Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[CH3:18][C:19]12[CH2:29][C:23]3([OH:30])[CH2:24][C:25]([OH:28])([CH2:27][C:21]([CH3:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[CH3:31][C:21]12[CH2:27][C:25]3([OH:28])[CH2:24][C:23]([O:30][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:29][C:19]([CH3:18])([CH2:26]3)[CH2:20]1)[CH2:22]2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: CC12CC3(C)CC(O)(C1)CC(O)(C2)C3
Product: C=CC(=O)OC12CC3(C)CC(C)(CC(O)(C3)C1)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1,3-dimethyl-5,7-dihydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1,3-dimethyl-5-hydroxy-7-acryloyloxyadamantane (yield: 87%, white solid) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:7]=1Cl)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([C:30]([N:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Yield: 93.9 %

Procedure:
The compound of step 9 (1.880 g, 2.96 mmol) in 29.6 ml of ethanol/THF (1:1) was hydrogenated under a hydrogen pressure of 2 bar for 3.5 h at room temperature in the presence of 0.315 g of 10% palladium on charcoal and triethylamine (0.62 ml, 4.44 mmol). The catalyst was filtered off and the filtrate was washed with brine (50 ml), dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 1.67 g of the title compound were obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[O:31]1[CH:32]=[CH:33][C:29]([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:24]=2)=[O:28])=[CH:30]1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)cc1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.19 min, MH− 428. NMR: δH [2H6]-DMSO 10.38,(1H, s), 10.00,(1H, s), 9.19,(1H, s), 8.38,(2H, m), 7.83,(1H, s), 7.80,(1H, s), 7.76,(1H, s), 7.73-7.69,(3H, m), 7.32,(1H, s), 7.01,(1H, s), 6.96,(2H, d), 3.76,(3H, s), 2.34,(3H, s).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])=[N:5][C:4]=1[I:30])[CH3:2].[OH-].[Li+]>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH2:13][C@H:12]2[O:28][CH3:29])=[O:9])=[N:5][C:4]=1[I:30])[CH3:2]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(I)c(CC)[nH]3)[C@H](OC)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1I
Yield: 32.7 %

Procedure:
The same operation as in Example (1i) was performed using ethyl cis(±)-2-(4-{[(5-ethyl-4-iodo-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (58d) (130 mg, 0.24 mmol) and 2 N lithium hydroxide (3 mL), to obtain 40.7 mg of the title compound as a pale red solid (32%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][OH:33])[CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][OH:33])[CH2:27]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: OCC1CCCNC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCCC(CO)C1

Procedure:
5-(3-Hydroxymethyl-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-piperidinemethanol. Mass spectrum (ES) MH+=435.
Reaction SMILES: [CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[C:16]([O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.N.[OH:31]O>CO.C(Cl)Cl>[CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]([NH2:20])=[O:31])[C:16]([O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: OO
Reactant: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C#N)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C(N)=O)cc1
Reaction time: 1.5 h
Yield: 26 %

