Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 34.6 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.5 g, 0.96 mmol) was reacted with NaOH (69 mg, 1.72 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 35%).
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[N-:16]=[N+:17]=[N-:18].[Li+]>CN(C)C=O>[N:16]([CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)=[N+:17]=[N-:18]
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(Cn1ccnc1)c1ccc(Cl)cn1
Reaction time: 18 h

Procedure:
0.92 g of 1-chloro-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane are added under argon to a solution of 0.37 g of lithium azide in 2 ml of dry dimethylformamide and the reaction mixture is stirred at 60° for 18 hours. Working up according to process A (see Example 1) gives the substance as a yellowish oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>CN1CCN(C)C1=O.O1CCCC1>[CH2:26]([S:29]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:31])=[O:30])[CH2:27][CH3:28]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCS(=O)(=O)Cl
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
5.53 g of triethylamine was added to 6.03 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of 1,3-dimethyl-2-imidazolidinone, and then 5.10 g of propanesulfonyl chloride dissolved in 20 ml of tetrahydrofuran was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The precipitated crystals were recrystallized from methanol-acetonitrile to obtain 5.34 g of 2-(propylsulfonylaminomethyl)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.[OH-:30].[Na+].OO>CCO.CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:30])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: N#Cc1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (350 mg, 0.91 mmol) in EtOH (4 mL) and DMSO (4 mL) was added NaOH aqueous solution (5 N, 2 mL) and H2O2 (2 mL). After stirring at 60° C. for 3 hr, the mixture was partitioned between 100 mL of H2O and 100 mL of EA. The organic layer was separated from aqueous layers, washed with saturated brines (100 mL×2), dried over Na2SO4 and concentrated. The residue was purified by chromatography column on silica gel (elution with DCM/MeOH) to afford 150 mg (41%) of desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J=8.8 Hz, 2H), 6.97-6.92 (m, 3H), 6.75 (br s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.27 (d, J=7.6 Hz, 1H), 5.58-5.54 (m, 1H), 5.16 (s, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.27-3.24 (m, 1H), 3.01-2.92 (m, 1H), 2.23-2.13 (m, 1H), 2.13-2.07 (m, 1H), 1.24-1.18 (m, 1H), 0.59-0.54 (m, 2H) and 0.34-0.30 (m, 2H). MS (ESI) m/e [M+1]+ 404.0.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]([CH3:42])[CH3:41]>O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45.5 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In a 22 L 3 neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple charge DMSO (1385 mL) and 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (206.71 g, 0.5 mol, 1 eq). Heat the resulting suspension to 43-48° C. then add sodium hydroxide powder (50 g, 1.25 mol, 2.5 eq) in one portion. Stir the resulting suspension for 1 hour at 43-48° C. To this suspension add 2-chloro-N,N-dimethylethanamine hydrochloride (90 g, 0.625 mol, 1.25 eq). Stir the resulting suspension for 35-40 minutes. Cool the reaction mixture to 18-23° C. and add cold water (227.4 mL). Once water addition is complete, bring the reaction mixture temperature to 20-25° C., stir for 60-90 minutes and filter the suspension. Wash the solids with a mixture of DMSO (103.4 mL) and water (51.7 mL) two times. Wash the solids with water (2×517 mL) and dry solids on a filter with suction to afford the target compound (219.9 g, 87.5% yield) as a tan solid. 1H NMR (300 MHz, DMSO): 8.04-8.00 (m, 2H), 7.74 (s, 1H), 7.46 (t, J=9.9 Hz, 1H), 4.06-3.99 (m, 4H), 3.03-2.93 (m, 3H), 2.57 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.81-1.77 (m, 2H), 1.70-1.55 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([N+:26]([O-:28])=[O:27])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:26]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24])[CH2:16][N:6]1[C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([O-:28])=[O:27]
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2 g (10.4 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate, 2.97 g (11.4 mmol) of 4-bromomethyl-1,2-dinitrobenzene (prepared in a corresponding manner to DE 3904797) and 5.7 g (41.4 mmol) of potassium carbonate are suspended in 50 ml of acetonitrile, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is poured into 50 ml of water, extracted with 500 ml of MTBE, dried and evaporated to dryness. The residue is purified by column chromatography on silica gel; product: 1.5 g;
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](C(=O)C)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[C:26]([O:28][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)(=[O:27])[CH3:22]
Reactant: CC(=O)c1ccc(CCCc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 104.1 %

