Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:16][CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2ccc(C3=CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CC=C(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 427, cyclopropanesulfonyl chloride (6.0 uL, 0.06 mmol), and triethylamine (26.0 uL, 0.19 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([O:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Product: CCOC(=O)c1cc2ccccc2n1Oc1ccc(OC)cc1
Yield: 51 %

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (231 mg, 1.10 mmol) with 4-methoxyphenol (1.4 equiv., 186 mg, 1.5 mmol) as described in General Synthetic Procedure VIII to afford 3-(4-methoxyphenoxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=4-methoxyphenyl, 169 mg, 51%) as an ivory-colored solid. Hydrolyze the ester to the carboxylic acid 7 (R1=4-methoxyphenyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Im as a colorless oil, tlc (silica gel) Rf=0.10.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][OH:20])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][O:20][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCCCCCCCCC(=O)N(CCO)CCO
Product: CCCCCCCCCCCC(=O)N(CCOC(=O)c1ccco1)CCOC(=O)c1ccco1

Procedure:
N,N-bis(2-furoyloxyethyl)lauramide was prepared by the procedure of example 1 from 28 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)lauramide and 26 gms. (0.2 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:43])[CH2:9][N:10]([C:15](=[O:42])[C@H:16]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:17][S:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[CH3:32][O:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:33][CH3:34])[CH:22]=[C:21]([S:18]([NH:17][C@H:16]([C:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([OH:43])=[O:7])=[O:42])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:19])=[O:20])[CH:30]=[CH:29]2
Reactant: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.43 g (79 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid, I.R. (KBr): 3,360, 3,140, 1,622 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[C:42](=[O:44])=[O:43]>>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[C:11](=[O:21])[N:12]3[C:17](=[C:8]([C:6](=[O:7])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:9]=2)[C:16]2[S:18][C:19]([C:42]([OH:44])=[O:43])=[CH:20][C:15]=2[CH:14]=[CH:13]3)=[CH:23][CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=O
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(C(=O)O)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with carbon dioxide.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2>CO>[OH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: C1CCC2OC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (18.5 g), 0.20 mole) was added to methanol (125 ml) containing sodium methoxide [prepared from sodium (9.3 g, 0.40 mole)] cooled by an ice bath. After 20 minutes, cyclohexene oxide was added slowly during 20 minutes. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours at which time it was poured into water (250 ml) containing concentrated hydrochloric acid (50 ml) and brine (200 ml). The reaction mixture was extracted three times with 150 ml of diethyl ether. The combined diethyl ether extracts were washed twice with 50 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator to give the product as an oil. The structure was supported by NMR.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N(CC)CC)C.C([O:43][CH:44]=[CH:45][CH3:46])C>O>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:44](=[O:43])[CH2:45][CH3:46]
Reactant: CC=COCC
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2.5 mmol), bis[1,2-bis(diphenylphosphino)ethanelpalladium(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5 mmol) in DMP (45 ml) was heated at 100° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was then dissolved in DMP (25 ml) and 2M HCl (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate. The extracts were separated, evaporated under reduced pressure, and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (1.3 g, >99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH2:21]([C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[CH3:22]
Reactant: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (13 g) and vinylboronic acid pinacol ester (10 g) were added toluene (90 mL) and water (4.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in ethanol (90 mL), 5% palladium carbon-ethylenediamine complex (2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (20 mL), 4N hydrogen chloride/ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the precipitate was collected by filtration to give the title compound (5 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:14][C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[CH:11]=1>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:1][C:11]1[C:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=2[S:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(s1)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 67776.3 %

