Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[N:34]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35]1.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[N:34]1([CH2:37][CH2:38][O:39][C:21]2[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:19]([Cl:33])[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([C:10]4[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=4)[OH:9])[CH:17]=3)[N:22]=2)[CH2:36][CH2:35]1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: OCCN1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN3CC3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), 2-(aziridin-1-yl)ethanol (16.2 μL, 0.20 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 20.2 mg, 0.51 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight, cooled and stirred at room temperature an additional night before workup. Reaction contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) to afford the title compound. MS (ESI): mass calcd. for C30H26Cl2N4O2, 544.1; m/z found, 545.1 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.31 (m, 1H), 7.28-7.23 (m, 6H), 6.18 (d, J=1.1 Hz, 1H), 4.51-4.44 (m, 2H), 3.37 (s, 3H), 2.50-2.39 (m, 2H), 1.48-1.37 (m, 2H), 0.97-0.94 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH2:15][OH:16])(=[O:3])[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1CO
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C=O

Procedure:
A 6.27 gm. portion of 1-(2-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole is refuxed with 13.3 gm. of lead tetraacetate in 200 ml. of benzene for 18 hours, cooled, and filtered. The filtrate is washed with 50 ml. of saturated sodium carbonate solution, and the organic phase is separated therefrom. The remaining aqueous phase is twice extracted with 30 ml. of chloroform, and then combined with the above separated organic phase. The combined organic phases are dried under magnesium sulfate, and filtered. The organic solvents are then removed in vacuo, giving the above aldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][C:6]([C:8]2[NH:25][C:11]3=[N:12][CH:13]=[CH:14][C:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][CH3:24])=[C:10]3[CH:9]=2)=[CH:5][CH2:4][NH:3]1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:25][C:8]([C:6]4[CH2:7][C:2]([CH3:26])([CH3:1])[N:3]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:4][CH:5]=4)=[CH:9][C:10]=23)[CH:21]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNC(C)(C)C3)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)OC(C)(C)C)C(C)(C)C3)cc12

Procedure:
A mixture of Example 272B (0.388 g, 0.915 mmol), tert-butyl bromoacetate (0.264 g, 1.35 mmol) and triethylamine (0.7 mL, 5.02 mmol) in N,N-dimethylformamide (2 mL) was heated at 70° C. for 8 hours and was concentrated. The residue was partitioned between ethyl acetate and water and the organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes gave the title compound. MS (ESI) m/e 466.4 (M+1)1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]#[N:28])=[C:17]3[CH:16]=[N:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Cl)ncnc32)C1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)C1
Temperature: 160 °C
Yield: 43.6 %

Procedure:
A mixture of 3-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 32; 40 mg, 0.12 mmol), 2-hydroxybenzonitrile (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 15.5 mg, 0.13 mmol) and potassium carbonate (15 mg, 0.25 mmol) in dimethylformamide (0.6 mL) was heated in a microwave oven at 160° C. for 10 min. The reaction mixed was cooled and filtered. Volatiles were evaporated and the residue purified twice by chromatography on silica gel, eluting first with 25% ethyl acetate/hexanes and then with 20% ethyl acetate/hexanes to give 3-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (22 mg, 47%) as a viscous oil
Reaction SMILES: [OH:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:21]I.O>C1COCC1>[CH3:21][O:1][CH:2]1[C:8]2=[N:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(O)CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c(nc1C)C(OC)CCCC2
Reaction time: 1 h
Yield: 58.4 %

Procedure:
In an atmosphere of argon, ethyl 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.04 g, 4.16 mmol) was dissolved in anhydrous THF (8.0 ml), and the solution was mixed with sodium hydride (182.3 mg, 4.56 mmol) at 0° C. This was stirred at the same temperature for 1 hour, mixed with methyl iodide (0.33 ml, 4.76 mmol) by its dropwise addition and then stirred at room temperature for 1.5 hours. The reaction solution was mixed with water and extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (639.8 mg, 58.4%) as yellow oil.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([S:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][CH:7]=1>CN(C=O)C.[Cl-].[Na+].O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:3][CH:2]=[CH2:1])=[CH:17][CH:18]=3)[C:13]([S:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[C:12]2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:35][CH:36]=1
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)OCC)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.2 %

