Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A mixture of 80 parts of intermediate 47, namely N-[4-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]acetamide, 150 ml of an aqueous hydrochloric acid solution 2N and 15.8 parts of methanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was basified. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 14.1 parts (20.2%) of 4-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]benzenamine interm. 48).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([Cl:14])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:14][C:5]1[N:4]([CH3:15])[C:3](=[O:16])[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(N)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(Cl)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.42 mmol) in dichloromethane was added diisopropylethylamine (0.51 mmol) and benzoyl chloride (0.51 mmol). The reaction was stirred overnight at room temperature. The reaction solution was washed with 5% NaHCO3, and the organic layer was purified on silica. M+1=341.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:19]([CH3:29])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].[CH3:34]O>>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:34])[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[C:19]([CH3:29])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(NS(=O)(=O)CC)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(=O)(=O)CC)c(C)c1

Procedure:
The title compound is prepared from N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-ethanesulfonamide and methanol using a procedure analogous to Example 18 (78%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.Cl[CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[N:24][C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[N:2]3)=[N:20][CH:21]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1cc(Cn2nnc3ccccc32)cc(-c2ncc(OCCN3CCOCC3)cn2)c1
Temperature: 90 °C

Procedure:
49 mg (0.41 mmol) of 1H-benzotriazole, 150 mg (0.41 mmol) of 4-{2-[2-(3-chloromethylphenyl)pyrimidin-5-yloxy]ethyl}morpholine hydrochloride and 136 mg (1.62 mmol) of sodium hydrogencarbonate are suspended in 4 ml of acetonitrile and stirred at 90° C. for 18. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated and purified by means of column chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[CH:23][C:22]=2[F:30])=[CH:18][C:17]=1[F:33]>CN(C=O)C>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([CH2:28][O:29][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:23][C:22]=2[F:30])=[CH:18][C:17]=1[F:33]
Reactant: OCc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-(4-chloro-3-fluorophenoxy)-3,5-difluorophenyl)methanol (78 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)sc2c1
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccc2[nH]c(=O)sc2c1
Yield: 96 %

Procedure:
Treatment of 6-(2-chloroethanoyl)-3H-benzothiazol-2-one with sodium azide, following the procedure described in Example 6, Step 4, gave 6-(2-azidoethanoyl)-3H-benzothiazol-2-one (6.95 g, 96%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)—N—((R)-1-(4-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (5.4 g, 19.4 mmol) in methanol (150 mL) at 0° C. was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 19.4 mL, 77.6 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The solvent removed in vacuo, and the crude material was dissolved in saturated aqueous sodium bicarbonate and dichloromethane. The mixture was stirred for 45 min to give a clear solution. The phases were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (3.1 g, 92%, >96% ee, determined by Mosher's method).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C([O:17]O)(C)(C)C.Cl>C1COCC1.O>[OH:17][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[N:9]=1
Reactant: CC(C)(C)OO
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(O)n1
Temperature: -78 °C

Procedure:
To a cooled suspension of Na t-OBu (6.24 g, 64.9 mmol) in liquid ammonia was added dropwise a solution of 6-methoxy-3-nitropyridine (2.0 g, 12.98 mmol) and t-butyl hydrogenperoxide (1.53 mL, 14.31 mmol) in THF (20 mL). After the completion of addition, the resulting mixture was stirred at −78° C. under Ar and warmed gradually to room temperature, and then stirred at room temperature overnight, which gave a yellow solid. It was diluted with H2O (30 mL). The resulting mixture was neutralized with the addition of 1N HCl solution. The solid formed was collected and washed with H2O and DCM, and then dried (1.18 g). The filtrate was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the second portion (0.59 g, total 1.77 g, 80%). NMR (MeOD-d3, 400 MHz) □ 8.20 (d, J=8.8 Hz, 1H), 5.79 (d, J=8.8 Hz, 1H), 4.87 (s, 3H). MS: m/z=171 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][O:20][CH2:21][CH:22]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOC3)cc2C1
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3CCOC3)cc2C1

