Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C)C=O>[F:1][C:2]1[C:3]([N:17]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (1.00 g, 4.2 mmol) in N,N-dimethylformamide (DMF, 20 mL) was added N,N-dimethylformamide dimethyl acetal (0.55 g, 4.6 mmol) and stirring was continued 16 h at RT. The solution was poured into 100 mL of ice water, whereupon a white precipitate was produced. The mixture was cooled at 0° C. for 1 h and then filtered to produce the title compound (1.10 g, 89%) as a white solid: mp 113-115° C.; 1H NMR (CDCl3) δ 8.65 (s, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.98 (m, 2H), 5.30 (s, 2H), 3.17 (s, 3H), 3.16 (s, 3H); MS (ESI) m/z 292 (M+H)+. Anal. Calcd for C14H14F2N4O: C, 57.53; H, 4.83; N, 19.17. Found: C, 57.67; H, 4.84; N, 19.09.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:19][C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[CH:23][NH:22][N:21]=1>>[F:1][CH:2]([F:18])[C:3]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)=[C:20]2[N:19]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 78.6 %

Procedure:
Reaction of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (133 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (159 mg, 79%). MS (ISP) 405.4 [(M+H)+]; mp 213° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:27])=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)[CH:2]=[CH2:3].F[B-](F)(F)F.[CH3:34][O+](C)C.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:27][CH3:34])=[C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][C:18]3=[O:26])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C[O+](C)C
Reactant: C=CCOC(=O)NC1(c2ccc(C(O)=C3C(=O)Oc4ccccc43)cc2)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)NC1(c2ccc(C(OC)=C3C(=O)Oc4ccccc43)cc2)CC1

Procedure:
1 g of allyl(1-{4-[hydroxy-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)-carbamate, 0.78 g of trimethyloxonium tetrafluoroborate (Meerwein salt), and 1 mL of diisopropylethylamine (Hünig base) were refluxed in 20 mL of dichloromethane for 2 hours, then another 1 mL of Hünig base and 0.5 g of Meerwein salt were added and the mixture was refluxed again for 2 hours. After cooling, the mixture was extracted 3× with water, and the organic phase was dried over MgSO4 and evaporated down to the residue. Yield: 1.05 g of crude.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.Cl>CN(C=O)C>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][S:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reactant: Sc1ccncn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCN(CCCSc3ccncn3)CC2)c1
Yield: 58.5 %

Procedure:
1.5 g (13.4 mmol) of 4-mercaptopyrimidine, 4.3 g (14 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl) piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with MTB ether. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography (mobile phase: CH2Cl2/CH3OH═98/2). 3.0 g of product were obtained as a yellowish oil (=59% yield).
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(C)([O-])C.[K+].[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]([CH2:37][O:36][CH2:34][CH3:35])[C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(S(=O)(=O)c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(p-chlorophenyl)sulfonyl]-2-(trifluoromethyl)pyrrole (0.92 g, 1.84 mmol) and potassium tert-butoxide (0.26 g, 2.21 mmol) in tetrahydrofuran is stirred at room temperature for 5 minutes, treated with a solution of chloromethyl ethyl ether (0.21 g, 2.21 mmol) in tetrahydrofuran, stirred at room temperature overnight, diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid (0.98 g, mp 107°-112° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[CH2:13][CH2:14][C:15](=[O:16])[C:7]1=[C:6]2[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:26](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]3[CH2:13][CH2:14][C:15](=[O:16])[C:7]3=[C:6]2[C:17]2[CH:18]=[CH:19][C:20]([C:21]#[CH:26])=[CH:23][CH:24]=2)=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(C=O)cc4)c2c1)C(=O)CC3
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2c3c(cc4ccc(N(C)C)cc24)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A flame-dried 25 mL two-necked round-bottomed flask equipped with a nitrogen inlet, a septum and a stir bar was charged with compound 19 (0.031 g, 0.094 mmol) and methanol (7 mL). To this solution was added potassium carbonate (0.064 g, 0.48 mmol) followed by the Bestmann-Ohira reagent (0.054 g, 0.28 mmol) in methanol (5 mL). The reaction was stirred at rt overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 2:8). The solution was diluted with ether (10 mL) and then transferred to a separatory funnel containing sat'd aq NaHCO3 solution (15 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 2:8, to provide 0.018 g of the title compound as an orange solid in a 59% yield.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[CH:6]([CH2:16][CH2:17]Br)[CH2:5]1)(=[O:3])[CH3:2].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[CH:6]([CH2:16][CH2:17][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2cc3c(cc21)OCO3
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(CCN2CCC(c3ccccc3)CC2)c2cc3c(cc21)OCO3

