]c2c(-c3ccccc3F)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (150 mg), 2-fluorophenylboronic acid (93 mg), tetrakis(triphenylphosphine)palladium(0) (51 mg), potassium carbonate (122 mg), 1,2-dimethoxyethane (5.0 mL) and water (0.5 mL) was stirred overnight at 90° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (38.3 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25][C:26](=[O:28])[CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([O:24][CH2:23][C@@:20]23[C@@H:19]4[C@H:10]([C@H:11]5[C@@:15]([CH2:17][CH2:18]4)([CH3:16])[C@@H:14]([O:25][C:26](=[O:28])[CH3:27])[CH2:13][CH2:12]5)[CH2:9][CH:8]=[C:7]2[CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Reaction time: 96 h

Procedure:
To a solution of 3β,17β-diacetoxy-19-hydroxyandrost-5-ene (14.4g) in pyridine (370ml) at 25° is added p-toluenesulfonyl chloride (38.1g) and the solution is left at 25° for 4 days. Water is then added, and the mixture is extracted with ethyl acetate, and the organic extract is washed successively with water, 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and water, and then dried (Na2SO4) and evaporated in vacuo. The residue is crystallized from methylene chloride-hexane to give the compound of this Example (11), mp. 135°-137°; mass spectrum m/e 484, 372, 312.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](Cl)=[O:23])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22]([O:8][C@@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:23])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Example 2) and pyridine (0.18 kg, 2.28 mol) stirring at 65° C. The reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25° C. and stirred for a 14 hours. The solution was diluted with toluene (16 kg), washed with 5% is aqueous sodium chloride (6.4 kg), then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]3[N:17]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][F:26])=[N:19][C:15]=3[CH:14]=[C:13]([C:35]#[N:36])[N:12]=2)[CH:8]=[N:9][CH:10]=1>CO>[CH3:1][O:2][C:35]([C:13]1[N:12]=[C:11]([C:7]2[CH:8]=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)[C:16]2[N:17]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][F:26])=[N:19][C:15]=2[CH:14]=1)=[NH:36]
Reactant: C[O-]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (5.20 mg, 0.096 mmol) was added to a solution of 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.1, Step 1; 150 mg, 0.321 mmol) in methanol (321 μL), and the vial was sealed and allowed to stir at ambient temperature overnight. The reaction was concentrated to afford crude methyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate. MS ESI calc'd. for C26H32ClFN6O [M+H]+ 499. found 499. This material was taken on to Step 2 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: Oc1cc(F)ccc1Br
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 2-bromo-5-fluorophenol (1.46 g, 7.64 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.94 mL, 9.17 mmol, 1.2 equiv), and PPh3 (2.40 g, 9.17 mmol, 1.2 equiv) in THF (26 mL) was added DIAD (1.78 mL, 9.17 mmol, 1.2 equiv). After stirring 2 h, the yellow solution was diluted with ether, washed with 1 N NaOH, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (hexane) to provide the product (1.18 g, 60%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J=8.7, 6.3 Hz, 1H), 6.67 (dd, J=10.6, 2.8 Hz, 1H), 6.62-6.56 (m, 1H), 5.91 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.22-5.12 (m, 2H), 4.49-4.38 (m, 1H), 2.62-2.52 (m, 1H), 2.49-2.40 (m, 1H), 1.39 (d, J=6.1 Hz, 3H).