Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](CO)=[N:10]2)=[CH:5][CH:4]=1.BrCC(OCC)=O.C([O:29][C:30](=[O:34])[CH2:31][O:32][CH3:33])C.[OH-].[Na+]>C1COCC1.C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([CH:31]([O:32][CH3:33])[C:30]([OH:29])=[O:34])=[N:10]2)=[CH:7][CH:8]=1
Reactant: OCc1nn(-c2ccc(Br)cc2)c2c1CCCC2
Reactant: CCOC(=O)COC
Agent: CCOC(=O)CBr
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(C(=O)O)c1nn(-c2ccc(Br)cc2)c2c1CCCC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of sodium hyride (0.63 g) in THF (65 ml) was treated with the compound of Example 77 (4.0 g) and heated at 60° C. for 3 hours. Ethyl bromoacetate (10.9 g) was added to the cooled mixture and the reaction was allowed to proceed at ambient temperature overnight. The crude methoxy acetic acid ethyl ester was poured into ethanol (200 ml), treated with 3N sodium hydroxide and heated at reflux temperature for 1.5 hours. The solution was concentrated to 100 ml, diluted to 250 ml with water and unreacted compound of Example 77 extracted into ethyl acetate. The aqueous phase was acidified and crude product filtered. Ethanol crystallization gave the title compound (2.18 g, m.p. 123° C.). An analytical sample, m.p. 183° C., was obtained from ethanol solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:22][C:23]([C:25]1[C:26]([OH:36])=[N:27][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:29][CH:30]=1)=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:20])[O:17]CC)=[CH:12][CH:11]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:22][C:23]([C:25]1[C:26]([OH:36])=[N:27][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:29][CH:30]=1)=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:17])[OH:20])=[CH:12][CH:11]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2F)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((R)-(2,4-difluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinate, 20-f, (400 mg, 0.78 mmol) was dissolved in 5 ml of dioxane and treated with 0.5 ml of 5N NaOH. The mixture was heated at 80° C. for one hour. The mixture was then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with AcOH and evaporated to dryness. The residue was used for prep-HPLC to afford the product, 20-1, (100 mg, 26%). 1H NMR (300 MHz, CD3OD): δ 8.67 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.81 (m, 2H), 7.48 (m, 3H), 7.04 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 1.66 (d, 3H). (M−H)−=484.0.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[S:19][C:18]3[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:16][C:15]([C:26]4[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=4)=[N:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[OH:32][C:28]1[CH:27]=[C:26]([C:15]2[N:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:18]3[S:19][C:11]([CH2:10][N:7]4[CH2:6][CH2:5][CH:4]([NH:3][C:40](=[O:42])[CH3:41])[CH2:9][CH2:8]4)=[CH:12][C:13]=3[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Cl
Reactant: NC1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-[6-(4-Amino-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenol di-hydrochloride salt (80 mg, 0.16 mmol) in dichloromethane (1.5 mL) and triethylamine (5 eq., 110 μL) was added acetyl chloride (2.5 eq., 29 μL). After stirring at rt for 2 hours, the reaction mixture was diluted with dichloromethane, washed with brine, separated and dried (MgSO4). The crude product was evaporated in vacuo, re-dissolved in methanol (2 mL), to this was added sodium carbonate. The reaction mixture was stirred at RT overnight, evaporated in vacuo, diluted with dichloromethane, washed with brine, separated and dried (MgSO4). The residue was purified by chromatography to give the title compound as a white solid (55 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)=[O:6].Cl[CH2:19][C:20]#[N:21].C>ClCCl.[OH-].[Na+].[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]1[CH2:8][CH2:9][C:10]2([O:13][CH:19]2[C:20]#[N:21])[CH2:11][CH2:12]1)=[O:6]
Reactant: O=C1CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Reactant: N#CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC1OC12CCN(C(=O)c1ccc(F)c(Cl)c1)CC2
Temperature: 15 °C

Procedure:
A suspension of 1-(3-chloro-4-fluorobenzoyl)piperidin-4-one (4160 g, 16.27 mol) in 28.4 liters of dichloromethane and 11.7 liters of sodium hydroxide at 30.5%, supplemented with 186 g of tetrabutylammonium chloride, is cooled to 15° C. Chloroacetonitrile (1540 ml, 24.4 mol) is then added slowly and with vigorous stirring and the mixture is stirred for 3 hours at 20° C. Further addition of chloroacetonitrile (500 ml) is carried out in order to complete the reaction. The reaction medium is diluted with dichloromethane (8.5 liters) and water (20 liters) and then separated by decantation and washed again with water. The brown solution obtained is decolorized with 2 kg of silica and 500 g of animal charcoal and then evaporated to dryness. The residue obtained is crystallized from isopropanol in order to give, after filtration, 3426 g of brown crystals. m.p.=100–101° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH2:23][C@H:22]3[N:19]([C:20](=[O:27])[C@@H:21]3[C@H:24]([OH:26])[CH3:25])[C:18]=2[C:28]([O:30]CC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>P([O-])([O-])([O-])=O.[Pd]>[OH:26][C@@H:24]([C@H:21]1[C:20](=[O:27])[N:19]2[C@@H:22]1[CH2:23][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[C:18]2[C:28]([OH:30])=[O:29])[CH3:25]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C3=CCN(C(=O)OCc4ccccc4)CC3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNCC3)C[C@H]12
Yield: 58.6 %