Procedure:
A solution of 580 mg. (18.6 mmol) of 5-acetyl-6,7-dihydro-7-(2-bromoethyl)-5H-1,3-dioxolo[4,5-f]indole and 600 mg. (37.2 mmol) of 4-phenylpiperidine in 30 ml. of toluene is heated at reflux temperature for 18 hours. The solvent is removed, and the residue is extracted with diethyl ether (2 × 25 ml.), and the solid is removed by filtration. The filtrate is evaporated to give a residue that crystallizes on trituration with petroleum ether. The material is recrystallized from dilute acetone to give crystals, m.p. 101°-103°C.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30].O>O1CCCC1>[CH2:1]([C:8]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of diethyl 2-(6-heptenyl)malonate (3.83 g, 14.92 mmol) in anhydrous tetrahydrofuran (50 ml) was slowly added dropwise to a suspension of 60% sodium hydride (0.52 g, 12.94 mmol) in anhydrous tetrahydrofuran (150 ml) at 0° C., and the resulting mixture was stirred for 1 hour. The 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane prepared in Example 2 (4.0 g, 9.95 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and then slowly added dropwise to the mixture, followed by stirring for 2 days at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, Yield 89%).
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.O.S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(Cl)(Cl)Cl>[C:4]1(=[O:13])[N:5]([CH:6]2[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]2)[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3 h

Procedure:
95 g (0.388 Mol) of 4-(phthalimido)-cyclohexanol are dissolved in 600 ml of chloroform and, after the addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 Mol) of potassium dichromate are added in batches. The internal temperature of the mixture is maintained at between 25° and 30° C. by slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated off and the mixture extracted twice more with chloroform. After drying and concentration of the extracts 82 g (86.9% of theory) are obtained.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=[N:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([Zn]CC)C>C1COCC1>[C:14]([S@:12]([NH:11][C@@:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])([CH:2]([F:18])[F:1])[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:13])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)[S@@](=O)N=C(c1ccccc1F)C(F)F
Agent: CC[Zn]CC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of (R)—N-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (4.60 g, 16.6 mmol), ethyl 2-bromo-2,2-difluoro-acetate (6.73 g, 33.18 mmol) and Rh(PPh3)3C1 (469 mg, 498 μmol) in THF (90 mL) was added a solution of diethyl zinc (1 M in THF, 33 mL) dropwise at −78° C. over a period of 20 minutes under Ar, during which the temperature was maintained below −65° C. The reaction mixture was warmed to 0° C. over a period of 10 minutes and stirred at 0° C. for 2 hours. TLC (petroleum ether/ethyl acetate=3:1) showed the starting material was consumed completely. The dark red solution was quenched by water (40 mL) and then filtered. The filtrate was extracted with ethyl acetate (100 mL, twice). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to give ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-2,2,4,4-tetrafluoro-3-(2-fluorophenyl)butanoate (4.26 g, 62.1% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.65-7.31 (m, 1H), 7.49-7.44 (m, 1H), 7.23-7.12 (m, 2H), 6.93-6.66 (m, 1H), 5.00 (s, 1H), 4.39-4.29 (m, 2H), 1.39 (s, 9H), 1.32 (t, J=8.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: NCCO
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(CCO)CCC(=O)OC
Reaction time: 20 h
Yield: 100.6 %

