Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:37][CH:38]([NH:40][CH:41]([CH3:43])[CH3:42])[CH3:39].C([O-])([O-])=O.[K+].[K+]>>[CH3:37][CH:38]([N:40]([CH:41]([CH3:43])[CH3:42])[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:39]
Reactant: CC(C)NC(C)C
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N(CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1)C(C)C
Yield: 12.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (100 mg, 0.313 mmol) and N-(1-methylethyl)-2-propanamine (0.22 mL, 1.55 mmol) were allowed to react in the presence of K2CO3 (172.5 mg, 1.28 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% triflucaroacetic acid) to give the title compound (20.5 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Temperature: 0 °C
Yield: 67.1 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,4,5-trimethoxybenzoyl chloride (1.0 g) in methylene chloride (25 ml). The reaction mixture is stirred for one hour at room temperature. The reaction mixture is pourd into ice-water (100 ml), and extracted with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is crystallized from ethyl acetatehexane to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.3 g), as obtained in Example 62, as colorless prisms, m.p. 164°-165° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:23][C:24]1([F:70])[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[CH:38]([O:40]CC4C=CC(OC)=CC=4)[CH2:37][C:36]([CH3:51])([CH3:50])[CH2:35][C:34]=3[N:33]=[C:32]([CH:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)[C:31]=2[CH:58]([F:69])[C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=2)[CH2:26][CH2:25]1>>[F:70][C:24]1([F:23])[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[CH:38]([OH:40])[CH2:37][C:36]([CH3:50])([CH3:51])[CH2:35][C:34]=3[N:33]=[C:32]([CH:52]3[CH2:57][CH2:56][N:55]([C:2]4[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=4)[CH2:54][CH2:53]3)[C:31]=2[CH:58]([F:69])[C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:67])([F:68])[F:66])=[CH:61][CH:60]=2)[CH2:26][CH2:25]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: FC(F)(F)CCCc1cnc(Cl)nc1
Agent: Clc1ncc(Br)cn1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(CCCC(F)(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(4,4,4-trifluorobutyl) pyrimidine, which was prepared by a method similar to that of Reference Example 26, instead of 5-bromo-2-chloropyrimidine, and from 70 mg (0.10 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 45 mg of the title compound was obtained as a white solid (yield: 61%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:44]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Reaction time: 2 h

Procedure:
Alternative synthesis: To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (prepared as described in Example 1, Step 1 but using EtOH in place of MeOH; 44.9 g, 0.114 mol) in CH2Cl2 (450 mL) at room temperature was added triethylamine (24 mL, 0.17 mol), followed by benzylisocyanate (16.7 mL, 0.136 mol), and the reaction was stirred for 2 hours until no starting material was seen by analytical LCMS. The mixture was partitioned between H2O and CH2Cl2, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated, and the residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester. Hydrolysis of the ethyl ester according to the procedure described in Example 1, Step 7 provided [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid.
Reaction SMILES: [C:1]1([C:7]2N=N[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](N1CCCC1)=[CH2:26]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:25]=[CH:26][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccc(C)cc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C)cc2)n1

Procedure:
Following General Procedure D, ethyl 6-phenyl-5-p-tolyl-1,2,4-triazine-3-carboxylate (Compound 17, 361 mg, 1.13 mmol) and crude 1-vinylpyrrolidine (Compound 38, 806 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20](Br)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(OCC)(=O)C>C(Cl)Cl>[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(C(c1ccccc1Cl)N1CCc2sccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 39.2 %

Procedure:
10 ml of methylene chloride were added to 0.39 g (2.6 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 0.28 g (2.6 mmole) of sodium carbonate, and then a solution of 0.67 g (2.2 mmole) of 2-chloro-α-trifluoroacetylbenzyl bromide in 10 ml of methylene chloride was slowly added to the resulting mixture, whilst stirring at room temperature. The mixture was then stirred at room temperature for 3 hours. At the end of this time, 200 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a 100:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.31 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccc(F)cc1
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 0.062 mmol, example 56) was dissolved in DMF (1.5 ml) and 4-fluorophenol (14 mg, 0.125 mmol) and Cs2CO3 (61 mg, 0.187 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. Then water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel chromatography (DCM/EtOAc 9:1) to obtain the title compound (21 mg, 63%) as white solid. MS (EI): 491.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:25]1([NH:24][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 37 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (215 mg, 0.69 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (78 mg, 0.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (244 mg, 0.76 mmol) and N,N-diisopropylethylamine (446 mg, 3.4 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (101 mg, 37%) as a white gum. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11](O)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc(Br)cc1
Yield: 97 %