Procedure:
A mixture of 6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile (171.0 mg), 28% aq. NH3 (5 mL), and 30% aq. H2O2 (1.0 mL) in MeOH (4.0 mL) was stirred for 1.5 h. The mixture was diluted with DCM and washed with satd. aq. Na2S2O3. The organic layer was dried and concentrated. The residue was purified by reverse-phase HPLC followed by FCC to give the title compound (46.4 mg, 26%). MS (ESI): mass calcd. for C22H26N4O3S, 426.17; m/z found, 427.8 [M+H]+. 1H NMR (d6-acetone): 7.74-7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (br s, 1H), 7.51-7.49 (dd, J=8.5, 1.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.82 (br s, 1H), 3.71-3.68 (m, 2H), 3.65-3.61 (m, 2H), 2.93-2.88 (m, 2H), 2.85-2.80 (m, 2H), 2.49 (s, 3H), 1.96-1.80 (m, 3H), 0.46-0.44 (m, 1H), 0.42-0.40 (m, 1H), 0.37-0.36 (m, 1H), 0.32-0.30 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][O:11][C@@H:10]([O:23][CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][OH:15])[CH2:12][O:11][C@H:10]([O:23][CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OC(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C(CO)CO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dissolve (R)-5-(tert-butyldimethylsilanyloxymethyl)-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.39 g, 1.04 mmol) in tetrahydrofuran (3 mL) and add tetrabutylammonium fluoride (2.1 mL, 2.1 mmol, 1.0 M in tetrahydrofuran). Stir 45 minutes at room temperature and concentrate. Purify on silica gel, eluting with 10:90 to 40:60 ethyl acetate in hexanes to give the desired compound.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[O:29])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)nc1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 173B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 2.27 (s, 3 H) 3.14-3.29 (m, 1 H) 5.62 (s, 2 H) 6.64 (d, J=8.09 Hz, 2 H) 6.82 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.09 Hz, 2 H) 7.64 (d, J=8.46 Hz, 2 H) 7.87 (dd, J=8.27, 1.29 Hz, 1 H) 7.97-8.11 (m, 2 H) 8.19 (s, 1 H) 8.32 (s, 1 H) 8.50-8.61 (m, 1 H) 8.89 (d, J=8.82 Hz, 1 H) 10.12 (s, 1 H) 10.63 (s, 1 H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([Cl:24])=[C:22]([CH3:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([Cl:24])=[C:22]([CH3:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:24]([O:16][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])(=[O:26])[CH3:25]
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 75 ml of N,N-dimethylformamide are suspended 7.5 g of 3-(3-ethoxy-3-oxopropyl)-4-hydroxybenzoic acid, 17.5 g of potassium carbonate and 7.4 ml of acetic anhydride. The mixture thus obtained is stirred at ambient temperature for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.8 g of 4-(acetyloxy)-3-(3-ethoxy-3-oxopropyl)benzoic acid as a light brown-colored solid product.
Reaction SMILES: [O:1]([C:8]1[C:9]([C:18]#[N:19])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21].[OH-].[NH4+]>>[O:1]([C:8]1[C:9]([C:18]([NH2:19])=[O:21])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ncc(C(F)(F)F)cc1Oc1ccccc1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
3-Phenoxy-5-(trifluoromethyl)picolinonitrile (0.190 g, 0.719 mmol) was combined with 2 ml of sulfuric acid and agitated for 3 hours. Ice was added to the mixture, and the solution was basified with ammonium hydroxide solution. The resulting slurry was filtered and solids washed with water and dried in the air to afford 3-phenoxy-5-(trifluoromethyl)picolinamide (0.171 g, 84.3% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[C:7](=[O:9])[CH3:8])[CH3:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH:7]([OH:9])[CH3:8])[CH3:2]
Reactant: CCOC(CC(C(C)=O)c1ccc2c(c1)OCO2)OCC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(CC(c1ccc2c(c1)OCO2)C(C)O)OCC
Temperature: -78 °C
Yield: 91.2 %

