Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 2-methoxybenzyl alcohol (1.0 g, 7.2 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.32 g, 7.91 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.0 g, 7.2 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered and dried to afford 1.55 g of 2-fluoro-5-(2-methoxybenzyloxy)benzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([C:24]5[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=5)([CH2:17]4)[CH2:15]2)[CH2:21]3)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8]>C(OC(=O)C)(=O)C.OS(O)(=O)=O>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:21][CH:20]4[CH2:19][CH:18]([CH2:17][C:16]([C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=5)([CH2:22]4)[CH2:15]2)[CH2:23]3)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:12](=[O:13])[CH3:14])(=[O:1])[CH3:7]
Reactant: O=C(NCCc1ccc(O)c(O)c1)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CCNC(=O)C23CC4CC(C2)CC(c2ccc(Cl)cc2)(C4)C3)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
Compound 1 (1 g) was dissolved in 10 mL of acetic anhydride with a catalytic amount of 98% H2SO4 and stirred under N2 for 3 days at room temperature. The solution was then concentrated under a vacuum and filtered to give the product Compound 2 (yield=54%), with a melting point of 160-162° C. 1H NMR (500 MHz, CDCl3) δ 1.74 (m, 2H, Admant-H), 1.81-1.88 (m, 8H, Admant-H), 1.93 (s, 2H, Admant-H), 2.26-2.27 (m, 2H, Admant-H), 2.28 (s, 3H, COCH3), 2.31 (s, 3H, COCH3), 2.83-2.85 (t, J=5 Hz, 2H, CH2), 3.50-3.54 (q, 2H, NCH2), 5.69 (s, 1H, NH), 7.01-7.02 (d, J=5 Hz, 1H, Ar—H), 7.07-7.09 (d, d, 1H, H—Ar), 7.13-7.15 (d, J=10 Hz, 1H, Ar—H), 7.30 (s, 4H, Ar—H). 13C NMR (500 MHz, CDCl3) δ 20.6, 20.7, 28.8, 35.0, 35.5, 36.5, 38.3, 40.2, 40.3, 41.7, 42.0, 44.5, 123.5, 124.0, 126.4, 127.0, 128.3, 131.5, 138.0, 140.6, 142.0, 148.4, 168.4, 168.5, 177.5. Mass spectroscopy m/z (relative intensity) 510.24 (M+, 100), 511.24 (38), 512.24 (45).
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:6][C:5]=2[CH:1]=[C:2]1[CH3:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CCC1=O
Product: Cc1cc2c(n1Cc1ccccc1)CCN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl-4-piperidone may be reacted with benzylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[C:28]([F:34])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=1[I:26]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:30]=[C:29]([NH2:31])[C:28]([F:34])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:6]=1[I:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc(Oc2cc(F)c([N+](=O)[O-])cc2F)c1I
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc(Oc2cc(F)c(N)cc2F)c1I
Yield: 96.8 %