Procedure:
A suspension of 4'-(3-phenylpropyl) acetophenone (39.07 g) and m-chloroperbenzoic acid (124.48 g) in methylene chloride (400 ml) was refluxed. (Note: the m-chloroperbenzoic acid used in this reaction was a mixture of 1:1 m-chloroperbenzoic acid and m-chlorobenzoic acid.) After 23.5 hours, the reaction was allowed to cool to room temperature. After 2 hours at room temperature, the reaction mixture was filtered and the insolubles washed with methylene chloride (100 ml). To the filtrate was added water (500 ml). The pH of the biphasic solution was adjusted from 3.34 to 10.44 with 5N NaOH and the phases were separated. The organic phase was treated with 10% aqueous potassium carbonate (3×500 ml) then with brine (2×500 ml). The organic phase was dried over sodium chloride then magnesium sulfate, filtered, concentrated in vacuo to give 43.4 g of 4-(3-phenylpropyl)phenyl acetate..
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[CH:32]=[N:31]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:36]3[CH:37]=[C:38]4[C:33]([CH:32]=[N:31][NH:30]4)=[CH:34][CH:35]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3cn[nH]c3c1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 2.9 %

Procedure:
To a solution of Example 57a (0.700 g, 1.40 mmoles) in DMF (7 ml), ethanol (3.2 ml) and water (3.2 ml), 6-Indazoleboronic acid pinacol ester (0.687 g, 2.81 mmoles) and sodium carbonate (0.745 g, 7.03 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.320 g, 0.277 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.020 g, 3% yield). MP: 140-143° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.18(s,1H), 8.24(s,1H), 8.13(s,1H), 8.06(dd, J=7.9, 1.6Hz, 1H), 7.78(m,2H), 7.49-7.30(m, 7H), 6.89(q, J=7.7Hz,1H),5.53(s, 2H). Mass: 485.76(M++1).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([O:28][Si](C)(C)C)[C:16](=[CH:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:15](=[O:27])[CH:14]=[CH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.C1(C)C=CC=CC=1>CC(O)=O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([OH:28])[C:16](=[CH:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C:15](=[O:27])[CH:14]=[CH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCCC(C)=CC=C1C(=O)C=CC1(CCCCOc1ccccc1)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CC=C1C(=O)C=CC1(O)CCCCOc1ccccc1
Yield: 76.5 %

Procedure:
50 mg (0.11 mmole) of 4-(4-phenoxybutyl)-4-trimethylsilyloxy-5-(3,7-dimethyl-2,6-octadienylidene)-2-cyclopentenone was dissolved in 10 ml of a mixture of AcOH:THF:H2O (=3:1:1), and the solution was stirred at 40° C. for 3 hours. After the reaction, toluene was added, and AcOH and water were distilled off under reduced pressure. The residue was chromatographed on a silica gel column (hexane:AcOET=1.5:1) to give 32 mg (75%) of the desired compound indicated above.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Nc1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Fc1ccccc1Nc1ccccc1
Temperature: 115 °C
Yield: 83.9 %

Procedure:
A reaction vessel was charged with iodobenzene (1.42 g, 7 mmol), palladium(II) acetate (0.079 g, 0.35 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.217 g, 0.35 mmol), cesium carbonate (6.8 g, 21 mmol), 2-fluoroaniline (0.777 g, 7 mmol) in anhydrous toluene (18 mL). Under a nitrogen atmosphere, the mixture was heated at 115° C. for 24 hours. The cooled mixture was diluted with water and ether. The organic layer was isolated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to a residue. The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in hexanes) to give the desired product as a clear oil (1.1 g, 81%). 1H NMR (CDCl3, 300 MHz) δ 7.36-7.29 (m, 3H), 7.20-7.14 (m, 3H), 7.09-7.00 (m, 2H), 6.88-6.85 (m, 1H), 5.82 (br s, 1H). ESI m/z: 188.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.Cl.[NH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][C:30]([C:34]3[S:35][C:36]([CH2:39][O:40][CH3:41])=[CH:37][N:38]=3)([OH:33])[CH2:29][CH2:28]2)[CH2:23]1>CN(C=O)C>[CH3:41][O:40][CH2:39][C:36]1[S:35][C:34]([C:30]2([OH:33])[CH2:29][CH2:28][CH:27]([N:24]3[CH2:25][CH2:26][C@@H:22]([NH:21][C:14](=[O:16])[CH2:13][NH:12][S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=4)(=[O:10])=[O:11])[CH2:23]3)[CH2:32][CH2:31]2)=[N:38][CH:37]=1
Reactant: O=C(O)CNS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COCc1cnc(C2(O)CCC(N3CC[C@@H](N)C3)CC2)s1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1cnc(C2(O)CCC(N3CC[C@@H](NC(=O)CNS(=O)(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reaction time: 2 h

