Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:15]1[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]1[CH2:9][OH:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(CO)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.58 mL, 4.2 mmol) was added to a mixture of racemic tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.60 g, 2.8 mmol, racemic, AstaTech) and benzyl bromide (0.36 mL, 3.0 mmol) in acetonitrile (5.0 mL). The mixture was heated to 80° C. in an oil bath for 4 h, then allowed to cool and stir at ambient temperature overnight. Solvent was removed in vacuo and the residue was dissolved in methylene chloride. The solution was washed with 0.1N NaOH, dried over sodium sulfate and concentrated. Flash chromatography, using a 40 g silica gel cartridge and eluting with a gradient from 0-60% EtOAc in hexanes afforded product as a viscous oil (630 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.37-7.22 (m, 5H), 4.02 (d, 1H), 3.87 (dd, 1H), 3.69 (dd, 1H), 3.63-3.50 (m, 2H), 3.41 (d, 1H), 3.41-3.27 (br m, 1H), 3.22-3.06 (br m, 1H), 2.84-2.71 (br m, 1H), 2.64-2.50 (br m, 1H), 2.27 (ddd, 1H), 1.45 (s, 9H); LCMS (M+H)+: 307.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:28]
Reactant: CI
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 5.00 g (0.012 mol) of 5-bromo-2-(4-methoxy-benzenesulfonylamino)-3-methyl-benzoic acid methyl ester (U.S. Pat. No. 5,776,961) in 40 mL of DMF was added 0.604 g (0.015 mol) of 60% sodium hydride. The resulting mixture was stirred at room temperature foe 0.5 h and then 1.2 ml (0.018 mol) of iodomethane was added. The reaction was then stirred for 15 h and then diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether and the resulting white solid was collected by filtration and dried in vacuo to provide 4.45 g (86%) of the N-methyl sulfonamide. Electrospray Mass Spec 429.8 (M+H)+
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: CO
Reactant: CCC(CC)(c1ccc(NS(=O)(=O)CC)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
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: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:33][S:34][C:35]1[S:36][C:37]2[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][C:38]=2[N:39]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:44][C:42]2[CH:41]=[CH:40][C:38]3[N:39]=[C:35]([S:34][CH3:33])[S:36][C:37]=3[CH:43]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a stirred mixture of 4-(benzyloxy)-2-nitroaniline (2.0 g, 8.2 mmol) in TFA (14 mL) at −15° C. was added sodium triacetoxyborohydride (2.84 g, 12 mmol). Then a solution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.9 g, 9.0 mmol) from Step 1 of Example 100 in DCM (10 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. and stir for 2 h. The mixture was partitioned between DCM and water. The organic layer was separated and washed sequentially with saturated aq NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 10% EtOAc in petroleum ether to 100% EtOAc to afford 4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (2.3 g, 64%) as a red-brown solid. 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.33-7.43 (m, 6H), 7.14 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 5.02 (s, 2H), 4.64 (d, J=5.7 Hz, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10]>>[N:6]1[CH:7]=[CH:8][C:3]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: Cl
Product: CCOC(=O)c1cccc(-c2ccncc2)c1
Yield: 92 %

Procedure:
Obtained in 92% yield by an analogous procedure to Example 605, starting from 4-bromopyridine hydrochloride and 3-(ethoxycarbonyl)phenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:24]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]2[CH:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C:10](=[O:19])[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[CH:4]=3)[O:1]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COc1ccc(O)c(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=O)C(C(=O)OC(C)(C)C)C(c1ccc(Cl)c(Cl)c1)O2
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of tert-butyl 3-(2-hydroxy-5-methoxyphenyl)-3-oxopropanoate (500 mg, 1.88 mmol) in isopropanol (5.0 mL) was treated with 3,4-dichlorobenzaldehyde (329 mg, 1.88 mmol), piperidine (20 μL, 188 μmol) and acetic acid (10 μL, 188 μmol). The reaction mixture was heated at reflux overnight, and then treated with water (1.0 mL). The resulting mixture was cooled to rt and then concentrated under vacuum to yield a residue. The residue was purified by column chromatography (silica gel, 2-25% ethyl acetate-hexane) to provide racemic tert-butyl 2-(3,4-dichlorophenyl)-6-methoxy-4-oxochroman-3-carboxylate as a yellow oil (380 mg, 48%). This material was used without further purification in Step 3 below.
Reaction SMILES: [H-].[Na+].C(P([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CC)C.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O.O>CCCCCC.O1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1/[CH:16]=[CH:8]/[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: O=Cc1ccccn1
Reactant: CCP(CC)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride (60% oil, 0.6 g, 15.7 mmol) was washed with hexane and suspended in tetrahydrofuran (5 ml). To the mixture, a solution of tert-butyl diethylphosphinoacetate (2.5 g, 9.8 mmol) in tetrahydrofuran (2 ml) was added under ice cooling condition. The reaction mixture was stirred at room temperature for 30 minutes, cooled under ice cooling condition. A solution of 2-formylpyridine (1.0 g, 9.3 mmol) in tetrahydrofuran (3.0 ml) was added to the mixture, and the mixture was stirred at 0° C. for 1.5 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (1.5 g, 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CN(C=O)C.CC[O-].[Na+]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[N:13]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:12]2=[O:17])=[CH:2]1
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1NC(Cc2c[nH]c3ccccc23)C(=O)N1CCCN1CCC(c2ccccc2)CC1
Reaction time: 10 h