Procedure:
Palladium hydroxide on carbon (0.193 g, 0.275 mmol) (contains 60% water) was added to a solution of 4-(2,5-difluoro-4-nitrophenoxy)-3-iodo-2-[bis[(1,1-dimethylethoxy)-carbonyl]amino]pyridine (1.63 g, 2.75 mmol) in EtOAc (20 mL) and the mixture was hydrogenated (50) psi for 16 h. The completed reaction mixture was filtered through Celite® rinsing forward with EtOAc (2×10 mL). The combined filtrate was concentrated to afford 4-(2,5-difluoro-4-aminophenoxy)-3-iodo-2-[bis[(1,1-dimethylethoxy)carbonyl]amino]pyridine as colorless foam (1.5 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (dd, J=7.6 Hz, 5.6 Hz, 1H), 7.24 (dd, J=11.0 Hz, 7.4 Hz, 1H), 6.71 (m, 1H), 6.57 (d, J=5.6 Hz, 1H), 5.55 (s, 2H), 1.35 (s, 18H); MS (ESI) m/z: 564.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:1][CH2:2][CH:3]([NH:12][C:13]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:22])[CH2:4][C:5]1([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:33])=[O:32]
Reactant: CC1(CC(CO)NC(=O)OCc2ccccc2)CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.3607 g (1.18 mmol) of benzyl 1-hydroxy-3-(1-methylcyclohexyl)propan-2-ylcarbamate, 0.4 mL (2.87 mmol, 2.43 equiv) of triethylamine, 0.1 mL (1.29 mmol, 1.09 equiv) of methanesulfonyl chloride in CH2Cl2 (10 mL) was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice water, extracted with CH2Cl2, washed with aqueous NaHCO3, and dried over Na2SO4. After the solvent was removed in vacuo, the crude 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propyl methanesulfonate was used directly in the next step without further purification. MS ESI +ve m/z 406 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23]=[S:24])[CH2:20][CH3:21]>C(OCCC)(=O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:23](=[S:24])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CCCN=C=S
Solvent: CCCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a slurry of 2-amino-5-iodobenzoic acid (100 g, 0.38 mol) in n-propyl acetate (315 mL) was added triethylamine (58 mL, 0.42 mol) at room temperature. The resulting solution was heated to reflux and n-propyl isothiocyanate (43 mL, 0.42 mol) was added over a one hour period. The reaction mixture was maintained at reflux for 18 h, then cooled to room temperature and filtered. The wetcake was washed with fresh propyl acetate and dried at 60° C. under vacuum. In this manner, 113 g of the title compound was obtained as a tan solid. m.p.>200° C.; 1H NMR (Me2SO--d6): δ13.02 (bs,1H), 8.22 (d,1H), 8.06 (dd,1H), 7.21 (d,1H), 4.34 (m,2H), 1.69 (m,2H), 0.93 (t,3H).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1.[CH3:27][OH:28]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:27][O:28][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4][CH2:2]1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)OC
Reaction time: 2 h

Procedure:
Methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g) was dissolved in methylene chloride (13 ml) containing methanol. To the solution was added silver fluoroborate (0.45 g), and the mixture was stirred for 2 hours. After the reaction, the reaction mixture was filtered and the filtrate was washed with a dilute sodium bicarbonate aqueous solution and then with water. The solution was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The elute was separated into fractions of each about 20 ml and the seventh to tenth fractions were collected. The solvent was distilled off to give Methyl 3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.60 g).
Reaction SMILES: [Li+].[BH4-].CO.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)([CH2:17][CH3:18])[C:13](OC)=[O:14])=[CH:8][CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)([CH2:17][CH3:18])[CH2:13][OH:14])=[CH:8][CH:7]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of LiBH4 (22 mg) in THF (3 mL) was added MeOH (32 mg, 5.43 mmol) and a solution of methyl 2-(4-chlorophenyl)-2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indol-1-yl)butanoate (105 mg) in THF (3 mL). The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (25-35% ethyl acetate in hexanes) to afford the title compound as a pale yellow solid. LC/MS m/z=393.2 [M+H]+.
Reaction SMILES: [C:1](O)(C)(C)C.CC(C)([O-])C.[K+].[CH3:12][C:13]1[C@@H:17]([OH:18])[CH2:16][C:15](=O)[C:14]=1[CH2:20][C:21]#[CH:22].P([O-])(O)(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][C:13]1[C@@H:17]([OH:18])[CH2:16][C:15](=[CH2:1])[C:14]=1[CH2:20][C:21]#[CH:22]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])(O)O
Solvent: CCOCC
Product: C#CCC1=C(C)[C@@H](O)CC1=C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ether (70 ml), t-butanol (6.6 ml) and methyltriphenylphosphonium bromide (25 g) were mixed with stirring at room temperature, then potassium t-butoxide (12.9 g) was added to the mixture and then the resulting solution was stirred for 5 hours at the same temperature. To the solution was added a solution of (S)-3-methyl-2-(2-propynyl)-4-hydroxycyclopent-2-ene-1one (12.42 g) in ether (13 ml) under ice-water cooling and the resulting reaction mixture was stirred at the same temperature for 2 hours and then for 6 hours at room temperature. The reaction solution was poured into a saturated aqueous solution of sodium dihydrogenphosphate, and extracted with ether. The obtained ether layer was washed with brine and dried over anhydrous magnesium sulfate. Then the filtered solution was evaporated. The obtained oily residue was then subjected to silica gel column chromatography, however, neither the desired product, (S)-2-methyl-4-methylidene-3-(2-propynyl)cyclopent-2-ene-1-ol nor the starting material was obtained.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([O:19][NH:20][C:21]([C:23]1[N:28]=[CH:27][C:26]2[C:29](=[O:32])[O:30][CH2:31][C:25]=2[C:24]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(ONC(C1C(OCC2C=CC=CC=2)=C(CO)C(C(NCC2C=CC(F)=CC=2)=O)=CN=1)=O)C1C=CC=CC=1>>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][C:29]([C:26]3[C:25]([CH2:31][OH:30])=[C:24]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:23]([C:21]([NH:20][O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:22])=[N:28][CH:27]=3)=[O:32])=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C1OCc2c1cnc(C(=O)NOCc1ccccc1)c2OCc1ccccc1
Agent: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Product: O=C(NCc1ccc2c(c1)OCO2)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Yield: 61.6 %

