Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([C:20]1[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][CH:25]=1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[Pd]>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:2])[CH3:3]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3=CCCN(C(=O)OC(C)(C)C)C3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3CCCN(C(=O)OC(C)(C)C)C3)nc21
Temperature: 60 °C
Yield: 75.3 %

Procedure:
A solution of tert-butyl 3-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (821 mg, 1.87 mmol) in ethanol (35 mL) was degassed with nitrogen and to this was added 10%-Pd/C (150 mg), and ammonium formate (650 mg, 10 mmol). The resulting mixture was stirred and heated at 60° C. for 3 hr. The reaction was cooled to ambient temperature and the catalyst was removed by filtration. The filtrate was evaporated to give a residue, which was taken into ethyl acetate (100 mL) and the solution washed with water (30 mL), brine (30 mL), dried over Na2SO4 and evaporated to give a residue that was purified via flash chromatography with a gradient from 100% heptane to 100% ethyl acetate to afford the title compound (620 mg), which was used in the following step.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25]C)[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[CH:23]=[CH:22][NH:21][C:20](=[O:25])[C:19]=3[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NCC2CC2)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 71 %

Procedure:
The product from Example 44B (0.035 g, 0.091 mmol) and 4 M hydrogen chloride in dioxane (0.023 mL, 0.091 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated. Purification by reverse phase chromatography (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.024 g, 53%) as the TFA salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (d, J=5.43 Hz, 1H) 7.62 (dd, J=8.82, 2.37 Hz, 1H) 7.45-7.48 (m, 2H) 6.86-6.91 (m, 1H) 6.84 (d, J=8.82 Hz, 1H) 6.21 (dd, J=6.78, 1.02 Hz, 1H) 5.50 (s, 1H) 4.12 (s, 3H) 3.09 (s, 3H) 3.05 (d, J=6.44 Hz, 2H) 0.95-1.14 (m, 1H) 0.38-0.45 (m, 2H) 0.17-0.24 (m, 2H). MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[N+:26]([C:29]1[NH:30][CH:31]=[C:32]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[N:33]=1)([O-])=O.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[N:35]1([CH2:34][C:32]2[N:33]=[C:29]([NH:26][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:24])[NH:30][CH:31]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: O=[N+]([O-])c1nc(CN2CCCC2)c[nH]1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCCC4)c[nH]3)c3nccnc23)c1F
Temperature: 65 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 6 h at 65° C. and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1). 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step 19.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 495.0 [M+H]+; tR=3.28 min (System 1); TLC: Rf=0.08 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
In an argon atmosphere, 5.63 g (24.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding 5.38 g (54.3 mmol) of 2,2,2-trifluoroethylamine, the mixture was stirred at room temperature for 15 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./4.7×102 Pa) to obtain 1,3-di-tert-butyl-2-(2,2,2-trifluoroethyl)amino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHCH2CF3) as a pale yellow liquid (yielded amount: 4.74 g, yield: 66%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]=2[CH:4]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[CH3:21])[C:3]=1[C:22]#[N:23].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:24][N:7]1[C:2]([CH3:1])=[C:3]([C:22]#[N:23])[CH:4]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[CH3:21])[C:5]2[C:10](=[O:11])[O:9][CH2:8][C:6]1=2
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(COC2=O)N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(COC2=O)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.326 mmol) 2-methyl-4-(3-methyl-1H-indazol-5-yl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 1) in DMF (2 ml) was cooled to 0° C. 128 mg (0.392 mmol) caesium carbonate were added at this temperature, and after 30 min 14 μl (0.229 mmol) methyl iodide were added dropwise. After stirring overnight at rt, additional methyl iodide (2 μl) was added, and stirring at rt was continued for further 3 h. Again, methyl iodide (6 μl) and a small amount of caesium carbonate were added, and the reaction mixture was stirred at rt overnight before water (1 ml) was added. The solution was directly purified first by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) followed by preparative TLC (eluent: dichloromethane/ethanol 20:1) to give 11 mg (11% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:16]([CH2:29]Br)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:18])[CH2:29]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C(Br)CBr
Reactant: CCNCCNc1ccc(Cl)c(Cl)c1
Product: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to preparation 23, react N-(3,4-dichlorophenyl)-N'-ethyl-1,2-ethanediamine with 2,3-dibromo-N-(4-nitrophenyl)propanamide to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1Cc1sc3ncccc3c1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Yield: 63.7 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[2-methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.13 g, 0.23 mmoles), methanol (6 ml) and 4N HCl (2 ml). Recrystallization from chloroform/hexanes provided 70 mg (63%) of the title compound as a white crystalline solid, m.p. 182-184° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[S:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(O)c(S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)SC(c1ccc(Cl)cc1Cl)O2
Reaction time: 2 h
Yield: 18.7 %