Procedure:
Prepared in analogy to Example A68(a) from 5-chloro-6-(2,5-dihydro-furan-3-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and platinum(IV) oxide. Off-white solid. MS (m/e): 270.3 ([{37Cl} M+H-Me2C═CH2]+, 38%), 268.3 ([{35Cl} M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]3[CH:10]=[CH:11][C:12]([C:15](=[NH:18])[NH:16][OH:17])=[N:13][CH:14]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:19](OC(=O)C)(=O)[CH3:20]>N1C=CC=CC=1>[CH3:19][C:20]1[O:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:5]34[CH2:8][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3][CH2:4]4)=[CH:14][N:13]=2)[N:18]=1
Reactant: N=C(NO)c1ccc(C23CCCN(CC2)C3)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C34CCCN(CC3)C4)cn2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.2 %

Procedure:
0.28 g (1.14 mmol) of (−)-5-(azabicyclo[3.2.1]oct-5-yl)-N-hydroxypyridine-2-carboximidamide, prepared in step 7.1, dissolved in 10 ml of pyridine is introduced into a 10 ml reactor. 0.1 ml (1.13 mmol) of acetic anhydride is then added and the medium is stirred at room temperature for 15 hours and then heated at 110° C. for 5 hours. The solvent is concentrated under reduced pressure and the residue is taken up in saturated aqueous sodium carbonate solution. The aqueous phase is extracted with chloroform and the combined organic phases are dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 96/4/0.4 proportions. 0.077 g of (−)-5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is thus obtained, and is dissolved in 1 ml of isopropyl alcohol to add 0.05 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>CCOCC>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
Oxalyl chloride (10 ml) was slowly added to a stirred solution of 11.7 g of indole in 50 ml of anhydrous ether at 0° C. The temperature was allowed to reach room temperature and the mixture stirred for a further 2 hours. The orange precipitate was filtered off, washed with anhydrous ether and dried at 50° C. to give 3-indolylglyoxylyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.C(O)C.[H][H].Cl>[Pd].C.C(O)(C)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 250 ml absolute ethanol, and 20 g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 60 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and concentrated under vacuum to a volume of about 100 ml. The product concentrate was treated, under nitrogen at ice temperature, with a cold solution of hydrogen chloride (0.5 mole) in 85 ml anhydrous isopropyl alcohol. The trihydrochloride salt of 2,3,5-triamino-4,6-dimethylpyridine was obtained after vigorous stirring, filtering under nitrogen, and vacuum drying under high vacuum over P2O5 at 80° - 90° C.
Reaction SMILES: [CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2Br)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2[C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Br)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1c(-c2ccncc2)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 170.7 %

Procedure:
A mixture of (4-benzyl-4-hydroxypiperidin-1-yl) (5-bromo-1,3-benzodioxol-4-yl)methanone (0.50 g), pyridine-4-boronic acid (0.22 g), sodium carbonate (0.38 g), tetrakis(triphenylphosphine)palladium(0) (0.069 g), water (0.50 mL) and DME (2.5 mL) was stirred at 150° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.85 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:25]
Reactant: CNC
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Solvent: CO
Product: CN(C)c1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Yield: 93.3 %

Procedure:
2-[2-(N,N-Dimethylamino)pyrimidine-4-yl]-6-(2-fluoroethoxy)benzothiophene (1-36, 77 mg, 93%) was prepared in the same manner as in Example 35 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 0.26 mL, 0.52 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C@@H:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:16]=2)=[CH:11][CH:10]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:42]([C:39]4[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:46])[F:47])=[CH:41][CH:40]=4)(=[O:44])=[O:43])[CH2:22][CH:21]3[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc([C@@H]2CNCC[C@H]2c2cc(-c3ccc(Cl)cc3)[nH]n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(c2cc(-c3ccc(Cl)cc3)[nH]n2)C(c2ccc(F)cc2)C1
Temperature: 60 °C