Procedure:
To a solution of ({[3-(trifluoromethyl)phenyl]sulfonyl}amino)acetic acid (64 mg, 0.22 mmol) and 4-[(3R)-3-aminopyrrolidin-1-yl]-1-[5-(methoxymethyl)-1,3-thiazol-2-yl]cyclohexanol dihydrochloride (72 mg, 0.19 mmol) in DMF (5 mL) at 0° C. was added TEA (38 mg, 0.38 mmol) and BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (99 mg, 0.22 mmol). The reaction mixture was stirred for 2 h, and quenched with water (5 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with saline solution (10 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 1% ammonium hydroxide in ethyl acetate/methanol (100/0 to 90/10). The appropriate fractions were combined to provide two isomers of the desired compound in 1 to 1 ratio with the following characteristics: MS: 577.4 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][N:21]([CH2:20][C:4]1[CH:3]=[C:2]([C:32]2[CH:33]=[CH:34][S:30][CH:31]=2)[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: OB(O)c1ccsc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Yield: 69.4 %

Procedure:
Using tert-butyl [(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (437 mg), 3-thiopheneboronic acid (223 mg), sodium carbonate (275 mg) and tetrakis(triphenylphosphine)palladium (50.8 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 305 mg, 69%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:28][C@@H:29]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=4)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (100 mg, 0.26 mmol) in chloroform (2 ml) was added methyl (S)-2-amino-3-(4-hydroxyphenyl)propionate (154 mg, 0.78 mmol). The mixture was stirred at room temperature for 12 hr, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (102 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[O:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCCCCC>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(C=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
In 4 ml of ethanol was dissolved 440 mg (1.3 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 51 mg (1.3 mmol) of sodium borohydride at room temperature. After 10 minutes, the mixture was neutrized by acetic acid and sodium bicarbonate, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was then concentrated under reduced pressure and the residue was recrystallized by isopropyl ether:n-hexane to provide 340 mg (yield 77%) of Compound I-8. mp 157 to 158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH2:10][CH:9]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[CH:7]4[C:6]=3[C:5]=2[CH:4]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[C:9]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(C(=O)OCc1ccccc1)C3
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Yield: 91.6 %

Procedure:
Activated manganese dioxide (69 g) was added to a solution of benzyl 9-methoxy-1,3-dioxo-1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 0.034 mol), prepared as in example 2, in p-dioxane (300 mL) and the mixture was refluxed with vigorous stirring for 0.5–2 h. The mixture was filtered while hot through a plug of Celite, which was washed exhaustively with a MeOH/p-dioxane (1:1) mixture until the washings were colorless. The combined washings and filtrate were concentrated to dryness and the residue triturated several times with diethyl ether to give benzyl 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate (4) as a yellow/orange powder (12.47 g, 91.5%), mp 245° C. A small sample was recrystallised from EtOAc to give benzyl 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate as orange cubes; mp 289–292° C. 1H NMR δ (CD3)2SO] 12.11 (br s, 1H), 11.27 (br s, 1H), 8.45 (d, J=2.6 Hz, 1H), 7.98 (s, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.55–7.51 (m, 2H), 7.44–7.34 (m, 3H), 7.27 (dd, J=8.9, 2.6 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 3H). Found: C, 68,99; H, 4.09; 6.91. C23H16N2O5 requires C, 69.00; H, 4.03; N, 6.99.
Reaction SMILES: O1CCC[CH2:2]1.C(NC(C)C)(C)C.[Li].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](=[O:52])[CH2:25][CH2:26][C:27]2[N:28]=[CH:29][N:30]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH3:32])=[CH:16]1.IC.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(O)(=O)C>[CH3:2][CH:25]([CH2:26][C:27]1[N:28]=[CH:29][N:30]([C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:31]=1[CH3:32])[C:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH3:14])[CH:16]=1)=[O:52]
Reactant: C1CCOC1
Reactant: Cc1c(CCC(=O)c2cn(C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]
Solvent: O
Solvent: CC(=O)O
Solvent: CI
Product: Cc1c(CC(C)C(=O)c2cn(C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Lithium diisopropylamine mono(tetrahydrofuran) (1.5M in cyclohexane, 11.5 ml) was added dropwise to a cold (-70°) solution of 1-(1-methyl-1H-indol-3-yl)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-propanone (8.8 g) in dry THF (175 ml) under nitrogen. The stirred solution was allowed to warm to 20° over 1 h then cooled to -70°. Iodomethane (2.15 ml) was added and the mixture was allowed to reach 20° over 1 h and stirred for a further 2 h. More iodomethane (1.08 ml) was added and stirring was continued for 2 h. The mixture was treated with acetic acid (10 ml) and water (10 ml), poured into saturated potassium carbonate solution (200 ml) and extracted with ethyl acetate (2×100 ml). The combined, dried organic extracts were filtered and evaporated to give a yellow foam (11.3 g). FCC (column made up of EtOAc:Et3N 99:1) eluting with ethyl acetate gave the title compound (5.0 g) as a white solid, m.p. 209°-210°.