Procedure:
A mixture of 5-(indol-3-ylmethyl)hydantoin (6.4 g, 0.028 mole), 1-(3-chloropropyl)-4-phenylpiperidine (6.6 g, 0.028 mole) and 200 ml of DMF in 200 ml of anhydrous C2H5OH and 0.028 mole of NaOC2H5 was heated under reflux with stirring for 10 hours. The mixture was filtered and the filtrate was diluted with H2O. The solid was collected and twice recrystallized from aqueous C2H5OH, yield 2.0 g, mp 179°-80°.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:22]([C:23]3[CH:28]=[C:27]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:26]=[CH:25][C:24]=3[O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:21][N:20]([CH3:43])[C:15]2=[C:16]([O:18][CH3:19])[N:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[O:34][C:24]1[CH:25]=[CH:26][C:27]([CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][C:23]=1[C:22]1[C:14]2[C:15](=[C:16]([O:18][CH3:19])[N:17]=[C:12]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:10])[CH:13]=2)[N:20]([CH3:43])[CH:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1nc(-c2c(C)noc2C)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 60 °C
Yield: 101 %

Procedure:
3,5-dimethylisoxazole-4-boronic acid (0.016 g, 0.112 mmol), the product from Example 91E (0.05 g, 0.093 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.56 mg, 2.79 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (2.72 mg, 9.30 μmol) and potassium phosphate (0.059 g, 0.279 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (0.8 mL) was sparged with N2 for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was heated at 60° C. for 2 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated to afford the title compound (0.052 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[CH:4]1[O:6][CH2:5]1.[CH3:15][Al](C)C>ClCCl.CCCCCC>[F:1][C:2]1[C:3]([CH:4]([CH3:15])[CH2:5][OH:6])=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: C[Al](C)C
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F

Procedure:
To a solution of 1.05 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 10 ml of dichloromethane, was added a 6 ml of 1.0M solution of trimethylalumimum in hexane, to react for one hour at 40° C. The similar work-up to Example 1 gave 1.10 g of (+)-2-(pentafluorophenyl)-1-propanol. The specific rotation was compared with that of Example 1, and the optical purity was determined to be 69%ee.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:12](OC(OCC)OCC)C.CC(O)=O>C(Cl)Cl>[Cl:9][C:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]2[N:1]=[CH:12][NH:8][C:7]=2[CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nc(Cl)cc(N)c1N
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1nc(Cl)cc2[nH]cnc12

Procedure:
A mixture of 3,4-diamino-6-chloropicolinonitrile (3.2 g), triethylorthoformate (16 ml) and AcOH (5.4 ml) was heated to 150° C. in DCM (16 ml) in a microwave for 15 minutes. Solvent was evaporated, residue was dissolved in EtOAc (250 mL) and washed with water (150 mL). Organic layer was dried over sodium sulphate. Solvent was evaporated under reduced pressure to yield 6-chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (2.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:41]=[CH:40][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
To a dichloromethane (120 mL) solution of di-tert-butyl (3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)imidodicarbonate (11.8 g, purity about 70%) described in Manufacturing Example 1-4-2 was added trifluoracetic acid (40 mL) at 0° C., which was stirred at room temperature for 14 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate at 20° C. or less, which was then extracted with ethyl acetate and purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1). The solvent was concentrated under a reduced pressure, tert-butylmethyl ether was added to the resulting residue, and the solids were filtered to obtain the title compound (7.29 g).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[C@H:8]1[CH2:12][O:11][CH2:10][N:9]1[C:13](=[O:26])[CH2:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:18].[O:27]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:17]([OH:18])[CH2:16][CH2:15][CH2:14][C:13]([N:9]2[C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH2:12][O:11][C:10]2=[O:27])=[O:26])=[CH:20][CH:21]=1
Reactant: O=C(CCCC(=O)N1COC[C@@H]1C1C=CC=CC1=O)c1ccc(F)cc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1c1ccccc1