Procedure:
To 18.3 g of 5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentan-2-one in 200 ml of tetrahydrofuran, 65 ml of 1M tetrahydrofuran solution of lithium tri-sec-butylborohydride was added under cooling at -78° C. with stirring, and the resulting solution was stirred at the same temperature for 1 hour. To the reaction solution stirred and cooled with ice, 109 ml of 3N aqueous sodium hydroxide was added, and then 48 ml of 30% aqueous hydrogen peroxide was gradually added dropwise. The reaction solution was stirred at room temperature for 1 hour and partitioned between ethyl ether and water. The organic layer was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1→3/1] to give 16.8 g of the title compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]3C(OC(=O)[C:11]=3[CH:10]=2)=O)=[O:8])=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O>CO>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
To a 1 liter flask were added 420.00 g of benzophenone tetracarboxylic dianhydride and 503.52 g of methanol, a 50% by weight methanol solution of (A1) was prepared in the same manner as that of the process I of Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][CH:10]([C:11](OC)=[O:12])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:11][OH:12])[CH2:15][CH2:16]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
1-(4-Pyridinyl)piperidine-4-methanol was prepared using a procedure similar to the following: A solution of methyl N-(4-pyridinyl)isonipecotate (600 mg, 2.72 mmol) in tetrahydrofuran was added to a solution of lithium aluminum hydride (100 mg) in tetrahydrofuran (14 mL) cooled to 0° C. Upon consumption of the starting material (0.5-2 h), the mixture was treated with water (0.10 mL), 15% aqueous sodium hydroxide (0.10 mL), and water (0.30 mL). After 0.25 h, the mixture was sonicated for 0.25 h, then poured into a mixture of ethyl acetate, water, sodium tartrate, and potassium tartrate. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 357 mg (68%) of 1-(4-pyridyl)piperidine-4-methanol, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:19][N:20]=[C:21]=S)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:21]([NH:20][CH2:19][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:1][C:2]=2[CH:7]=1
Reactant: S=C=NCC1CCCCC1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NCC2CCCCC2)Nc2cc(Cl)ccc21
Temperature: 150 °C
Yield: 26 %

Procedure:
A mixture of 2-amino-4-chlorobenzenesulfonamide (2.1 g, 10.16 mmol) and cyclohexylmethyl isothiocyanate (6.31 g, 40.6 mmol) was heated at 150° C. for 4 h. The mixture was allowed to cool and then stirred with 25 ml of ethyl acetate for 1 h. The precipitate was isolated by filtration and recrystallised from ethanol to give 867 mg (26%) of the title compound; m.p. 317-323° C.; 1H-NMR (DMSO-d6): δ 0.8-1.8 (m, 11H, cyclohexyl), 3.08 (t, 2H, CH2), 7.78 (m, 3H, ArH+NH), 7.68 (d, 1H, ArH), 10.52 (br.s, 1H, NH); MS: m/e 327/329 (M+); (C14H18N3Cl1O2S1) calc. C, 51.29; H, 5.53; N, 12.82; found C, 51.21; H, 5.72; N, 12.81.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24 f), the condensation of the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=343 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14](Cl)=[O:15].Cl.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[F:9][C:10]([F:24])([F:25])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:15]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (5 mL), added dropwise 2 N sodium hydroxide (0.1 mL, 0.2 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (288 mg, 73.6%) as a light pink crystal.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C)c(-c2ccccc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-methyl-5-phenyl-2-propylpyrimidin-4(3H)-one (0.26 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.37 g) in N,N-dimethylformamide (6 mL) was added 60% sodium hydride (0.06 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.30 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([CH2:28][NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][N:22]=[CH:21]2)[C:13]([O:15]C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:25]1[C:24]2[NH:23][N:22]=[CH:21][C:20]=2[C:19]2[CH2:28][N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:13](=[O:15])[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][C:18]=2[CH:26]=1
Reactant: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1CNCc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(cc(Cl)c4[nH]ncc34)CC(NC(=O)OCc3ccccc3)C2=O)cc1
Temperature: 25 °C

Procedure:
A solution of Methyl 2-{[(benzyloxy)carbonyl]amino}-3-(7-chloro-4-{[(4-methoxybenzyl)amino]methyl}-1H-indazol-5-yl)propanoate from Step A in toluene (100 mL) was heated at reflux for 3 hours and then cooled to room temperature. The reaction mix was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with Ethyl acetate (2×200 mL). The combined organic extracts were washed once with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure. The resulting solid was swished once with a 1:1 mix of ethylacetate/hexane and the solid collected by filtration to give 3.1 g of the title compound to give the title compound. MS: m/z 505 (M+1).