Procedure:
Piperonylamine (0.035 g, 0.288 mmol, 2 eq) and N,7-bis(benzyloxy)-3-oxo-1,3-dihydrofuro[3,4-c]pyridine-6-carboxamide (0.056 g, 0.144 mmol, 1 eq), compound 1c of example 1, were heated neat at 70° C. for 30 min. The crude product was purified by silica gel (30% ethyl acetate) yielding 0.048 g of N5-(benzo[d][1,3]dioxol-5-ylmethyl)-N2,3-bis(benzyloxy)-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (62% yield) as a white solid; MS-ESI m/z 542 [MH]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].C(O[C:11](=O)[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>C1COCC1.[NH4+].[Cl-]>[CH3:4][C:3]1[N:5]=[C:11]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:1][N:2]=1
Reactant: CC(=N)NO
Reactant: CCOC(=O)CSc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(CSc2ccccc2)n1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
565 mg (7.65 mmol, 1.5 eq) of N-hydroxy-acetamidine in 50 ml of THF were treated at RT with 306 mg (7.65 mmol, 1.5 eq) of NaH portionwise within 30 min. 1.0 g (5.1 mmol) of phenylsulfanyl-acetic acid ethyl ester was added in a THF solution, and stirring was continued for 1 hour at 60° C. The reaction mixture was diluted with saturated aqueous NH4Cl, extracted with EtOAc, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 1:1 yielded 480 mg (46%) of 3-methyl-5-phenylsulfanylmethyl-[1,2,4]oxadiazole as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1noc2cc(Oc3ccc(F)cc3CN)ccc12
Temperature: 0 °C
Yield: 78.2 %

Procedure:
5-fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzonitrile (3v) (84 mg, 0.31 mmol; prepared as described in Example 108) was dissolved in THF (3 mL) and cooled to 0° C. A solution of lithium aluminum hydride in THF (0.35 mL, 0.35 mmol) was added slowly and the reaction was allowed to warm to room temperature. After 1 hour the reaction was quenched by the portion-wise addition of sodium sulfate decahydrate at 0° C. until gas evolution ceased. THF was added and the mixture was filtered through celite and eluted with EtOAc. The solution was concentrated to provide crude product (9v) (66 mg) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:16]1[C:24]2[C:19](=[C:20]([CH2:26][S:27][CH3:28])[CH:21]=[C:22]([F:25])[CH:23]=2)[NH:18][CH:17]=1)[CH2:10][C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:16]1[C:24]2[C:19](=[C:20]([CH2:26][S:27][CH3:28])[CH:21]=[C:22]([F:25])[CH:23]=2)[NH:18][CH:17]=1)[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cc(F)cc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.48 g (3.36 mmol) of the compound from Example 39A in 20 ml of tetrahydrofuran was added dropwise to 11.8 ml (11.8 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 50 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. 1.32 g (99% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].O>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2cc[nH]c2c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of 2-amino-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (336.7 mg, 2.0 mmol) in CH2Cl2 (14.3 mL) was added benzyl bromide (0.26 mL, 2.2 mmol) and TBABr (644 mg, 2.0 mmol). The reaction mixture was cooled to 0° C., and to it was added 50% NaOH (1.7 mL). The resulting mixture was stirred for 2 h as it warmed from 0° C. to room temperature. Water was then added, and the solution was washed with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with CH2Cl2/Acetone (5:1-1:1), afforded the product as a tan solid (423 mg, 82%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](Cl)(C)C.[C:19](#[N:22])[CH:20]=[CH2:21].Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:20][C:19]#[N:22])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C=CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CCCP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.44 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.68 ml), trimethyl silylchloride (0.61 ml) and acrylonitrile (0.17 ml) and the reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a highly crystalline solid 0.5 gm (90% yield), m.p. 80°-82° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Cl-].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:23]([O:25][C:26](=[O:41])[CH:27]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:28](=[O:36])[C:29](=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:24]>C(OCC)(=O)C.OCC(CO)O.CS(C)=O>[CH2:23]([O:25][C:26](=[O:41])[CH:27]([CH2:37][CH:38]([CH3:39])[CH3:40])[C:28](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:24]
Reactant: CCOC(=O)C(=O)C(=O)C(CC(C)C)C(=O)OCC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Reaction time: 48 h