Procedure:
N-bromosuccinimide (52 mg, 0.3 mmol) was added to a solution of 238 (42 mg, 0.3 mmol) in acetonitrile (1.4 mL). The resulting mixture was stirred at room temperature for 2 days. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-5% ethyl acetate in hexane) provided 239 (47 g, 73%) as a liquid.
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]=[O:39])[N:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:31]=1>O1CCCC1>[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]([OH:39])[C:7]2([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:16][CH:17]=3)[S:8][CH2:9][CH2:10][CH2:11][S:6]2)[N:30]([S:32]([N:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])[CH:31]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C=O
Reactant: c1ccc(-c2ccc(C3SCCCS3)cc2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)C1(c2ccc(-c3ccccn3)cc2)SCCCS1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M in hexane) (0.14 mL, 0.17 mol) was added to a −78° C. solution of 2-[4-(1,3-dithian-2-yl)phenyl]pyridine (50 mg, 0.18 mmol) in tetrahydrofuran (3 mL). After stirring at 0° C. for 10 min, the reaction mixture was re-cooled to −78° C. and a solution of 4-(2,2-dimethylpropyl)-2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 13) (100 mg, 0.37 mmol) in tetrahydrofuran (1 mL) was added. After stirring at −78° C. for 5 min then at ambient temperature for a further 10 min, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparative plate chromatography eluting with 50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1.[F-].[K+]>C(Cl)Cl>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][C:14]=1[CH3:19])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(Br)ccc1N
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
A mixture of 2.9 ml (27.5 mmol) of 2-fluoro-nitrobenzene, 10.55 g (55 mmol) of 4-bromo-2-methyl-aniline and 1.60 g (27.5 mmol) of spray-dried potassium fluoride is heated to 180° C. After cooling the reaction mixture is taken up in methylene chloride, washed with H2O, with 10% hydrochloric acid and again with H2O, dried with Na2SO4, concentrated and purified by flash chromatography (silica gel; petroleum ether/ethyl acetate=75:25).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[NH2:27][CH2:26][CH2:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:40]4[CH:39]=[C:38]([F:51])[C:37]([OH:52])=[C:36]([Cl:35])[CH:41]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 25.6 %

Procedure:
Following general procedure D, tert-butyl 2-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yloxy)ethylcarbamate (100 mg, 0.19 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (24 mg, 26% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.34-8.24 (m, 2H), 8.13-8.03 (m, 2H), 7.82 (dd, J=8.8, 2.8 Hz, 1H), 7.24-7.10 (m, 3H), 4.65 (t, J 5.1=Hz, 2H), 3.43 (t, J=5.1 Hz, 2H), 2.87-2.81 (m, 1H), 1.23-1.15 (m, 4H); ESI MS m/z 493 [C26H22ClFN4O3+H]+; HPLC>99% (AUC), tR=11.00 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=O>>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][N:11]1[CH2:12][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccccc3c2)C1

Procedure:
This compound was obtained via the reductive amination method described in 49.2, by reaction of (S)-3-tert-butyloxycarbonylaminopyrrolidine with 2-naphthaldehyde. The residue is purified on a column of silica (eluent: from 100/0 to 90/10 (v/v) dichloromethane/methanol).
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].Cl.Cl[CH2:22][C:23]1[S:24][C:25]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:35])[C:26]=2[N:36]=1>CN(C)C=O>[NH2:35][C:27]1[C:26]2[N:36]=[C:23]([CH2:22][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[S:24][C:25]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: Nc1nc2ccccc2c2sc(CCl)nc12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc2ccccc2c2sc(CON3C(=O)c4ccccc4C3=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Triethylamine (7.3 mL, 52 mmol) was added to a solution of N-hydroxyphthalimide (3.42 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (50 mL). 2-(Chloromethyl)[1,3]thiazolo[4,5-c]quinolin-4-amine hydrochloride (5.0 g, 18 mmol) was added to the resulting deep red solution, and the reaction was stirred overnight at ambient temperature. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried in a vacuum oven to provide 3.34 g of 2-[(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a tan solid. The filtrate was concentrated under reduced pressure, and the residue was mixed with dichloromethane, filtered, washed with dichloromethane, and dried in a vacuum oven overnight to provide an additional 2.06 g of product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:21][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]cc(C2CCNCC2)c2ccccc12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(c2c[nH]c(=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
4-(Piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (0.5 g) obtained in Example 31 and 35% aqueous formalin solution (0.33 g) were dissolved in acetonitrile (20 mL), and sodium triacetoxyborohydride (0.81 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, diluted hydrochloric acid was added to the reaction mixture. The mixture was once heated under reflux, and the solvent was evaporated. Aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform, and purified by silica gel column chromatography (chloroform:methanol=4:1+triethylamine 2%) to give 4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one (88 mg) as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[CH:10]([CH3:14])[NH:9][N:8]=1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[C:10]([CH3:14])=[N:9][N:8]=1
Reactant: CC1NN=C(c2ccccn2)NC1=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nnc(-c2ccccn2)[nH]c1=O