Procedure:
2-Mercapto-4-nitrophenol (2.0 g) and 2,4-dichlorobenzaldehyde (2.0 g) were heated under reflux for 6 hours in toluene (70 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate. Water formed in the reaction was separated by means of a Dean-Stark apparatus. The resulting reaction mixture was evaporated under reduced pressure, and the residue extracted with cyclohexane. The cyclohexane solution was then evaporated and the residue chromatographed on silica gel using methylene chloride/5% (v/v) methanol as eluant. The material obtained at this stage was contaminated with unreacted aldehyde. This was removed by stirring a methylene chloride solution of the crude product with 30% aqueous sodium bisulphite for 2 hours and then washing the solution successively with saturated sodium bicarbonate solution and water. After drying over anhydrous sodium sulphate, the methylene chloride was removed under reduced pressure. Crystallisation of the residue afforded the pure product as pale yellow crystals (0.7 g, 21%), mp 106°-108° C.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[CH:8]=[O:9])=[O:4])[CH3:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[CH:8]=[O:9])(=[O:16])=[O:4])[CH3:2]
Reactant: CCOc1cc(C=O)cc(S(=O)CC)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc(S(=O)(=O)CC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of (±)-3-ethanesulfinyl-5-ethoxy-benzaldehyde (0.39 g, 1.72 mmol, 1.0 equiv) in conc. acetic acid (10 mL) was added a solution of 35% hydrogen peroxide in water (0.60 mL, 0.67 g, 6.89 mmol, 4.0 equiv). After stirring the reaction mixture for 18 h at rt, the pH was adjusted to 10 by addition of a 1 M solution of NaOH, extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 0.09 g (22%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.31 (t, J=7.4 Hz, 3H), 1.48 (t, J=7.0 Hz, 3H), 3.17 (q, J=7.4 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 7.63-7.66 (m, 2H), 7.94-7.95 (m, 1H), 10.04 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.46, 18.59, 54.59, 68.89, 122.74, 123.94, 125.68, 142.60, 145.26, 164.29, 194.24. MS (ISP): 243.3 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[C:29]([O:30][CH3:31])=[C:28]4[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]4[CH:32]4[CH2:34][CH2:33]4)=[C:22]([N+:39]([O-])=O)[C:21]=3[F:42])[CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[OH-].[Na+].C(=O)=O>C(O)(=O)C.[C].[Pd].O>[NH2:39][C:22]1[C:21]([F:42])=[C:20]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:19]3)[C:29]([O:30][CH3:31])=[C:28]2[C:23]=1[C:24](=[O:38])[C:25]([C:35]([OH:37])=[O:36])=[CH:26][N:27]2[CH:32]1[CH2:33][CH2:34]1
Reactant: COc1c(-c2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1c(-c2ccc3c(c2)CNC3)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 10 ml of acetic acid and 60 mg of 5% palladium carbon was suspended 85 mg of 7-[2-(benzyloxycarbonyl)isoindolin-5-yl]-1-cyclopropyl-6-fluoro-8-methoxy-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the suspension was stirred at room temperature for two hours under a hydrogen stream. The reaction mixture was filtered, and thereafter, 2 ml of 6N hydrochloric acid was added to the filtrate obtained, after which the resulting mixture was concentrated under reduced pressure. To the residue obtained were added ethanol, and the crystals formed were collected by filtration. To the crystals obtained were added 0.5 ml of ethanol, 0.5 ml of 1N aqueous sodium hydroxide solution and 0.5 ml of water to dissolve the crystals. Thereafter, a carbon dioxide gas was blown into the solution, and the crystals precipitated were collected by filtration, to obtain 55 mg of pale yellow, crystalline 5-amino-1-cyclopropyl-6-fluoro-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.C(=[NH:27])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(Cl)(Cl)Cl>[NH2:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)cnc1OC
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(N)cnc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
In an atmosphere of nitrogen gas, 11.4 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was dissolved in 227 mL of toluene, and 10.3 g of benzophenoneimine, 0.42 g of tris(dibenzylideneacetone)dipalladium, 0.86 g of (s)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 6.20 g of sodium tert-butoxide were successively added. The mixture thus obtained was stirred at 80° C. for one hour. After cooling the reaction mixture, it was filtered. The filtrate was purified by column chromatography [eluent: toluene:ethyl acetate=20:1]. The oily product thus obtained was dissolved in 140 mL of tetrahydrofuran, 7 mL of 2 mol/L hydrochloric acid was added, and the mixture thus obtained was stirred at room temperature for 15 minutes. A mixture of 200 mL of chloroform and 50 mL of water was added to the reaction mixture and then 1 mol/L sodium hydroxide was added to alkalinize the mixture, and the organic layer was separated. The organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: toluene:ethyl acetate=1:1] to obtain 3.64 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a yellow-colored oily product.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([O:60]C)=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([OH:60])=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 114 was prepared analogous to compound of example 98 by hydrolysis of compound of example 113.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:17]=1.[OH-].[K+]>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63 %

