Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.CO>C1C=CC=CC=1>[O:30]=[C:22]1[N:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:20][CH2:19]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 8 parts of 1-(4-fluor-2-methoxybenzoyl)-aziridine, 3.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 4 parts of N{2-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-1-yl)-1-piperidinyl] ethyl}-4-fluoro-2-methoxybenzamide; mp. 197.3° C.
Reaction SMILES: Br[C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].Cl[Si:13]([CH3:16])([CH3:15])[CH3:14].CN(CCN(C)C)C>C1COCC1.[Zn]>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:8][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[CH2:9][CH2:10][CH3:11]
Reactant: CCCC1(Br)CCCCC1=O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCC1=C(O[Si](C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
A solution of 2-bromo-2-propylcyclohexanone (6.21 g, 28.3 mmol) and chlorotrimethylsilane (9.35 mL, 8.0 g, 73.7 mmol) in 65 mL THF was added dropwise to a slurry of Zn (2.78 g, 42.5 mmol) and TMEDA (2.2 mL, 1.65 g, 14.2 mmol) in 35 mL THF cooled in an ice bath. The mixture was allowed to stir in the cold for an additional 1.5 hrs, then allowed to warm to room temp. The mixture was filtered to remove the insolubles. The solvent was evaporated under reduced pressure and the residue extracted with Et2O (200 mL in 2 portions). The combined ethereal extracts were evaporated under reduced pressure and the residue fractionated under reduced pressure. A fraction boiling at 92°-96° (13 torr) was collected to afford 4.79 g (80%) of trimethyl(2-propylcyclohex-1-enyloxy)silane. MS (EI) 212 M(+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][C@H:25]1[CH2:44][N:28]2[C:29](=[O:43])[N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[CH2:31][C@@H:27]2[CH2:26]1)(C)(C)C.O>C1COCC1>[OH:24][C@H:25]1[CH2:44][N:28]2[C:29](=[O:43])[N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:34][CH:33]=3)[CH2:31][C@@H:27]2[CH2:26]1
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Tetrabutyl ammonium fluoride (1.0 g, 3.8 mmol) was added to a solution of (6R,7aS)-6-(tert-Butyl-diphenyl-silanyloxy)-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (1.8 g, 3.3 mmol) in anhydrous THF (20 mL). The mixture was stirred for 2 hours at room temperature. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2=1:20) to give 0.95 g (94%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][O:33]C3CCCCO3)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1.C(O)(=O)C.O>C1COCC1>[F:47][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][OH:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1
Reactant: O=C(c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1c(CO)noc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Dissolve [1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-methanone (0.136 g, 0.20 mmol) in THF (1.5 mL), add acetic acid (1.5 mL) and H2O (0.5 mL). Attach a reflux condenser and stir 20 hours in a 60° C. oil bath. Concentrate under vacuum, neutralize with saturated aqueous NaHCO3, and extract with EtOAc. Dry over MgSO4, filter through paper, and concentrate under vacuum. Recrystallize in ether/hexane (1:10) to give the title compound: MS (ES) 607.1 (M+1), 1H NMR (CDCl3) δ 8.69 (br s, 1H), 8.58 (br s, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7.44–7.28 (m, 5H), 7.23 (s, 2H), 5.14 (s, 2H), 4.76 (s, 2H).
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[O:33][C:34]([C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]3[CH:7]=[CH:8][C:9]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:10][CH:11]=3)=[CH:35][CH:36]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(OC)cc(-c2ccco2)c1
Product: COc1cc(OC)cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)c1

Procedure:
N,2-Dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide was coupled with 2-(3,5-dimethoxyphenyl)furan following the procedure of Example 12. 1-(5-(3,5-Dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was isolated as a yellow oily foam (0.343 g, 62% yield). MS: m/z 438.2 [M+H]+.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([CH3:34])=[N:16]2)=[CH2:10])(C(C)(C)C)(C)C.[Br:35]N1C(=O)CCC1=O.O>C1COCC1.C(Cl)Cl>[Br:35][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([CH3:34])=[N:16]2)=[O:10]
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of tert-butyl (2-((8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339b), 1-bromopyrrolidine-2,5-dione (0.41 g, 2.30 mmol), and water (0.60 mL, 33.5 mmol) in THF (21 mL) was stirred at 0° C. and warmed to RT and stir for 30 min when product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 10-40% EtOAc in hexanes to give tert-butyl (2-((8-(2-bromoacetyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339c) (0.49 g, 1.08 mmol, 52% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 1.57 (s, 6H) 2.55 (s, 3H) 3.32 (d, J=6.85 Hz, 2H) 5.00 (s, 2H) 5.11 (dd, J=7.63, 5.09 Hz, 1H) 6.73 (s, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.85 (d, J=7.24 Hz, 1H) 7.93 (d, J=8.02 Hz, 1H). MS (ESI, pos. ion) m/z: 451.2/453.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[Si:21]([O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To the resultant compound from Example 4 (0.264 g, 0.932 mmol) in DMF (4 mL) was added tert-butyldimethylsilyl chloride (0.300 g, 1.99 mmol) and imidazole (0.269 g, 3.95 mmol). The mixture was stirred at room temperature for 12 hours, poured into ethyl acetate and washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution and brine, then dried over Na2SO4 and evaporated to afford 0.355 g (96%) of the desired compound. Mass spectrum: (M+H)+ =398.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[CH3:25][C:24]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)([CH3:27])[CH3:26]
Reactant: c1ccc(OCC2CO2)c(CCCc2cccc3[nH]ccc23)c1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccccc1CCCc1cccc2[nH]ccc12
Temperature: 80 °C