Procedure:
In a 500 ml four-necked flask was charged a solution of 7.4 g of the above prepared 3-(2-pyridyl)-6-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-5-one in 200 ml of acetone, and a solution of 3.2 g of potassium permanganate in 200 ml of acetone was added dropwise thereto at 10° to 15° C while stirring. The resulting mixture was stirred for 2 hours, and then the produced manganese dioxide was removed by filtration. The acetone was removed under reduced pressure to obtain 6.5 g of 3-(2-pyridyl)-6-methyl-4,5-dihydro-1,2,4-triazin-5-one as white crystals. M.P. 299°-300° C. Anal. Calcd. for C9H8N4O: C, 57.45%; H, 4.26%; N, 29.79%. Found: C, 57.31%; H, 4.22%; N, 29.95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[N:9]2)=[CH:5][CH:4]=1.C[O-].[Na+].[Cl-].[NH4+:25].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:25])[NH2:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: [NH4+]
Reactant: COc1ccc(Cn2nc(C#N)c3ccccc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.25 g of 1-(4-methoxybenzyl)-1H-indazole-3-carbonitrile (1-1-1, 35.1 mmol, 1 eq.) were suspended in 128 ml of dry methanol under a nitrogen atmosphere. 0.949 g (17.6 mmol, 0.5 eq.) of sodium methanolate were added. The reaction mixture was stirred for 18 hours at room temperature. To the resulting mixture were added 2.82 g (52.7 mmol, 1.5 eq.) of ammonium chloride and 1.0 ml (17.6 mmol, 0.5 eq.) of 100% acetic acid and stirred for 5 hours at 50° C. After cooling down at room temperature the mixture was concentrated in vacuo. The residue was partitioned between aq. half saturated sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted three times with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to yield 6.45 g (23 mmol, 65.5%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:27][O:28][C:29](=[O:47])[CH2:30][N:31]1[C:35](=[O:36])[N:34]([CH2:37][CH:38]=[O:39])[C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[N:32]1.Cl>C1COCC1>[CH3:27][O:28][C:29](=[O:47])[CH2:30][N:31]1[C:35](=[O:36])[N:34]([CH2:37][CH:38]([OH:39])[C:2]([F:4])([F:3])[F:1])[C:33]([C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)=[N:32]1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reaction time: 1 h

Procedure:
6.69 ml of a 0.5 M solution of (trifluoromethyl)trimethylsilane in THF (3.34 mmol) and 39 μl of a 1 M solution of tetra-n-butylammonium fluoride in THF (39 μmol) are successively added at 0° C. to a solution of 948 mg (2.57 mmol) of the compound from Example 225A in 17 ml THF. The temperature is allowed to rise to RT and the mixture stirred for 1 hr more. For the workup, the reaction mixture is treated with 8 ml of 1 N hydrochloric acid. It is stirred for 1 hr at RT, before the THF is removed on the rotary evaporator. The aqueous residue is extracted with ethyl acetate. The organic phase is washed twice with water and once with sat. sodium chloride solution, dried over magnesium sulphate and freed of solvent on the rotary evaporator. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 100:1→100:2). 630 mg (65% of theory) of the title compound are obtained.