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (500 mg) in 0.1M phosphate buffer (pH 6.93, 20 ml) was added 20% (W/W) palladium on carbon (50% wet) and the solution was stirred under atmospheric pressure of hydrogen at ambient temperature for 5 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a residual solution, which was chromatographed on "Diaion HP-20" (100 ml) eluting in turn with water and a mixture of water and acetone (50:1-20:1, V/V). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(piperidin-4-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (150 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:30])[CH2:28][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCN(CC(=O)N2CCC(c3ccc(NC(=O)OC(C)(C)C)cc3)CC2)CC1
Reaction time: 16 h
Yield: 80 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1occc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1occc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 95.1 %

Procedure:
A solution of 4-(2-methoxycarbonylfuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.1 g, 6.8 mmol, 1.0 eq.) and Raney Ni (1.0 g) in MeOH (150 mL) was degassed and purged with hydrogen (3×). The mixture was hydrogenated (1 atm) for 2 days, then purged with nitrogen, filtered and washed with MeOH (50 mL). The filtrate was concentrated to yield 4-(2-methoxycarbonylfuran-3-yl)piperidine-1-carboxylic acid t-butyl ester (2.0 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2Cl)CC1
Reaction time: 48 h
Yield: 61.2 %

Procedure:
A solution of 2-chloro-5-nitroaniline (1 g, 5.79 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.309 g, 11.59 mmol) in dichloroethane (15 mL) and acetic acid (0.995 mL, 17.38 mmol) was stirred at room temperature for 30 minutes. At this time, the reaction was treated with sodium triacetoxyborohydride (3.07 g, 14.49 mmol), and the resulting mixture was stirred over the weekend. Additional tert-butyl 4-oxopiperidine-1-carboxylate (2.309 g, 11.59 mmol), sodium triacetoxyborohydride (3.07 g, 14.49 mmol), and dichloroethane (15 mL) were added. Stirring was continued for 2 days. The mixture was then diluted with water and 1N sodium hydroxide (basified to pH 10) and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 ethyl acetate:hexanes, giving a yellow/orange foam (1.26 g, 61.1%). 1H NMR (DMSO-d6) δ 7.54 (d, J=8.7 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.39 (dd, J=8.7, 2.4 Hz, 1H), 5.76-5.63 (m, 1H), 3.99-3.90 (m, 2H), 3.74-3.62 (m, 1H), 3.05-2.80 (m, 2H), 1.89-1.80 (m, 2H), 1.49-1.32 (m, 11H); ESI-MS (m/z, %): 378 (M+Na, 100), 356 (MH+, 40), 300 (62).
Reaction SMILES: [H][H].[CH2:3]([N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-])=O)[CH:30]=2)[NH:25][C:24]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Ni]>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][C:24]=1[C:35]1[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Ni]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a stirred solution of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}-(4-pyridin-3-yl-butyl)amine (350 mg in 30 mL absolute ethanol) was added ca. 30 mg of Raney” nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 3 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) gave the title compound (246 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CN(C=O)C.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C.O>[C:22]([Si:26]([O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:29])[CH3:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O)cc(OC)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 95.4 %

Procedure:
To a mixture of 3,5-dimethoxyphenol (3.00 g, 19.5 mmol) and DMF (45 mL) were added imidazole (2.66 g, 39.0 mmol) and tert-butyldimethylchlorosilane (2.94 g, 19.5 mmol) in that order, and the mixture was stirred for 19.5 hours at room temperature. Water was added to the reaction mixture, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=9/1) to obtain the title compound (4.98 g, 18.6 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.OS(O)(=O)=O.[CH2:17]([N:24]1[C:36]2[CH:35]=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH2:40][C:41]#[N:42])[C:31]=2[C:30]2[C:29]([C:43]([NH2:45])=[O:44])=[CH:28][CH:27]=[CH:26][C:25]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH2:42][CH2:41][CH2:40][O:39][C:32]1[C:31]2[C:30]3[C:29]([C:43]([NH2:45])=[O:44])=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:36]=2[CH:35]=[C:34]([O:37][CH3:38])[CH:33]=1
Reactant: COc1cc(OCC#N)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(OCCN)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To 1.25 ml (1.25 mmol) 1M lithium aluminum hydride/THF in 8.3 ml THF at 0° C. was added H2SO4(34.5 μl, 0.63 mmol) dropwise over 5 min. The mixture was allowed to stir at room temperature 1 hour, then a suspension of 9-benzyl-4-cyanomethyloxy-2-methoxycarbazole-5-carboxamide (0.32 g, 0.83 mmol) in 8.3 ml THF was added dropwise at a rate which kept the temperature below 26° C. After an additional 45 minutes, the reaction was quenched with 0.32 ml 1:1 THF/H2O, 0.48 ml 13% NaOH, and finally 51 μl H2O. The reaction was diluted with EtOAc and saturated NaHCO3, and the layers separated. The organic layer was extracted with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 9:1:0.1 CH2Cl2/MeOH/NH4OH to give the subtitled product (148 mg, 46%). MS (ES+) 390
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][CH2:7][CH2:8][OH:9])([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>CCO>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][CH2:7][CH2:8][OH:9]
Reactant: O=[N+]([O-])c1ccccc1NCCO
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1NCCO
Yield: 85.9 %