Procedure:
A mixture of 2.2 g of the product of Step B and 7.6 ml of tert.-butylamine and 20 ml of methanol was heated at 80° C. for 2 hours and was evaporated to dryness. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 2.7 g of 1-(1,1-dimethylethylamino)-3-[2-[3-[1H-indol-4-yl]-propyl]-phenoxy]-2-propanol melting at 96° C.
Reaction SMILES: ClC1C=NC=CN=1.NN.[NH:10]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[NH2:11].[F:18][C:19]([F:24])([F:23])[C:20](O)=O.[OH-].[NH4+]>>[NH:10]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[NH2:11].[F:18][C:19]([F:24])([F:23])[C:20]1[N:13]2[CH:14]=[CH:15][N:16]=[CH:17][C:12]2=[N:10][N:11]=1
Reactant: O=C(O)C(F)(F)F
Agent: Clc1cnccn1
Agent: NN
Agent: NNc1cnccn1
Product: FC(F)(F)c1nnc2cnccn12
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A sample of 2-hydrazinopyrazine was prepared from 2-chloropyrazine and hydrazine using a procedure analogous to that described in the literature [P. J. Nelson and K. T. Potts, J. Org. Chem., 27, 3243 (1962)], except that the crude product was extracted into 10% methanol/dichloromethane and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate followed by 10% methanol in dichloromethane. A mixture of 2-hydrazinopyrazine (820 mg, 7.45 mmol), trifluoroacetic acid (2.55 g, 22.4 mmol), and polyphosphoric acid (10 mL) was heated to 140° C. with stirring for 18 h. The solution was added to ice and neutralized by the addition of ammonium hydroxide. The aqueous solution was extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded the title compound as a solid.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17]O)[CH2:6]1)(=[O:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:20])[CH3:21].[C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:7]([CH2:17][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[S:27](=[O:28])(=[O:29])[NH2:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)NS(N)(=O)=O
Product: CC(=O)S[C@@H]1C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1

Procedure:
N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) in Step A-6 in Preparative Example 7-A. (2S,4R)-4-Acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with N-t-butoxycarbonylsulfamide in the similar manner as in the paragraph (b) in Step A-6 in Production Example 7-A under a condition for Step C-8 shown in Table 2 to give (2S,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino) methylpyrrolidine.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[C:9]2=[N:8][CH:7]=1)C.[OH-].[Na+].Cl>C(O)C.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]2[C:9]3=[N:8][CH:7]=[C:6]([CH2:5][C:4]([OH:32])=[O:3])[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CC(=O)OCC)cnc23)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(OCc2cccn3c(=O)c(CC(=O)O)cnc23)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
0.81 g (1.85 mmoles) of [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester and 20 ml (5.00 mmoles) of a 1% aqueous solution of sodium hydroxide were mixed with and dissolved in 30 ml of ethanol, and this mixture was stirred at room temperature for 3 hours. The resulting reaction solution was diluted with an appropriate amount of water and then neutralized with dilute hydrochloric acid. The solid matter which separated out was collected by filtration, washed with water and then dried. This precipitate was recrystallized from acetonitrile to obtain 0.59 g (78% yield) of [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid in the form of white crystals. These crystals had a melting point of 239°-243° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C1OCCOCCOCCOCCOCCOC1.[CH:37]([Mg]Br)([CH2:39][CH3:40])[CH3:38].O1CCCC1.S(=O)(=O)(O)O>>[CH3:38][CH:37]([CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Reactant: CCC(C)[Mg]Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCC(C)CCCCCCCCCCCCCCC(=O)O
Reaction time: 1 h
Yield: 95 %

