Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:7]1[CH2:6][CH:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:19][C:2]=2[CH3:1])[CH2:8]1
Reactant: Cc1cc(CN2CCN(C)CC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CN2CCN(C)CC2)ccc1OC1CNC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 9B (2.18 g, 5.81 mmol) in DCM (40 mL) was treated with TFA (10 g, 88 mmol) and stirred at 0° C. for 3 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.) and extracted several times with DCM. The organic solutions were filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 10% triethylamine and 10% MeOH in EtOAc as eluent. There was obtained 1.44 g (90%) of 9C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.22 (s, 3H), 2.28 (s, 3H), 2.27-2.70 (bm, 8H), 3.40 (s, 2H), 3.75-3.85 (m, 2H), 3.88-3.98 (m, 2H), 4.92-5.02 (m, 1H), 6.43 (d, 1H), 7.01 (d, 1H), 7.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH2:27])=[O:26]>>[C:25]([C@@H:24]([NH:23][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:21])([F:22])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:26])[NH2:27]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=437.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.[OH-].[Na+:37]>C1COCC1>[Na+:37].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CCC(=O)O)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CCC(=O)[O-])c4)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 150 mg (0.322 mmol) of 3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)propanoic acid in 5 ml of THF and add 0.322 ml of 1N sodium hydroxide solution. Stir the mixture at RT for 1 h, then concentrate under reduced pressure and dry the residue under high vacuum overnight. 155.7 mg (99.1% of theory) of the target product are obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11](S(C)(=O)=O)[C:10]([CH3:17])([CH3:16])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:16][C:10]1([CH3:17])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=[C:2]([O:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[CH:3]=[C:4]2[NH:11]1
Reactant: N#Cc1cccc(CO)c1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1

Procedure:
To a solution of 7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (200 mg, 0.720 mmol) and 3-(hydroxymethyl)benzonitrile (288 mg, 2.16 mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K2CO3 (299 mg, 2.16 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h. Purification via mass-directed auto-preparation afforded the title product as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:21])[O:6][C:7]2[C:14]([O:15][CH2:16][CH3:17])=[C:13]([O:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:19]([O:18][C:13]1[CH:12]=[CH:11][C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:5](=[O:21])[O:6][C:7]=2[C:14]=1[O:15][CH2:16][CH3:17])[CH3:20]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1ccc2c(C)c(CCCl)c(=O)oc2c1OCC
Product: CCOc1ccc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1OCC
Yield: 13 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-7,8-diethoxy-4-methyl-2H-1-benzopyran-2-one (Example 33) and 1-(2-methoxyphenyl)piperazine; yield 13% of crude product.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([CH:42]([CH3:44])[CH3:43])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([CH:42]([CH3:44])[CH3:43])[N:35]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(C(C)C)ccc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (70 mg) is dissolved in ethanol (2 ml), and thereto is added 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (62 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (729 mg). MS (m/z): 729 [M−Na]−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C#Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
A solution of 4-fluorophenylacetylene (2.86 mL, 3.00 g, 24.97 mmol) in tetrahydrofuran at −78° C. was treated with a solution of n-butyllithium in hexanes (2.29 M, 12.0 mL, 27.5 mmol) followed by stirring at −78° C. for 45 minutes. The solution was then treated rapidly with methyl chloroformate (2.12 mL, 2.60 g, 27.5 mmol) followed by stirring at −78° C. for 30 minutes and warming to room temperature for 18 hours. The mixture was treated with water and concentrated in vacuo to remove tetrahydrofuran. The residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a yellow solid, which was chromatographed over a 340 g silica gel cartridge, eluting with 15-50% dichloromethane in hexanes. These procedures afforded the product (2.95 g, 66%) as an off-white fluffy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:7]3[N:15]=[C:14]([O:21][CH3:20])[CH:13]=[CH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C[O-]
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Temperature: 90 °C
Yield: 82 %