Procedure:
Using General Esterification Procedure A; 4-bromobenzoic acid (1.50 g, 7.46 mmols) was combined with isopropyl alcohol to give 1.76 g (97%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=C)=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=[O:35])=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (Preparation 62G, 0.060 g, 0.146 mmol) and a 50% aqueous solution of NMO (0.030 mL, 0.146 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.046 mL, 5.85 μmol). The reaction mixture was stirred at room temperature for 5 h. The intermediate diol had an HPLC ret. time=3.09 min and an LCMS M+1=445.0. Sodium periodate (0.047 g, 0.219 mmol) was added to the homogeneous mixture followed by water (0.10 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole-7-carbaldehyde (0.057 g, 0.138 mmol, 95% yield) as a pale yellow solid. The product had an HPLC ret. time=3.49 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Bromo-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (21, 17.8 mg, 0.04 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (73 mg, 0.12 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 8 mg (42%). 1H NMR (CD3OD) δ 8.58 (s, 1H), 8.16 (s,1H), 8.11 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.35 (t, 4H), 3.70 (t, 2H), 3.40 (t, 2H), 2.40 (m, 2H), 2.15 (m, 2H); ES-MS m/z 478 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 39.4 %

Procedure:
2-Bromophenol (50.0 g, 0.289 mol) was dissolved in acetone (400 ml) and after adding thereto in sequence anhydrous potassium carbonate (79.89 g, 0.578 mmol) and benzyl bromide (59.32 g, 0.347 mol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:AcOEt=95:5) to obtain the titled compound (30.0 g, 0.114 mol, 40%).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]([C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:27])[C:25]=1[Cl:26])[C:22](=[O:28])[C:21]([CH2:32][CH:33]=[C:34]([Cl:36])[CH3:35])([CH2:29][CH2:30][CH3:31])[CH2:20]2)(C(OCC)=O)[C:7]([O:9]CC)=[O:8])=[O:4].[OH-].[Na+].Cl>CO.O>[Cl:26][C:25]1[C:24]([Cl:27])=[C:23]2[C:19]([CH2:20][C:21]([CH2:32][CH:33]=[C:34]([Cl:36])[CH3:35])([CH2:29][CH2:30][CH3:31])[C:22]2=[O:28])=[CH:18][C:17]=1[CH:6]([CH2:5][C:3]([OH:4])=[O:2])[C:7]([OH:9])=[O:8]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)OC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)O)C(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 94 %

Procedure:
Diethyl methoxycarbonylmethyl[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]malonate (10.7 g, 0.019 mole) was stirred at reflux for 21/2 hours in a mixture of methanol (120 ml), water (120 ml) and sodium hydroxide (6 g). The solution was cooled, diluted with water, acidified with hydrochloric acid, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated to obtain 8.0 g of the product as a gum.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10]>C(O)(C)C>[C:1]1([NH:7][N:8]=[CH:24][C:20]2[CH:21]=[CH:22][C:23]3[N:11]([CH2:9][CH3:10])[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: NNc1ccccc1
Solvent: CC(C)O
Product: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, commercially available from Aldrich, Milwaukee, Wis.) and 9-ethyl-3-carbazolecarboxaldehyde (0.1 mole, available from Aldrich Chemical, Milwaukee, Wis.) were dissolved in 100 ml of isopropanol in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The 9-ethyl-3-carbazolecarbaldehyde phenylhydrazone crystals formed upon standing were filtered off and washed with isopropanol and dried in a vacuum oven at 50° C. for 6 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][CH2:33][CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NCCO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 36.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-ethanol (61 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 36.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Yield: 81.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.19 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (90 mg, 0.29 mmol) in DME/water (3 ml:1 ml). PdCl2 (dppf)-CH2Cl2 adduct (7.9 mg, 0.009 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (48.7 mg, 0.58 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, 2 mL of water was added and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1), the solids filtered and washed with EtOAc and DCM, and then dried to afford the title compound (83 mg, 78%) as a white solid. LCMS E-S (M+H)=537.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.79 (t, J=4.93 Hz, 1H) 8.47 (m, J=8.59 Hz, 2H) 7.90 (m, J=8.59 Hz, 2H) 7.80 (s, 1H) 5.89 (s, 1H) 5.28 (quin, J=6.69 Hz, 1H) 4.40 (d, J=5.05 Hz, 2H) 2.66 (s, 6H) 2.47 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H).
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:25][C:17]=2[CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].C([SiH](CC)CC)C>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[C:27](=[O:28])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[CH:18][C:17]=3[CH2:25]2)=[CH:35][CH:34]=1.[C:39]([OH:41])([C:38]([F:43])([F:42])[F:37])=[O:40]
Reactant: O=C1c2c(cc3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(cc3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 283b (11 mg) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 285, TFA salt, (3.9 mg) as a yellow solid: 1H NMR (CDCl3) δ 9.1 (d, 1H), 8.3 (d, 1H), 7.6 (m, 1H), 7.35 (s, 1H), 7.33 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.4(s, 2H); MS: 309 (M+1).