Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][CH2:42][C:7]1[CH:15]=[CH:14][C:13]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:12][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(CO)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 128.1 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (9.6 mL), and the solution was treated with 4-(hydroxymethyl)phenylborate (62.0 mg, 0.405 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.027 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.098 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-[4-(hydroxymethyl)phenyl]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (47.7 mg, yield 64%).
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33](O)=[O:34]>C(OCC)(=O)C>[CH:1]1([C:7]([N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH:33]=[O:34])=[CH:20][C:19]=3[O:25][CH3:26])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Reactant: O=CO
Solvent: CCOC(C)=O
Product: COc1cc(NC=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Yield: 89 %

Procedure:
A solution of 0.140 g of the compound of Example 6 and 0.4 mL of formic acid in 8 mL of ethyl acetate was stirred at room temperature for 8 h. Afterwards, the reaction mixture was diluted with 40 mL of ethyl acetate, washed with 1 N sodium hydroxide and water, dried on sodium sulphate and evaporated to dryness in vacuo. The crude was purified by flash chromatography (ethyl acetate—3N ammonia in methanol 95:5) to afford 0. 130 g (89%) of the title product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[NH2:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1.[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][CH2:16][C:17]1([OH:20])[CH2:19][CH2:18]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: NCC1(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Yield: 189 %

Procedure:
1-(Aminomethyl)cyclopropanol was prepared using the method of I. L. Lysenko and O. G. Kulinkovich, Russ. J. Org. Chem., 37, pp. 1238-1243 (2001). A solution of 4-chloro-3-nitroquinoline (7.28 g, 34.9 mmol) in dichloromethane (30 mL) was added dropwise to a 0° C. stirred suspension of 1-(aminomethyl)cyclopropanol (36.7 mmol) and triethylamine (6.30 mL, 45.4 mmol) in dichloromethane (120 mL). The mixture was stirred at room temperature for 3 days, then was concentrated under reduced pressure. The residue was suspended in water (150 mL) and was stirred for 3 hours. The solid was isolated by filtration, washed with water (50 mL), and dried in a vacuum oven at 75° C. to afford 8.99 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol as a yellow solid.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:19][C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(OC)cc1
Yield: 35.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (7.5 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methoxyphenyl)-2-(l-naphthyl)imidazole-4-carboxylate (5.2 g). 5.0 g therefrom was dissolved in ethyl alcohol (300 ml), and 1 M sodium hydroxide solution (50 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(1-naphthyl)imidazole-4-carboxyic acid (3.9 g), melting point 178° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[N:22](S(C2C=CC(C)=CC=2)(=O)=O)[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(C)c2cc1C
Yield: 54.6 %

Procedure:
2-(5-Methoxy-1,6-dimethyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]-pyridine is prepared by following the procedure described in example 189a, but using 0.028 g of 2-(5-methoxy-1,6-dimethyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.283 ml of a 5N aqueous potassium hydroxide solution. 0.01 g of 2-(5-methoxy-1,6-dimethyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]-pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[N:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:17]=2)=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:6][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2[N:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[N:18]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[N:17]=2)=[CH:12][CH:13]=1)([CH3:35])[C:4]([OH:36])=[O:3]
Reactant: CCCn1c(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCc2ccc(OC(C)(C)C(=O)O)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Yield: 90.4 %

Procedure:
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid ethyl ester (94 mg, 0.19 mmol) and a 2N solution of sodium hydroxide (2.3 mL) in ethanol (5 mL) was heated to 80° C. for 35 min. The solvent was evaporated, water added and the solution made acidic with concentrated hydrochloric acid (pH 0-1), extracted with ether. The combined organic extracts were washed with water, brine, dried and evaporated to dryness to afford the pure compound (82 mg, 92.3%): 1HNMR (400 MHz, CDCl3) δ 8.06 (d, 2H, J=8.3 Hz), 7.59 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, 6.4 Hz), 6.83 (d, 2H, J=8.3 Hz), 3.45 (t, 2H, J=7.4 Hz), 3.02 (d, 2 H, J=7.3 Hz), 2.79 (m, 2H), 1.60 (m, 2H), 1.52 (s, 6H), 0.87 (t, 3H, J=7.8 Hz); ESMS m/z (relative intensity) 476.1 (M−H+, 50).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[Cl:1])[CH2:31][CH2:32]3)=[O:26])[CH2:23][CH2:24]2)(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=C(N1CCN(c2ccncc2Cl)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 48 h
Yield: 72.4 %