Procedure:
To a four-necked 50 mL of flask equipped with a refluxing condenser tube, a 10 mL of dropping funnel, a magnetic stirrer and a temperature sensor, 15-bromopentadecanoic acid of 1.01 g (3.14 mmol) and 18-crown-6 of 823.3 mg (1.0 eq) were added and dried under reduced pressure. Under argon atmosphere, copper bromide (I) of 13.3 mg (0.03 eq) and anhydrous tetrahydrofuran of 6 mL were added to dissolve the materials. At room temperature, sec-butyl magnesium bromide of 7.85 mL (2.5 eq, 1.0M tetrahydrofuran solution) was added dropwise thereto over thirty minutes. After stirring for one hour, 5 mL of 6N aqueous sulfuric acid solution was added and the extraction was carried out by using 10 mL of hexane. After washing twice with 10 mL ion exchange water, the mixture was dried over magnesium sulfate. After the filtration, the crude product (0.84 g) was obtained by concentration under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Br:24][C:22]1[N:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:9](=[O:16])[NH:10][CH2:11][CH2:12][N:13]3[CH2:14][CH3:15])=[CH:6][CH:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CCN1CCNC(=O)C1c1ccc(N)cc1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 33 (450 mg, 2.05 mmol), isopropanol (5 mL), 13 (603 mg, 2.26 mmol) and DL-10-camphorsulfonic acid (813 mg, 3.50 mmol), and the reaction mixture was then stirred at reflux for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with isopropanol (10 mL). The resulting solid was dissolved in methylene chloride/methanol (3:1), absorbed onto silica gel and purified by flash chromatography to afford 34 in 79% yield (654 mg) as an orange solid: mp 152-153° C.; 1H NMR (500 MHz, CDCl3) δ8.28 (bs, 1H7.73 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 6.74 (s, 1H), 5.90 (d, 1H, J=3.5 Hz), 4.12 (s, 1H), 3.60 (m, 1H), 3.52 (s, 3H), 3.36 (m, 1H), 3.12 (m, 1H), 2.60 (m, 2H), 2.28 (m, 1H), 1.00 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 406.0 (M+H).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5]2.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>Cl>[CH2:9]([NH:13][C@@H:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5][C@H:6]1[OH:1])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN
Reactant: CCN1CC2OC2C1
Agent: Cl
Product: CCCCN[C@@H]1CN(CC)C[C@H]1O
Temperature: 150 °C

Procedure:
A mixture of 22.6 g (0.20 mole) of 3,4-epoxy-1-ethyl-pyrrolidine, 29.2 g (0.40 mol) of n-butylamine and one drop of conc. hydrochloric acid was heated in a bomb at 150° C. for 20 hr. The mixture was cooled to room temperature, diluted with 350 ml of petroleum ether, cooled in an ice bath and the precipitate was collected. The yield of pure compound as white flakes in this step was 18.0 g (48%); m.p. 57.5°-59.0° C. The filtrate was concentrated under high vaccum leaving a residue of 17.5 g (47%) of quite pure product. Total yield in the two steps was 35.5 g (about 95%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:26][O:27][NH:28][CH3:29].Cl>ClCCl.O1CCOCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:28]([O:27][CH3:26])[CH3:29])=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 1-acetylpiperidine-4-carboxylic acid (58.50 g, 341.7 mmol) in dichloromethane (700 ml) was added di(1H-imidazol-1-yl)methanone (58.18 g, 358.8 mmol) in portions. The mixture was agitated for two hours and N-methoxymethanamine hydrochloride (35.00 g, 358.8 mmol) was added at once. The mixture was stirred overnight at ambient temperature, and then 4M HCl in dioxane (75 ml) was added slowly. The slurry was agitated for 30 minutes and then filtered. The filtrate was washed twice with sodium bicarbonate solution, dried and concentrated in vacuo to give the desired product (59.10 g, 80.72% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[N:35]=[C:34]([N:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([N:36]([CH3:37])[CH3:38])[N:35]=2)[CH2:26][CH3:27])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccc(N(C)C)n1
Product: CCN(Cc1cccc(N(C)C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C2=CC=CN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2CCCN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
Platinum(IV) oxide (60 mg) was added to a solution of 9-(2-methylbiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (265 mg) in THF (dry) (75 mL), MeOH (75 mL) and the mixture was stirred at room temperature under hydrogen for 12 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN-THF/IPE to give the title compound (200 mg) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][C:23](O)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(N(CC)CC)C.[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:22][C:23]([N:45]4[CH2:46][CH2:47][C:42]5([O:41][CH2:40][CH2:39][O:38]5)[CH2:43][CH2:44]4)=[O:24])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a mixture of 20.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid and 250 ml of dimethylformamide were added 16 ml of triethylamine, 10.4 g of 1,4-dioxa-8-azaspiro[4.5]decane and 16 ml of diethyl phosphorocyanide, and the mixture was stirred for 20 minutes. After addition of water, the resulting crystalline precipitate was collected by filtration, washed with water and dried to give 26.4 g of crude crystals. Recrystallization from methylene chloride-ethyl acetate gave 27.1 g of colorless crystals melting at 238°-239° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)cc1CO
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-2-methoxy-benzaldehyde (7.00 g, 32.2 mmol) in MeOH (40 mL), cooled to 0 to 5° C., is added NaBH4 (1.40 g, 35.4 mmol). After stirring for 1 h, the mixture is poured into ice-water, followed by extraction with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated to give the title product as off-white solid. TLC, Rf (hexane/AcOEt 3:1)=0.19. 1H-NMR (CDCl3): δ 2.24 (m, 2H), 3.88 (s, 3H), 4.68 (d, 2H), 6.79 (dd, 1H), 7.41 (dd, 1H), 7.45 (d, 1H) ppm.