Procedure:
To the resin kettle is charged 5-((4S)-2-oxo-4-phenyl(1,3-oxazolidin-3-yl))-1-(4-fluorophenyl)pentane-1,5-dione (120 g) as a powder, followed by dextrose powder (91 g), toluene (200 ml), and buffer (750 ml of 0.02M potassium phosphate and 0.002 M Magnesium sulfate). The head plate is fitted and dogged down. All appropriate ports are closed except for the pH probe port which is fitted with the pH probe. The motor is then fitted to the coupling and stirring is initiated to a rate of 1200 rpm. The pH of the reaction mixture is measured and adjusted to 7.0+0.1. The temperature of the reaction mixture is brought to 30+1° C. While the reaction is brought to temperature, 0.4 g Na-NADP, 0.8 g GDH, and 2.00 g of lyophilized KRED were dissolved in 40 ml of de-ionized water. When the reactor temperature is in the appropriate range, the enzyme suspension is added in one portion while stirring. The titration program is started and the pH is maintained at 7.0+/−0.1 for the duration of the reaction by addition of 4N NaOH. The reaction is stirred at 30° C. for 16 hr. The reactor is sampled periodically and checked for substrate conversion by HPLC as described in Example 4. Periodic sampling and analysis is continued until the conversion reaches 99% or better.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CN([CH:33]=[O:34])C>O1CCCC1>[C:16]([O:20][C:21]([NH:23][C:24]1[C:29]([CH:33]=[O:34])=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccnc1C=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
After adding 4 ml of n-butyllithium (2.46 M, n-hexane solution) to a solution of 1.384 g of 2,2,6,6-tetramethylpiperidine in tetrahydrofuran (15 ml) at −20° C. under a nitrogen atmosphere, the mixture was stirred for 30 minutes while cooling on ice. The reaction mixture was cooled to −70° C., and then a solution of 800 mg of 2-(tert-butoxycarbonylamino)pyrazine in tetrahydrofuran (3 ml) was added dropwise, the mixture was stirred for 1 hour, 3 ml of N,N-dimethylformaldehyde was added, and stirring was continued for 30 minutes. After removing the cooling bath and stirring for 30 minutes, water was added and extraction was performed with ethyl acetate. The extract was dried and concentrated and then purified by silica gel column chromatography (solvent: ethyl acetate/n-hexane) to obtain 72 mg of crude 2-(tert-butoxycarbonylamino)pyrazine-3-carboxaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-:10].[Na+]>C(O)CCC.O>[CH2:9]([O:10][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: Cc1cc(N)cc(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCOc1cc(N)cc(C)n1
Temperature: 25 °C

Procedure:
2-chloro-6-methylpyridin-4-amine (36 g, 0.25 mol) and sodium hydroxide (24 g, 1 mol) were dissolved in 1-butanol (400 mL). The solution was heated at reflux for 10 h, and then cooled to rt. The reaction mixture was diluted with water (300 mL) and then extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to afford 2-butoxy-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.05 (d, J=0.6 Hz, 1H), 5.75 (d, J=0.6 Hz, 1H), 4.18 (t, J=6.4 Hz, 1H), 2.30 (s, 3H), 1.71 (m, 2H), 1.48 (m, 2H), 0.98 (t, J=7.6 Hz, 3H). LRMS calc'd for (C10H16N2O) [M+H]+, 181; found 181.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(C1C=CC(C)=CC=1)(O[CH2:11][CH:12]([CH3:23])[CH:13]([OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])(=O)=O.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH:13]([OH:22])[CH:12]([CH3:11])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)C(O)Cc2ccccc2F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under a nitrogen atmosphere, 2.28 g (60.2 mmol) of lithium aluminum hydride was added to 30 ml of THF. A solution of 21.1 g (60.2 mmol) of 4-(2-fluorophenyl)-3-hydroxy-2-methylbutyl tosylate in 210 ml of THF was added dropwise thereto at room temperature. After stirring for 0.5 hr at room temperature, sodium sulfate 10 hydrate was added slowly until no effervescence was observed. After stirring a while, the obtained suspension was filtered, the filtrate was distilled off and the residue was purified by silica gel column chromatography to obtain 9.6 g of the title compound as a colorless solid. (Yield: 88%) An optical purity was determined to be 98.1% ee by GC using Chirasil DEX CB according to a conventional method.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])C.C(O)(=O)C.Cl>C(O)C>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CCOC(CCCNC(=O)N1CCC(c2ccccc2)CC1)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=CCCCNC(=O)N1CCC(c2ccccc2)CC1
Reaction time: 16 h

Procedure:
1.39 g (4 mmol) N-(4,4-diethoxybutyl)-4-phenylpiperidine-1-carboxamide, 5 mL acetic acid, 2.5 mL 1N aqueous hydrochloric acid and 20 mL ethanol are put together and stirred for 16 hours under argon atmosphere. Ethanol is evaporated. Then the resulting residue is dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase is dried with sodium sulfate and the solvent evaporated in vacuum. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:46][C:47]1[C:48]([C:53](O)=[O:54])=[N:49][CH:50]=[CH:51][CH:52]=1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:53](=[O:54])[C:48]3[C:47]([CH3:46])=[CH:52][CH:51]=[CH:50][N:49]=3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: COc1ccc(-c2nc(CN)co2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCc1ccccc1

Procedure:
A 1.5 g quantity of the [2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 was suspended in 30 ml of acetone. To the obtained suspension were added 1.0 g of 1-hydroxybenzotriazole, 1.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.8 g of 3-methylpicolinic acid, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was cooled, and acetone was distilled off under reduced pressure. Water was added to the residue, and extraction was then performed with ethyl acetate. The organic layer was washed with water twice, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give 1.5 g of white powdery N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.