Procedure:
4-(3-Bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (described in a previous experimental) (0.11 g, 0.34 mmol) is added to a solution of NaOMe (prepared by the addition of Na metal (31 mg, 1.38 mmol) to dry MeOH (15 mL). After heating in a pressure vessel at 90° C. for 3 h, the solution is concentrated to dryness and the residue is partitioned between EtOAc and water. Workup of the organic portion gives 4-(3-bromophenyl) amino-6-methoxypyrido[3,2-d]pyrimidine (92 mg, 82%). 1H NMR (CDCl3) δ 8.73 (1H, s), 8.66 (1H, brs), 8.18 (1H, m), 8.05 (1H, d, J=8.9 Hz), 7.83-7.80 (1H, m), 7.30-7.24 (2Ht, m), 7.23 (1H, d, J=8.9 Hz), 4.12 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:26]=[CH:25][N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)[C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[CH:21]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:26]=[CH:25][NH:24][CH:23]=2)[C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[CH:21]=1
Reactant: CC(=O)c1oc2c(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)cc(F)cc2c1Cc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1oc2c(-c3cc[nH]c3)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
1-[5-Fluoro-3-(3-fluoro-benzyl)-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-benzofuran-2-yl]-ethanone (0.38 gm, 0.748 mmol) and tetrabutylammonium fluoride hydrate (0.28 gm, 0.89 mmol) were added to tetrahydrofuran (10 ml) and stirred at room temperature for four hours. The solution was concentrated under reduced pressure and purified by column chromatography to give 1-[5-fluoro-3-(3-fluoro-benzyl)-7-(1H-pyrrol-3-yl)-benzofuran-2-yl]-ethanone (0.205 gm, 79% yield).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (54 mg, 51%), MS (ISP) m/z=419.3 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)(Cl)Cl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:8]=2[N:7]2[C:3]([CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])=[N:4][N:5]=[C:6]2[CH2:12][N:11]=1
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)Nc1cccc(C)c1)CN=C2c1ccccc1Cl
Reaction time: 3 h
Yield: 100.1 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.07 g) was dissolved in chloroform (50 ml). 3-Methylphenyl isocyanate (0.44 g) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated, and crystallized from ethyl acetate. The crude crystals were recrystallized from methanol to give 1.47 g of N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethyl)-N'-(3-methylphenyl)urea.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17]C)=[O:16])[CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[CH:3]=1
Reactant: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Temperature: 70 °C
Yield: 95.1 %

Procedure:
To a solution of methyl 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate (Intermediate A, 16.3 g, 66.7 mmol) in ethanol (500 mL) was added NaOH (1N aq., 133 mL, 133 mmol), and the mixture was heated at 70° C. for 16 h. The organic solvent was evaporated under vacuum and the residue was acidified with HCl (1N aq., 150 mL) until a white solid completely precipitated from solution. The solid was filtered, washed with water (1.5 L), and was dried in a vacuum oven to afford the title compound as a white solid (14.6 g, 95%): 1H NMR (300 MHz, DMSO-d6) 7.0 (d, 2H), 7.08 (d, 2H), 6.56 (s, 1H), 5.35 (s, 2H), 2.30 (s, 3H), 2.27 (s, 3H); ES-MS m/z 231.0 (MH)+, HPLC RT (Method B) 3.12 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH2:27](P(CCCC)CCCC)[CH2:28][CH2:29]C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.CC(O)C>O1CCCC1>[CH3:27][CH:28]([O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)[CH3:29]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Reactant: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2[nH]1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 84 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g), tributylphosphine (2.6 mL), 1,1′-(azodicarbonyl)dipiperidine (2.69 g), 2-propanol (0.81 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 5.5 h. Furthermore, tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.7 g) were added to the mixture. After stirring at 70° C. for 2 h, the mixture was cooled to 0° C. and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane 1/99 to 40/60), followed by silica gel column chromatography (ethyl acetate/hexane=1/99 to 35/65, volume ratio) to give the title compound (1.87 g, 84%) as a white amorphous solid. MS 418 (MH+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:5]([C@@H:6]([OH:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1)=O.[OH-].[Na+].Cl.Cl.[NH2:28][CH2:29][CH2:30][O:31][NH2:32]>O1CCOCC1.O.O>[NH2:28][CH2:29][CH2:30][O:31]/[N:32]=[CH:1]\[C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:5]([C@@H:6]([OH:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1
Reactant: C[C@]12CCC(C=O)C[C@@H]1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](/C=N\OCCN)C[C@@H]1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
A solution of 3-formyl-5α-androstan-6α,17β-diol (II-c, Prep. 3, 240 mg) in dioxane/water (2/1, 30 mL) was treated with sodium hydroxide (0.1 N) to pH=13-14 and stirred for 15 minutes, then a solution O-(2-aminoethyl)-hydroxylamine dihydrochloride (170 mg) in water (3 mL) was poured in. After 1 hr. the organic solvent was distilled off and the acqueous solution was extracted with chloroform (5×20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (SiO2, chloroform/methanol/ammonia 90/10/1) to give (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol, which was dissolved in ethyl acetate/methanol 70/30 and treated with oxalic acid to give 85 mg of (Z)-3β-(2-aminoethoxyiminomethyl)-5α-androstan-6α,17β-diol oxalate (I-d) as a white solid mp 190-192° C.
Reaction SMILES: [CH:1]1([C:4]([OH:45])([C:21]2[N:22]=[CH:23][N:24](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:25]=2)[C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Cl.N1C=CC=CC=1>>[CH:1]1([C:4]([OH:45])([C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)[C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C3CC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C3CC3)cc2)c1
Yield: 38.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-[4′-[cyclopropyl(hydroxy)(1-trityl-1H-imidazol-4-yl)methyl][1,1′-biphenyl]-3-yl]acetamide (946 mg) and pyridine hydrochloride (334 mg), the colorless amorphous title compound (216 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][CH2:32][CH2:33]O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[Cl:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: ClCCOc1cccc2ncccc12
Yield: 79.5 %