Procedure:
To a solution of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g, 0.861 mmol) in THF (5.0 mL) was added KOH aqueous solution (0.096 g, 1.72 mmol) and the reaction mass was stirred at RT for 3-4 h. The reaction mass was quenched in water and extracted with ethyl acetate and concentrated to afford 0.200 g of the desired product.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:30])[N:20]2[CH2:27][CH2:28][OH:29]>O.C(N(CC)CC)C>[Cl:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:30])[N:20]2[CH2:27][CH:28]=[O:29]
Reactant: COc1ccc(Cl)c2ccc(=O)n(CCO)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Cl)c2ccc(=O)n(CC=O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1.2 mL of a dichloromethane solution containing 21 μL of oxalyl chloride, 26 μL of dimethylsulfoxide was added dropwise under nitrogen atmosphere at −78° C., and stirred for 15 min. 1 mL of a dichloromethane solution containing 31 mg of 5-chloro-1-(2-hydroxyethyl)-8-methoxyquinolin-2(1H)-one was added dropwise at the same temperature, and stirred for 30 min. 84 μL of triethylamine was added at the same temperature, the mixture was stirred for 1.5 hours while slowly raising the reaction mixture to room temperature, and 0.5 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (5-chloro-8-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)=O.[F:19][C:20]([F:31])([F:30])[C:21]([O:23]C(=O)C(F)(F)F)=[O:22]>>[F:19][C:20]([F:31])([F:30])[C:21]([O:23][CH2:1][S:2][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)=[O:22]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC(C)C(=O)c1ccc(S(C)=O)cc1
Product: COC(=O)CC(C)C(=O)c1ccc(SCOC(=O)C(F)(F)F)cc1

Procedure:
A solution of the sulfoxide from Step C of this Example (10 g) in trifluoroacetic anhydride (50 ml) was heated at 45° C. for 25 minutes and the mixture was evaporated, and then coevaporated with toluene, to dryness to give the title compound as an oil (15 g, crude) which was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:14][N:15]([CH3:19])[C:16](=[S:18])[S-:17].C[NH2+]C.C(=S)=S>CO>[CH3:14][N:15]([CH3:19])[C:16](=[S:17])[S:18][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Agent: C[NH2+]C
Solvent: S=C=S
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
2,4-Dichloro-β-nitrostyrene (6.6 grams, 0.030 mole) was added to a stirred solution of dimethylammonium dimethyldithiocarbamate (5.1 grams, 0.030 mole) and carbon disulfide (1.8 ml., 0.030 mole) in methanol (30 ml.). The temperature of the resulting reaction was 16-32° C. After two hours at room temperature, the precipitated product was filtered off, washed with cold methanol, and dried in air. Recrystallization without heating was accomplished by dissolving the sample in acetone and then adding absolute ethanol to give 2,4-dichloro-α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 127° C.-128° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(OCCOCCO)C.CO.C[O-].[Na+]>O.CCCCCCC>[O:16]=[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]#[N:13]
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOCCOCCO
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 85.3 %

Procedure:
In a 300 mL-reaction flask equipped with a rectification column and a separating tank, 11.3 g (65.2 mmol) of 4-tert-butylphenylacetonitrile, 10.8 g (59.5 mmol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 100 g of heptane, and 1.5 g of diethylene glycol monoethyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 13.8 g (71.5 mmol) of 28% sodium methoxide methanol solution was added dropwise over 3 hours, and the resulting mixture was further reacted for 7 hours. After cooling to 30° C. or less, 108 g of water was added to separate out heptane phase and obtain an aqueous phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 15.7 g (yield 85.8%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH2:23]Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[C:37]2[C:32](=[CH:33][N:34]=[CH:35][CH:36]=2)[NH:31][N:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH2:23][N:31]2[C:32]3=[CH:33][N:34]=[CH:35][CH:36]=[C:37]3[C:29]([S:26]([CH3:25])(=[O:27])=[O:28])=[N:30]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CC(C)(C)OC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
3-[5-Chloro-2-(3-methanesulfonyl-pyrazolo[3,4-c]pyridin-1-ylmethyl)-benzoimidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared in analogy to Example 2-1 by using 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine. MS obsd. (ESI+) [(M+H)+] 531.1.