Procedure:
According to the procedure of B. Agai, et al., Tetrahedron, 32, 839, (1976), a mixture of 2-(2-nitroanilino)ethanol (43.1 g, 0.237 mol), SnCl2.2 H2O (267.0 g, 1.18 mol), and EtOH (400 mL), was heated under reflux for 4 hours. The mixture was cooled, made basic (pH8) with 2.5N NaOH, and filtered through Celite. The filtrate was concentrated to remove the EtOH and the aqueous phase was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried, and concentrated. Recrystallization from EtOH gave 31.0 g (86%) of a brown solid m.p. 105°-106° C.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=2)(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=2[C:47]=1[O:48][CH3:49]>>[Cl:28][C:27]1[C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([N:9]2[CH2:10][CH2:11][C@H:7]([OH:6])[CH2:8]2)(=[O:13])=[O:14])=[N:23][C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[CH2:42][CH:41]([NH:43][CH2:44][CH2:45][OH:46])[CH2:40][CH2:39][CH2:38][C:37]=3[C:47]=2[O:48][CH3:49])=[N:25][CH:26]=1
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine (150 mg, 0.30 mmol) and 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a white foam. Mp: 92-5° C. LCMS (m/e) 603 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.50 (m, 1H), 8.18 (s, 1H), 8.00 (m, 2H), 7.62 (m, 1H), 7.50 (br s, 1H), 7.29 (m, 1H), 6.81 (m, 1H), 4.37 (m, 1H), 3.74 (s, 3H), 3.61 (m, 2H), 3.43 (m, 3H), 3.30 (m, 1H) 2.98-2.70 (m, 7H), 2.03 (m, 1H), 1.86 (m, 2H), 1.63 (m, 6H).
Reaction SMILES: O=[C:2]1[C:10]2([CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)O2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.[NH2:23][NH2:24]>C(O)(=O)C.CO>[NH:23]1[C:2]2[C:3]3[C:8]([CH2:9][C:10]=2[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[N:24]1)=[CH:7][CH:6]=[CH:5][CH:4]=3
Reactant: NN
Reactant: O=C(O)c1ccc(C2OC23Cc2ccccc2C3=O)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
4-(1-Oxospiro[indan-2,2′-oxiran]-3′-yl)benzoic acid from part b) (780 mg), methanol (50 ml), hydrazine hydrate (0.18 ml) and glacial acetic acid (6 drops) were boiled under reflux for 24 hours. The mixture was cooled in ice and filtered to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid, m.p. >320° C.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[S:28][C:27]([C:29](O)=O)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:54](=[N:57][OH:58])([NH2:56])[CH3:55].O>CN(C=O)C>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[S:28][C:27]([C:29]5[O:58][N:57]=[C:54]([CH3:55])[N:56]=5)=[N:26][C:25]=4[C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:36][CH:37]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(N)=NO
Reactant: CC(C)(c1cc(-c2cccc(-c3sc(C(=O)O)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)c(-c3cccc(-c4cc(C(C)(C)S(C)(=O)=O)cc5cccnc45)c3)s2)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of acid from step 1 in DMF (0.05M) was added CDI (1.1 eq) and, after 5 min, acetamidoxime (1.1 eq). The reaction mixture was stirred at rt for 1 h and 18 h at 110° C. The reaction mixture was cooled to rt and poured into water. The residue was purified by flash chromatography (toluene:EtOAc, 45:55) to afforded the title compound and decarboxylated analog EXAMPLE 73 (more polar product).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cnc2c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(N3CCOCC3)cnc2c1

Procedure:
Into 10 ml of THF was dissolved 1.16 g of 2-chloro-6-nitroquinoxaline, and then 20 ml of morpholine was added thereto, followed by heating under refluxing for 30 minutes. Then, the solvent was removed by evaporation. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline. After the solvent was removed by evaporation, the residue was crystallized from diethyl ether to obtain 1.5 g of the title compound.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:24](=O)[CH3:25])[CH:23]=1>CO.C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22](/[C:24](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:25])[CH:23]=1
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N(C)C)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 18.4 %

Procedure:
3-(Hydrazinecarbonyl)-N,N-dimethylbenzenesulfonamide (50 mg, 0.0.206 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (35.1 mg, 0.206 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (15 mg). 1H NMR (400 MHz, acetone-d6): δ 8.29 (m, 2H), 8.01 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.62 (d, 1H, J=2.4 Hz), 7.32 (dd, 1H, J=2.4 & 8.8 Hz), 6.96 (d, 1H, J=8.8 Hz), 2.73 (s, 6H), 2.58 (s, 3H). ESI-MS: 396.0 [M+H]+.