Procedure:
A 100 ml three-neck oven dry flask was cooled under nitrogen. 5-Hydroxy quinoline (2 g, 14 mmol) was added as well as triphenylphosphine (5.42 g, 21 mmol) suspended in 50 ml anhydrous tetrahydrofuran. 2-Chloroethanol (1.3 ml, 21 mmol) was slowly added to above reaction mixture via syringe, followed by adding DEAD (2.98 ml, 21 mmol) via syringe. A second 1.5 eq of 2-chloroethanol, triphenylphosphine and DEAD was added. The reaction mixture was poured into 100 ml water and extracted by methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatographed (20% ethyl acetate-hexanes) afforded 2.31 g (82%) of product as a solid: mp 75-78° C.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][NH2:13])[CH3:9]>C(O)C>[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[CH2:12][NH:13][C:2](=[NH:7])[CH3:3])[CH3:9]
Reactant: CCOC(C)=N
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(C)=N)OCC

Procedure:
N-(2,2-Diethoxyethyl)acetamidine was synthesized in the same manner as in Reference Example 2. That is, ethyl acetimidate hydrochloride (25.0 g, 0.202 mol) was reacted with aminoacetaldehyde diethyl acetal (31 mL, 0.21 mol) in ethanol (150 mL) to give 44.1 g of a pale-green oil containing the target compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:16]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]Cl)[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl>CN(C)C=O>[CH:20]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][N:13]3[CH2:14][CH2:15][N:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH2:11][CH2:12]3)[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(CCN1CCN(c2cccc3[nH]ccc23)CC1)c1ccccc1)N1C2CCCC1CC2

Procedure:
The title compound was prepared from 4-(1H-indol-4-yl)-piperazine (1.0 g, 4.97 mmole), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (1.6 g, 4.97 mmole), diisopropylethylamine (0.65 g, 4.97 mmole) and potassium iodide (0.83 g, 4.97 mmole) in dimethylformamide (8 mL) in the manner described in example 2 to yield 0.6 g of product as the hydrochloride 0.75 hydrate, m.p. 150°-170° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.[Cl:26][C:27]1[CH:32]=[C:31](I)[C:30]([F:34])=[CH:29][N:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:31]3[C:30]([F:34])=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Fc1cnc(Cl)cc1I
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Product: Cc1cc(-c2cc(Cl)ncc2F)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 2-Chloro-5-fluoro-4-iodpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=346.1, 348.2 (M+H)+.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CC(C)CCCCCCCC=CC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCC=CC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 102.8 %

Procedure:
A mixture of 2-isododecenylsuccinic anhydride (31.2 g, 111 mmol), 3-(3,5-di-t-butyl-4-hydroxy-phenyl)propanoic acid hydrazide (32.6 g, 111 mmol) and 60 ml of toluene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (135° C.) melt for 25 minutes to remove last traces of solvent. After cooling to room temperature, the vacuum was removed. Additional cooling in an acetone/dry ice bath allowed for easy removal of the thermally fractured solid from the vessel. 61.7 g of an amber solid was obtained having a melting range of 62°-68° C.