Procedure:
N-Chlorosuccinimide (3.06 g) was added to a stirred suspension of 1-(4-bromophenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (10.1 g) in acetonitrile (350 ml) at 20° C. The mixture was stirred for 48 hours and the acetonitrile evaporated. Water (200 ml) was added to the mixture and the aqueous phase was extracted with dichloromethane (3×200 ml). The organic extracts were combined, dried and evaporated, and the residue purified by column chromatography on silica gel, eluting with dichloromethane:methanol (97:3) to give a foam on evaporation. Trituration with diethyl ether (200 ml) gave 1-(4-bromophenylsulphonyl)-4-[1-(3-chloro-4-pyridyl)piperazin4-ylcarbonyl]piperazine as a cream-coloured solid (7.82 g): mp 194-195° C.: 1HNMR (CDCl3); 3.04 (t, 4H), 3.18 (t, 4H), 3.42 (m, 8H), 6.78 (d, 1H), 7.91 (d, 2H), 7.70 (d, 2H), 8.34 (d, 2H), 8.42 (s, 1H); EI-MS m/z 528 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.O1CCCC1>[CH2:15]([O:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-aminocaproic acid (7.8 g) and 5.0 g of sodium bicarbonate in 50 ml of water is added by dropwise addition 16 g of N-benzyloxycarbonyloxysuccinimide in 60 ml of tetrahydrofuran. The mixture is stirred for one hour at room temperature and then the tetrahydrofuran is removed at reduced pressure. The residue is acidified to pH 3 and extracted with methylene chloride and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and the solvent is removed by evaporation. Recrystallization from ethyl acetate/hexane provides N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH:19]([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:20][CH2:19][CH3:21])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)I
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CCCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 43 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.36 g, 1.2 mmol) was reacted with 2-iodopropane to afford 0.18 g (43%) of the title compound as a clear oil.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:25]=[CH:24][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([Cl:26])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(N2CCNCC2)cc1Cl)N1CCCCc2ccccc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)N3CCCCc4ccccc43)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a mixture of 1-[4-(1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g), 37% formaldehyde (0.45 g) and sodium cyanoborohydride (0.12 g) in methanol (5 ml) is added with stirring acetic acid (0.12 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the reaction solution is added ethyl acetate, and the mixture is washed with a 2 N aqueous sodium hydroxide solution and distilled water. The organic layer is dried over magnesium sulfate, filtered, and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=10:1) to give 1-[4-(4-methyl-1-piperazinyl)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.10 g) as white powder.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[C:14]([C@@:25]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)([NH2:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:17]=1>ClCCCl.C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C@:25]([NH:33][CH:8]=[O:10])([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:17]=1
Reactant: O=CO
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCCl
Product: O=CN[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (6 mL, 159 mmol) was heated at 60° C. for 3 h, then cooled to rt. An aliquot of the resulting solution (0.623 mL) was added to a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine prepared as described in Procedure 3, 4, 5 and 6 (83 mg, 0.2 mmol) in DCE (1 mL). The reaction mixture was stirred at rt for 1.5 h, then concentrated under reduced pressure to yield a clear oil. The resulting oil was dissolved in DCM and purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide as white solid (72 mg, 81% yield). LCMS: RT=2.02 min [M−NHCOH] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). At 0° C. to a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide (72 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and POCl3 (0.016 mL, 0.18 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc (15 mL). The organic layer was washed with sat. NaHCO3 and sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene as a white solid (60 mg, 87% yield). LCMS: RT=2.10 min [M−NC] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.65 (m, 2H), 5.74-6.01 (m, 1H), 6.84 (d, J=7.03 Hz, 2H), 6.94 (d, J=7.03 Hz, 3H), 7.04-7.10 (m, 2H), 7.16-7.26 (m, 3H), 7.32 (dd, J=9.01, 5.05 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([O:23]CC4C=CC=CC=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3ccc(OCc4ccccc4)nc3)cn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3ccc(=O)[nH]c3)cn2)CC1
Reaction time: 4 h
Yield: 104.2 %