Procedure:
At 20 to 30° C., 15.5 g of methyl acrylate was added to 5.00 g of 2-aminoethanol. The resulting mixture was allowed to stand for 20 hours, followed by concentration under reduced pressure, whereby 19.2 g of N-(2-hydroxyethyl)bis[2-(methoxycarbonyl)ethyl]amine was obtained (at a quantitative yield)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[C:2]#[CH:3].[OH2:18]>N1C=CC=CC=1CO.CC([O-])=O.CC([O-])=O.[Cu+2].O>[N+:15]([C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([F:11])=[CH:10][C:5]=1[NH:4][CH2:1][C:2]#[C:3][C:3]#[C:2][CH2:1][NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:13])=[O:18])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])([O-:17])=[O:16]
Reactant: C#CCNc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OCc1ccccn1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(NCC#CC#CCNc2cc(F)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of Cu(OAc)2.H2O (1.5 g) in pyridinemethanol (1:1, 10 ml) was added N-(2-propynyl)-2,4-dinitro-5-fluoroaniline (1.00 g, 4.18×10-3 mole). The reaction mixture was stirred at room temperature for 17 hours. The mixture was poured into excess water and filtered. The crude solid was chromatographed on a silica column, eluting with chloroform ethyl acetate. Soxhlet recrystallization of the resulting solid from ethyl acetate afforded yellow crystals, m.p. 225° C. dec. Yield: 0.21 g (12%). I.R. (KBr): 3360 (NH), 1680 and 1315 cm-1 (Ar-NO2).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH2:5][CH2:6][CH3:7])#[C-:2].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1.O>[CH2:4]([C:3]1[NH:1][CH:2]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:20]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C=CC(=O)OCC
Reactant: [C-]#[N+]C(CCCC)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution (120 mL) of 1-[(1-isocyanopentyl)sulfonyl]-4-methylbenzene (10.8 g) and ethyl acrylate (4.78 mL) in tetrahydrofuran was added dropwise to a solution (80 mL) of potassium tert-butoxide (5.79 g) in tetrahydrofuran while stirring at room temperature over 1 hr. The mixture was further stirred at the same temperature for 30 min, and the reaction product was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellow oil (yield 6.56 g, 78%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+:34]>CO.O.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[NH:34][C:9]3[C:8](=[O:23])[N:7]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:6](=[O:32])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=3[N:11]=2)=[CH:15][CH:16]=1
Reactant: CCCCn1c(NCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(Cc2ccccc2F)c1=O
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
1-Butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione (2.0 g, 4.46 mmol) was dissolved in methanol (100 mL) and treated with zinc dust (<10 μm, Aldrich; 2.91 g) followed by the addition of a solution of ammonium chloride (5.96 g, 112 mmol) in water (50 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated to remove methanol and the residual aqueous solution was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford 8-(4-amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione as a pale yellow solid (1.64 g, 87%). LCMS, m/z(M+H)=422.18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].C(O)C=C>>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@H:6]([OH:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC
Solvent: C=CCO
Product: CCOC(=O)C[C@H](O)CC
Yield: 100 %

Procedure:
Another method to increase the stereoselectivity is using inhibitors to block the enzyme(s) affording the unwanted isomer. A. C. Dahl et al. (1999), Tetrahedron: Asymmetry 10, 551–559, reported the reduction of ethyl-3-oxopentanoate with non heat-treated Baker's yeast and allyl alcohol to ethyl-3(R)-hydroxy-pentanoate (100% yield and 92–93 % ee). When heat-treated Baker's yeast (48° C. for 60 min) was used in combination with allyl alcohol the product was obtained in 80–95% yield and the ee was increased to 98%. However, for the successful reaction a substrate concentration of approximately 1 g/L was used and 250 times yeast relative to substrate, respectively 4 times inhibitor relative to substrate were required.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:15])[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
300 mg (1.61 mmol) of 2-oxo-pyrrolidin-1-carboxylic acid t-butyl ester was dissolved in tetrahydrofuran and then cooled to −78° C. To the resulting solution, was dropwise added a solution of 1.7 mL (1.7 mmol) of 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran, followed by stirring for 1 hour. 0.19 mL (3.05 mmol) of iodomethane was dropwise added thereto. Thereafter, the temperature was gradually raised to −30° C. for 2 hours. 50 mL of ethyl acetate was added to the solution, and the reaction solution was washed with aqueous ammonium chloride, and an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 130 mg (0.65 mmol) of the title compound in a yield of 40%.
Reaction SMILES: [C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:3])[NH2:2].Br[CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)C>[C:1]([CH:4]([NH:16][C:17](=[O:33])[NH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])[CH:8]=1)=[O:6])(=[O:3])[NH2:2]
Reactant: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2c[nH]c3ccccc23)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)n1cc(NC(=O)NC(C(N)=O)C(=O)c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A solution of 0.10 g (0.223 mmol) of the product from step d), 0.15 g (0.56 mmol) of N-(3-bromopropyl)phthalimide, 0.10 g (0.72 mmol) of K2CO3 and 1.5 ml of DMF. The flask was sealed and heated to 65° C. for 5 hours. The reaction mixture was partitioned between 10 ml of EtOAc and 10 ml of water. The organic phase was collected and the aqueous phase was extracted with an additional 10 ml of EtOAc. The combined organic phases were washed with water and brine. The organic phase was evaporated to give a yellowish solid. The solid was suspended in 20 ml of diethyl ether and stirred for 30 minutes. The precipitate was allowed to settle and the ethereal phase was removed. The residual precipitate was dried in vacuum to give 100 mg (70%) of the sub-title product.