Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2([CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1.C(O)(=O)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>CO>[CH3:1][C@@H:2]1[C:6]2([CH2:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1
Reactant: C[C@H]1NC(=O)OC12CNC2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1NC(=O)OC12CN(Cc1ccccc1)C2
Temperature: 0 °C

Procedure:
A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for min. The mixture was then cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (EI) for C13H16N2O2: 233 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1)#[N:2].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])(=[O:16])=[O:15]>N1C=CC=CC=1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:25])=[O:24])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#N)c2c1
Yield: 11.5 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 0.55 g of 3-cyano-5-amino-1H-indazole, 10 ml of pyridine and 0.88 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.15 g of N-(3-cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a yellow powder melting at 272° C. (analysis C15H12N4O4S2.0.85H2O, % calculated C, 47.87; H, 3.21; N, 14.88; S, 17.04. % found C, 47.88; H, 3.01; N, 14.75; S, 17.45).
Reaction SMILES: [OH-].[Na+].C(O)(=O)C(O)=O.[Cl:9][C:10]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:11]=1[CH:12]([S:19][C:20]([CH3:22])=O)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[CH:28]1C(CCl)=[CH:32][CH:31]=[C:30]([Cl:36])[CH:29]=1>CO>[Cl:9][C:10]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:11]=1[CH:12]([S:19][CH2:20][C:22]1[CH:32]=[CH:31][C:30]([Cl:36])=[CH:29][CH:28]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)SC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CSC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 330 mg sodium hydroxide in 30 ml methanol under nitrogen is added 810 mg of 1-[2,4-dichloro-β-(methylcarbonylthio)phenethyl]imidazole oxalate and the mixture is stirred at room temperature for ca. 30 minutes (until thin layer chromatography shows the disappearance of the ester). α,p-dichlorotoluene (350 mg) is then added, the solution stirred a further 15 minutes and the solvent removed under reduced pressure. Ether and water are then added to the residue and the ether extract washed with water, dried (MgSO4) and concentrated. Dropwise addition of nitric acid (d = 1.42) until precipitation is complete gives the nitrate salt of 1-[2,4-dichloro-β-(4-chlorobenzylthio)phenethyl]imidazole, recrystallized from acetone, mp 130.5°-132° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:33]([O:37][C:38](=[O:49])[NH:39][C:40]1([CH2:46][CH2:47]O)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:49])[NH:39][C:40]1([CH2:46][CH2:47][N:18]2[C:17](=[O:22])[C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:3]=3[C:2]([F:31])([F:1])[F:32])[N:7]=[CH:8]4)[S:20][C:19]2=[O:21])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1(CCO)CCOCC1
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
[4-(2-{5-[1-(2,4-Bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}ethyl)tetrahydro-2H-pyran-4-yl]carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 6) and ([4-(2-hydroxyethyl)tetrahydro-2H-pyran-4-yl]carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([OH:28])=O)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C([N:32]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([NH2:32])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
To a solution of 5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrole-2-carboxylic acid (1.3 g) in N,N-dimethylformamide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (980 mg) and 1-hydroxybenzotriazole ammonium salt (926 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (910 mg, yield 70%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 403 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.ClS([N:33]=[C:34]=[O:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:34]([NH2:33])=[O:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(N)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 0.75 h
Yield: 13.8 %