Procedure:
A mixture of allyl bromide (1.81 g, 15 mmol) potassium carbonate (4.14 g, 30 mmol) and ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl)-2,2dimethylpropionate (7.15 g, 15 mmol), prepared as in step 3, in anhydrous DMF (40 ml) was heated at 60° C for 3 hours, and stirred at ambient temperature for 17 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a white solid. The solid was triturated with hexane (100 ml), filtered and dried in vacuo dried to obtain 6.65g of ethyl 3-(1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-allyloxyindol-2-yl)-2,2dimethylpropionate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[O:16]([CH3:18])[Li]>CO>[CH3:18][O:16][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [Li]OC
Solvent: CO
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
3,5-Dinitrobenzoic acid (866 mg) was dissolved in 1 M LiOMe in MeOH (1.3 mL), then evaporated to dryness. The resulting solid was dissolved in 30 mL of hexamethyl phosphoramide and heated at 80° C. for 16 h. The mixture was then cooled and poured onto a mixture of crushed ice (250 g) and 6NH2SO4 (42 mL). The mixture was extracted with ether, and the extract was washed with water and brine, then dried over MgSO4, filtered and evaporated to yield an orange solid. Filtration through silica gel using 9:1 CH2Cl2/MeOH followed by evaporation provided 624 mg of product. 1H-NMR (d6-acetone): δ 8.36 (1H, dd, J=1.6, 2.0 Hz), 7.97 (1H, t, J=2.0 Hz), 7.91 (1H, dd, J=1.6, 2.0 Hz), 4.03 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:34]([F:37])([F:36])[F:35])[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]3)[O:19][CH2:18]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Cl>CO>[ClH:1].[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:34]([F:35])([F:37])[F:36])[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:24][NH:25][CH2:26]3)[O:19][CH2:18]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Agent: Cl
Solvent: CO
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)COC43CNC3)=NO2)cc1Cl
Temperature: 65 °C
Yield: 196.9 %

Procedure:
Chiral-tert-butyl 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 5, 1.1 g, 2.0 mmol) was dissolved in methanol (50 mL). A methanolic solution of HCl (5 mL of a 1.25M solution) was added and the reaction was heated to 65° C. for 18 hours. The reaction was cooled and concentrated under vacuum to afford the intermediate (980 mg, 100%) a solid. 1H NMR, 300 MHz (d6-DMSO) δ ppm: 9.86 (1H), 9.45 (1H), 8.14 (1H), 7.82 (3H), 7.70 (1H), 5.15 (2H), 4.41-4.30 (6H); m/z (CI) 461 [M+H] (free amine). The asterisk (*) depicts a chiral center.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>C(OCC)(=O)C>[Si:18]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H](C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (1.0 g; 8.47 mmole) and imidazole (1.15 g; 16.9 mmole) were dissolved in dry dimethylfofmamide (10 ml), t-butyl dimethylchlorosilane (1.30 g; 8.62 mmole) was added thereto, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (60 ml), washed with an aqueous sodium chloride solution (50 ml) three times and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give methyl (S)-3-t-butyldimethylsilyloxy-2-methylpropionate
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH:16]([OH:18])[CH3:17])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([OH:18])[CH3:17])[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:6]=2[N:7]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1C#CC(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)n1c(C(C)O)cc2cnc(Cl)nc21
Yield: 52.7 %

Procedure:
To a solution of 4-[2-chloro-4-(1-ethyl-propylamino)-pyrimidin-5-yl]-but-3-yn-2-ol (0.23 g, 0.85 mmol) in THF (0.5 mL) is added 1M TBAF (4.3 mL). The reaction mixture is heated at reflux for 16 h, diluted with water, extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/Hexane 1:3) to provide 0.12 g of 1-[2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanol.
Reaction SMILES: C(OC(C1C=C(OC2C=CC(NC)=C(N)C=2)C=CN=1)=O)(C)(C)C.NC(N)=S.IC.C([O:34][C:35]([C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:61]=[CH:60][C:47]3[N:48]([CH3:59])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=4)=[N:50][C:46]=3[CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:36])(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[CH3:59][N:48]1[C:47]2[CH:60]=[CH:61][C:44]([O:43][C:41]3[CH:40]=[CH:39][N:38]=[C:37]([C:35]([OH:36])=[O:34])[CH:42]=3)=[CH:45][C:46]=2[N:50]=[C:49]1[NH:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1
Reactant: Cc1ccc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)cc1
Agent: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CI
Product: Cc1ccc(Nc2nc3cc(Oc4ccnc(C(=O)O)c4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl-4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl-4-{1-methyl-2-[(4-methylphenyl)amino)benzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-{1-methyl-2-[(4-methylphenyl)amino]benzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=374.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1.C([O-])(=O)C.[K+].C(OCC)(=O)C>[Pd].CO>[OH:28][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:29][CH2:30][CH2:31][OH:32])[C:12]3[CH:11]=[C:10]([C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=4[O:8][CH3:9])[C:22]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=4[C:20]=3[C:19]=2[CH:18]=1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCO
Yield: 51 %