Procedure:
To 40 μL of 300 mM potassium phosphate buffer, pH=6.5, containing NaCl (100 mM), DMSO (3% v:v), glucose (200 mM), and glycerol (10% v:v), 40 mM of 2-isobutyl-3-ketoketoglutarate diethyl ester was added along with 100 mg of lyophilized KRED 1001 and 30 mg of glucose dehydrogenase. The reaction mixture was incubated for 48 hours at 37° C. Gas chromatographic analysis showed that the yield of hydroxy diester product was greater than 80%. The product was isolated by extraction of the reaction mixture with ethyl acetate and purification using silica gel chromatography. Isolated yield was in the range of 85–95%.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH:1]([CH:11]=[CH:10][C:9]([OH:13])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 48 h

Procedure:
Styrene and acrylic acid were dissolved in benzene in a total concentration of 30% by weight. An amount of 0.2% by weight based on the total monomers of azobisisobutyronitrile was added to the solution. The mixture was sealed in a tube under a nitrogen gas, and the polymerization was carried out at 70° C. over a period of 48 hours to provide a styrene-acrylic acid copolymer.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:12]C([N-]C(C)C)C.C1COCC1.CCCCCCC.CI.Cl>C1COCC1>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1cccc2ccoc12
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2o1
Temperature: -70 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A stirred solution of 7-bromobenzofuran (493 mg, 2.5 mmol) in dry THF (5 mL) was cooled to −70° C. and 2M LDA in 1:1 THF/heptane (1.4 mL, 2.8 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h and methyl iodide (0.19 mL, 3.0 mmol) was added. The mixture was stirred at −70° C. for 3 h and at 0° C. for 1 h. The mixture was poured into 5% aq HCl (60 mL) and extracted with ether (2×50 mL). The combined ether extracts were washed with sat'd aq NaHCO3 (20 mL) and dried over MgSO4. Removal of the solvent left an oil (470 mg) which was purified by chromatography on a 40-g silica cartridge eluted with hexanes to afford 7-bromo-2-methylbenzofuran (277 mg, 52%, estimated purity 80%).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12][C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:3]=1.CC1[O:51]C(=O)C=C(SC2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)N3C(=O)[C@@H](NC(=O)CC4C=CC=CC=4)[C@H]3SC=2)C=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12](=[O:51])[C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:3]=1
Reactant: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)cc(=O)o1
Reactant: Cc1cc(SC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc(=O)o1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)cc(=O)o1
Reaction time: 0.67 h

Procedure:
A stirred solution of diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthio) -7β-phenylacetamidoceph-3-em-4-carboxylate and diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthio) -7β-phenylacetamidoceph-2-em-4-carboxylate (763 mg) in dichloromethane (10 ml) was cooled in an ice bath, and a solution of m-chloroperbenzoic acid (211 mg of 85%) in dichloromethane (5 ml) was added. The mixture was stirred at 0° for 40 mins. and then washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (581 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 3390, 1805, 1720 cm-1, δH (CDCl3) 2.14 (3H, s) 3.36 (1H, d, J 18.1Hz), 3.60 (2H, s), 3.75 (1H, d, J 18.2Hz), 4.51 (1H, d, J 4.8Hz), 5.72 (1H, s), 5.95 (1H, s) 6.13 (1H, dd, J 4.8 and 9.7Hz), 6.94 (1H, d, J 9.7Hz), 6.97 (1H, s), 7.2-7.4 (15H, m).