Procedure:
To a solution of the compound from Example 6 (0.40 g) in tetrahydrofuran (10 mL) cooled to 0° C. was added dropwise chlorosulfonyl isocyanate (0.16 g) and the mixture was stirred for 45 min. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution (3 mL), diluted with ethyl acetate (10 mL), and the separated organic phase was washed (water, brine). TLC examination revealed that the major reaction product was present in the aqueous phase. Following saturation of the aqueous phase with sodium chloride, repeated ethyl acetate extractions (4×25 mL) were performed. The combined organic layers were dried (magnesium sulfate) and evaporated. Chromatography with dichloromethane:tetrahydrofuran (10:1) as the eluent, followed by overnight drying (50° C., 27 Pa) gave the title compound (0.061 g) as an off-white solid; TLC: Rf =0.36, dichloromethane:methanol (10:1); NMR: 8.85 (d,1), 8.69 (s,1), 8.35 (s,1), 7.48 (m,5), 6.47 (broad s, 2), 4.70 (dd,1), 4.55 (dd,2), 2.2 (m,1), 0.89 (dd,6); MS: m/z=440(M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12.O>CS(C)=O>[F:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12)[NH2:3]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
To a stirred suspension of NaH (0.432 g, 18.0 mmol) in DMSO (30 mL) was carefully added 4-amino-2-fluorophenol (1.91 g, 15.0 mmol) in portions. The reaction was stirred under N2 for 15 minutes. 7-Chlorothieno[3,2-b]pyridine (2.54 g, 15.0 mmol) was added as a solid. The reaction was heated to 100° C. for 2 hours. The reaction was allowed to cool to room temperature, and water (40 mL) was carefully added. The suspension was filtered. The brown solid was washed with water (2×10 mL), and dried by toluene azeotrope (5×20 mL) by rotary evaporation at 50° C. The solid was recrystallized from hot toluene (10 mL) to obtain a brown, crystalline solid (2.64 g, 68%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 7.73 (d, J=6 Hz, 1H), 7.56 (d, J=6 Hz, 1H), 7.04 (t, J=9 Hz, 1H), 6.51 (m, 3H), 3.83 (br s, 2H). LRMS (APCI pos) m/e 261 (M+1).
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:40])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC#N
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2O3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3H in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample 1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:36][NH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution containing 4-t-butoxycarbonylaminomethylbenzoic acid (5.0 g) and triethylamine (3.0 ml) in dry THF (180 ml) was treated at 10° C. with isobutyl chloroformate (2.7 ml) and the resulting mixture was stirred for 10 minutes. A solution of benzyl carbazate (3.4 g) in THF (20 ml) was added and the mixture was stirred for 15 hours at ambient temperature. The resulting precipitate was removed by filtration and the filtrate was diluted with ethyl acetate (500 ml) and washed with water (3×100 ml) and with saturated brine (100 ml). The organic solution was dried (MgSO4) and evaporated to a volume of 150 ml. After 1 hour the mixture was filtered to give benzyl 3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazate (3.6 g) as colourless prisms; m.p. 160°-162° C.; NMR Spectrum 1.4 (9H, s); 4.2 (2H, d); 5.1 (2H, s); 7.2-7.5 (2H+5H, m); 7.8 (2H, d); 9.3 (1H, s); 10.3 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[NH:11])=[CH:5][CH:4]=1.Br[CH:21]([CH3:29])[C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])(O)=O.[Na+]>CC(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:21]([CH3:29])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: COc1ccc(NC(=N)c2ccc(Cl)cc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OC)cc2)c1C
Yield: 41.8 %

Procedure:
Part A: N-(4-methoxyphenyl)-2,4-dichlorobenzenecarboxamidine (15.0 gram, 50.8 mmol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (23.5 g, 2 molar equivalents) and NaHCO3 (8.5 gram, 2 molar equivalents) are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxy-phenyl)-1H-imidazole-4-carboxylate (8.61 g, 42% yield) as a solid. 1H-NMR (200 MHz, CDCl3): δ 7.33 (d, J=8 Hz, 1H), 7.27 (d, J=2 Hz, 1H), 7.18 (dd, J=8 Hz, J=2 Hz, 1H), 7.03 (dt, J=8 Hz, J=2 Hz, 2H), 6.85 (dt, J=8 Hz, J=2 Hz, 2H), 4.42 (q, J=7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H), 1.43 (t, J=7 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]([O:15]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCCC1.C>[O:1]=[C:2]1[N:6]([C:12]([Cl:11])=[O:15])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Product: O=C(Cl)n1c(=O)[nH]c2ccccc21
Yield: 257 %