Procedure:
4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OH) (106) (0.20 g, 0.44 mmol) prepared as described in example 59, potassium acetate (0.20 g) and 5% Pd/C in a solution of ethyl acetate (25 ml) and methanol 1:1 (25 mL) under a atmosphere of hydrogen at 60 psi was reacted for 7 h. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was partitioned between ethyl acetate and water and the organic solution was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate/petroleum ether (2:1) gave 9-Hydroxy-6-(3-hydroxypropyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-methoxyphenyl, R10═CH2CH2CH2OH) (107) in a yield of 51% as an orange powder (from THF/petroleum ether), mp 296–300° C. 1H NMR δ [(CD3)2SO] 10.93 (br s, 1H), 9.31 (br s, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (m, 1H), 7.35 (dd, J=7.5, 1.7 Hz, 1H), 7.13–7.08 (m, 2H), 7.05 (dd, J=7.2, 7.2 Hz, 1H), 4.62 (t, J=4.8 Hz, 1H), 4.48 (t, J=6.8 Hz, 2H), 3.68 (s, 3H), 3.40 (m, 2H), 1.90 (m, 2H). Found: C, 69.29; H, 4.90; N, 6.54. C24H20N2O5 requires C, 69.22; H, 4.84; N, 6.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH2:43])=[O:42].O>CN(C)C=O>[NH2:43][C:41](=[O:42])[CH2:40][O:22][C:18]1[CH:17]=[C:16]([S:13]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:11]2)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)CBr
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (215 mg, 0.66 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol), and then the reaction solution was stirred for 16 h. 50 mL of water was added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title product tert-butyl ((1-((3-(2-amino-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 2a (100 mg, a yellow oil) in 90% yield.
Reaction SMILES: [Cl-].[NH4+].CC[N:5]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]1[NH:48][C:49]1[C:57]([F:58])=[CH:56][C:52]([C:53](O)=[O:54])=[C:51]([Cl:59])[N:50]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.O.CN(C=O)C>[NH2:5][C:53]([C:52]1[CH:56]=[C:57]([F:58])[C:49]([NH:48][C@H:43]2[CH2:44][CH2:45][CH2:46][CH2:47][C@H:42]2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:50][C:51]=1[Cl:59])=[O:54]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C(=O)O)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C(N)=O)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.7 %

Procedure:
Ammonium chloride (1.10 g), WSC.HCl (2.97 g), HOBt.H2O (2.37 g), and diisopropylethylamine (7.06 ml) were added to a DMF solution (40 ml) containing 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid (2.00 g), followed by stirring at room temperature for 7 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(5-aminocarbonyl-6-chloro-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.75 g) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][C:10]3(OCC[O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A mixture of 2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-dione (8-2) (3.1 g, 7.48 mmol) and Toluenesulfonic acid monohydrate (0.14 g, 0.75 mmol) in acetone (50 mL) was refluxed for 2 days. The cooled mixture was diluted with EtOAc, washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0˜100% EtOAc in hexane, to give 2-[1-(4-bromophenyl)-3-oxocyclobutyl]-1H-isoindole-1,3(2H)-dione (8-3) as a colorless form.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:23][CH2:22][CH2:21][C@H:20]3[N:15]2[C:16](=[O:32])[CH:17](P(=O)(OCC)OCC)[CH2:18][CH2:19]3)=[CH:10][CH:9]=1)([O:6][CH3:7])=[O:5].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1)[CH:38]=O.C(OCC)(=O)C>O1CCCC1.C(O)C.[Cl-].[Na+].O>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1)/[CH:38]=[C:17]1/[C:16](=[O:32])[N:15]2[C@@H:20]([CH2:19][CH2:18]/1)[CH2:21][CH2:22][CH2:23][C@H:14]2[C:11]1[CH:10]=[CH:9][C:8]([C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(C(=O)OC)cc3)N2C1=O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc([C@@H]2CCC[C@@H]3CC/C(=C\c4ccc(-n5cnc(C)c5)c(OC)c4)C(=O)N32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Lithium hydroxide monohydrate (55 mg) was added to a mixed solution of diethyl [(6S*,9aR*)-6-(4-carbomethoxyphenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate (185 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (94 mg) in tetrahydrofuran (4 mL) and ethanol (1 mL), and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 191 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(OCC)C.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:36])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CCCS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene (76 mg, 0.18 mmol) obtained in Example 44 was dissolved in methylene chloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (36 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (methylene chloride:methanol=100:1) to yield a pale yellowish brown oil. The resulting pale yellowish brown oil was solidified with diethyl ether/methylene chloride, whereby the title compound (61 mg, 77%) was obtained as a white powder.