Procedure:
To a solution of [1-(6′-benzyloxy-[3,3′]bipyridinyl-6-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.20 g, 0.48 mmol) in MeOH (10 mL) was added Pd(OH)2 (0.2 g). The flask was purged with H2 gas and then H2 gas passed over the solution for 4 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give [1-(6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-6-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.16 g, 0.50 mmol), m/z 328.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]3C=CC=[C:20](C)[C:19]=3S(OCCC)(=O)=O)[S:17][C:13]=2[N:12]2[C:32]([CH3:35])=[N:33][N:34]=[C:11]2[CH2:10][N:9]=1.[I-:36].[Na+]>CC(C)=O>[I:36][CH2:20][CH2:19][CH2:18][C:16]1[S:17][C:13]2[N:12]3[C:32]([CH3:35])=[N:33][N:34]=[C:11]3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CCCOS(=O)(=O)c1c(C)cccc1-c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nnc2n1-c1sc(CCCI)cc1C(c1ccccc1Cl)=NC2
Yield: 36 %

Procedure:
0.6 g (0.0011 mol) of propyl 3-[4-(2-chlorophenyl)-9methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepin-2-yl]-toluenesulphonate, prepared analogously to Example 6, and a solution of 0.2 g (0.0014 mol) of anhydrous sodium iodide in 15 ml of anhydrous acetone are stirred for 2 hours at ambient temperature. After the solvent has been removed, the residue is taken up in methylene chloride/water, the organic phase is washed several times with water, then dried, the solvent is removed and in this way 0.2 g (yield 36% of theory) of the amorphous title compound are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=[O:9])[CH3:2].[OH-].[Na+].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>O1CCOCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=1)[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(C=O)c(OC(=O)C(C)(C)C)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
In 25 ml of 1,4-dioxane, 1.93 g of 4-diethylaminosalicylaldehyde was dissolved. To the resulting solution, 1.08 g of powdery sodium hydroxide and 12 mg of tetrabutylammonium hydrogensulfate were added, followed by stirring at room temperature. To the resulting heterogeneous solution, a solution of 1.45 g of pivaloyl chloride dissolved in 10 ml of 1,4-dioxane was added over 20 minutes and the mixture was stirred for 1 hour as was. To the reaction mixture, 20 ml of water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was distilled off, whereby 2.48 g of the title compound was obtained in the form of a brown oil (yield: 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.036 min, m/z=512.1; 1H NMR (CDCl3) 1.49 (d, 3H), 1.60-1.70 (m, 1H), 1.84 (m, 1H), 1.89-1.99 (m, 2H), 2.10-2.20 (m, 2H), 2.25 (m, 1H), 2.74 (s, 3H), 3.01 (m, 2H), 4.22 (m, 1H), 5.64 (m, 1H), 6.97 (m, 4H), 7.16 (m, 3H), 7.58 (d, 1H), 7.70 (m, 3H), 8.60 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]\[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](\[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid (3.3 g) and 4-nitrophenol (2.1 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.67 g) and the mixture was stirred at room temperature for 3 days. After the usual work up, crystallization of the crude material from hexane gave 3.1 g of (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 50°-51° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[NH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])[NH2:33].C([O-])(=O)C.[K+].Cl>C(O)C.O>[OH:1][C@H:2]1[C@@H:15]2[C@H:6]([CH2:7][CH2:8][C:9]3[C@@:14]2([CH3:16])[CH2:13][C:12]2[CH:17]=[N:33][N:32]([C:34]4[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=4)[C:37]([OH:39])=[O:38])[C:11]=2[CH:10]=3)[C@H:5]2[CH2:20][CH2:21][C@@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@:4]2([CH3:31])[CH2:3]1
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Reactant: NNc1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@]12Cc3cnn(-c4cccc(C(=O)O)c4)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde (Steroids 2003, (68), 177-191) (1.4 g, 3.24 mmol) was dissolved in ethanol (10 ml) and water (1 ml). 3-hydrazinobenzoic acid (0.493 g, 3.24 mmol) and potassium acetate (0.491 g, 5 mmol) were added to give a brown solution which was stirred for 1 hour at room temperature. The mixture was poured into a separation funnel containing 1M HCl (200 ml) and was extracted with DCM (3 times 150 ml). The combined organic phases were washed with water (2 times 100 ml) and 1M NaOH. The organic phase was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to give 1.9 g of a brownish foam. The crude product was purified on a silica gel column (Heptane:EtOAc=1:1) and the product containing fractions were evaporated under reduced pressure to yield 1.5 g of the desired compound. APCI-MS m/z: 549 [MH+].