Procedure:
The product from Example 8 (23 mg, 0.049 mmol) in pyridine (1.0 ml) was treated with 4-trifluoromethoxybenzenesulfonyl chloride (63.8 mg, 0.245 mmol). The reaction mixture was heated to 60° C. for 12 h. The mixture was then concentrated and purified by RP-HPLC(C18, acetonitrile, water, 0.05% TFA) to afford the title compound. HPLC/MS: 580.0, 582.1; Rt=2.33 min (LC-4 HPLC conditions).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[N:29]1([C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]2O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]4[N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCCC3N3CCCCC3)cc2)cc1
Yield: 64.8 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), trans-2-piperidinylcyclohexanol (1.10 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 11 to give 1.08 g of the title compound. Yield: 65%. MS(FD) 555(M+). IR (CHCl3) ν max 3014, 2938, 2860, 1644, 1595, 1476, 1254, 1165.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27]N)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][N:6]2[C:5](=[O:15])[C:4]3[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=3)[C:7]2=[O:14])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CN2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)C1
Temperature: 140 °C
Yield: 45.9 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (994 mg, 4.8 mmol), 3-Aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and imidazole (493 mg, 7.25 mmol) in dioxane (140 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 61 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (400:10:1) afforded the title compound (830 mg, 46%). 1H NMR (MeOH-d4) δ 1.44 (s, 9H), 2.94 (m, 1H), 3.78 (m, 2H), 3.88 (d, J=6 Hz, 2H), 4.00 (m, 2H), 7.44 (s, 1H), 8.52 (s, 1H); ESI-MS m/z 377.3 (MH+).
Reaction SMILES: Br[CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].C(OCC)(=O)C>CN(C=O)C>[CH3:3][CH:2]([N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13])[C:4](=[O:7])[CH2:5][CH3:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(=O)C(C)Br
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
2-Bromo-pentan-3-one obtained in Example (15a) (8.47 g, 35.57 mmol) was dissolved in DMF (120 mL). Potassium phthalimide (6.9 g, 37.25 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was washed with hexane to obtain 6.5 g of the title compound as a white solid (79%).
Reaction SMILES: [C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](O)=[O:29]>>[C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[C:27]([Cl:32])([Cl:31])[Cl:26])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(Cl)(Cl)Cl)OC3=O)cc2F)CC1
Yield: 45 %

Procedure:
The title compound was prepared by following the procedure of Example 29 and by using (S)-N-{3-[4-(4-(1-cyanoethylidene)-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and trichloroacetic acid in 45% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[CH3:43]O>[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[C:31]([CH3:43])[CH:32]=[C:33]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: Cc1cc(OCCN(C)C)cc2c1CN(C(=O)c1cc(C(C)C)c(O)cc1O)C2
Yield: 35 %

Procedure:
(2,4-Bis-benzyloxy-5-isopropenyl-phenyl)-[5-(2-dimethylamino-ethoxy)-1,3-dihydro-isoindol-2-yl]-methanone (37 mg, 0.06 mmol) was hydrogenated in methanol at 50° C. over 10% palladium on charcoal using an H-cube hydrogenation apparatus, under free hydrogen conditions. The product was purified by preparative HPLC (basic method) to give the title compound as an off-white solid (9 mg, 35%). 1H NMR (MeOH-d4) 7.18 (1H, s), 6.77-6.65 (2H, br.m), 6.37 (1H, s), 4.85 (water obscuring CH2), 4.77 (2H, s), 4.08 (2H, t), 3.20 (1H, sept), 2.81 (2H, t), 2.39 (6H, s), 2.22 (3H, br.s), 1.21 (6H, d). MS: [M+H]+ 399.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].N1C=CC=CC=1.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:5])=[O:37])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a mixture of 2-amino-4-nitro-N-(4-methoxyphenyl)benzamide (2.0 g, 7.0 mmol) and pyridine (0.62 mL, 7.7 mmol) in methylene chloride (40 mL) was added 4-tert-butylbenzoyl chloride (1.44 mL, 7.35 mmol). After stirring for 1.5 h, silica gel (30 g) was added and the solvent evaporated with a stream of nitrogen. The resulting material was chromatographed (silica gel, 5% hexanes/95% methylene chloride to 1.25% ethyl acetate/98.75% methylene chloride) to give 2.41 g (77%) of the title compound as a yellow solid; mp 221° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:19](=[O:20])[C:18]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)=[N:12]2)(=[O:3])=[O:4]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Product: CS(=O)(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methanesulfonyl-benzene-1,2-diamine and (thiophen-2-yl)oxo-acetic acid via the method described in Example 12 to afford 6-Methanesulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one.