Procedure:
To a 1 L, 3-neck round bottom flask fitted with a thermometer, condenser, and an addition funnel was placed 2-hydroxybenzimidazole (36.9 g, 275 mmol), 275 mg of activated charcoal, and 750 mL of dry tetrahydrofuran. The bis(trichloromethyl)carbonate (36.3 g, 122 mmol), dissolved in 100 mL of tetrahydrofuran, was added dropwise at room temperature. The addition funnel was replaced with a gas outlet tube that was dipped into an aqueous concentrated ammonium hydroxide trap. The mixture was heated at reflux for about 18 hours. The solids which formed were filtered and the filtrate was evaporated under reduced pressure to give 61.64 g of a white solid which was used in subsequent reactions without further purification. Yield: >100%.
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH:11]=[O:25])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at −72 to −69° C. After 4 hours at −75° C., 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbalde-hyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0° C., to a solution, in which previously 5 g of triethyl-2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0° C. with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydro-furan/heptane/ethylbenzene. After 20 hours at room tempera-ture, water is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to 90° C. with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2SO4) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1O)=[O:2].[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:1]=[O:2])([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: O=Nc1c(O)ccc2ccccc12
Product: CC(C)Nc1ccc2ccccc2c1N=O

Procedure:
The starting N-isopropyl-1-nitroso-2-naphthaleneamine is prepared through reaction of 1-nitroso-2-naphthol with isopropylamine according to the method described in J. Am. Chem. Soc. 70, 2415 (1948).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCNCC1
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 51.6 g of isonipecotic acid in 200 ml of acetic anhydride is refluxed for 2 hours and allowed to stir at ambient temperature for 16 hours. The solution is concentrated and the resulting residue is triturated in ether. The solid is collected by filtration and recrystallized from an isopropyl alcohol-diisopropyl ether mixture giving 1-acetylisonipecotic acid as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([CH:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Product: CC(C)(C)C1CCC(Nc2cccc3nc(NC(=O)c4cccnc4)nn23)CC1

Procedure:
The title compound was prepared following procedure and work up described for example 79 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.) and 4-tert-butylcyclohexylamine (91 mg; 0.58 mmol; 2.0 eq.) as a white powder (32 mg, 27%). HPLC, Rt: 4.63 min. (purity 99.3%). LC/MS, M+(ESI): 393.1, M−(ESI): 391.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][CH2:35][CH2:36][CH3:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCCI
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCOc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.3 g) obtained in Example 2 was suspended in dimethyl sulfoxide (30 ml), and to the suspension was added potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 30 minutes. 1-iodobutane (0.1 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (0.25 g, 73%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14](Cl)(=[O:16])=[O:15])=[N:3]1.[NH3:18]>O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:18])(=[O:16])=[O:15])=[N:3]1
Reactant: N
Reactant: Cn1nc(-c2ccccc2S(=O)(=O)Cl)oc1=O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2S(N)(=O)=O)oc1=O
Reaction time: 1.5 h

Procedure:
To a suspension of 3.3 g of the product of Example 3 in 50 ml of tetrahydrofuran was added dropwise 3 ml of condensed ammonia while keeping the reaction temperature at -5° C. with external cooling. After stirring at 0° for 1.5 hours, the solvent was evaporated in vacuo and water was added to the residue to yield a precipitate. After filtration the isolated residue was washed with water, then dissolved in tetrahydrofuran and dried over MgSO4. After evaporation of the solvent in vacuo, 2.9 g of the subject compound was obtained as a crude solid; m.p. 168°-173° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]2[C:7]([N+:12]([O-:14])=[O:13])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)[nH]c2ccncc21
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c2ccnc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 1.73 g (11.6 mmol) of 3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 6.3 mL of concentrated sulfuric acid, cooled in an 0° C. ice bath, was slowly added a solution of 1.50 mL (36.0 mmol) of fuming nitric acid in 1.5 mL of concentrated sulfuric acid. The reaction was removed from the ice bath and stirred for 0.5 h at room temperature and then heated at 100° C. for 2 h. The reaction was quenched over 300 mL of ice and solid ammonium carbonate was added to adjust the pH to 9. The resulting slurry was filtered and the collected solids washed with water and dried under high vacuum to give 1.94 g (86%) of the title compound.