Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8](Br)=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3].C(N)[CH2:19][NH2:20]>CN1CCCC1=O.O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([C:19]#[N:20])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3]
Reactant: NCCN
Reactant: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1Br
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1C#N

Procedure:
A mixture of 4-bromo-2,5-diisopropylphenyl methyl sulfone (19.9 g) prepared in Example 10A and 7.2 g of cuprous cyanide was heated in 100 ml of N-methyl pyrrolidone at 195°C under nitrogen for 2 hours. The reaction mixture was poured into a stirred solution of 25 g of ethylenediamine in 500 ml of water. The mixture was filtered and the residual product extracted into tetrahydrofuran. The extract was washed with 5% HCl and finally with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed to give 4-cyano-2,5-diisopropylphenyl methyl sulfone. Further purification by recrystallization from n-hexane gave 4-cyano-2,5-diisopropylphenyl methyl sulfone having a mp of 134°-137°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1.FC(F)(F)C(O)=[O:33].[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:25][CH2:26][CH:27]([OH:33])[CH2:29][OH:28]
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC(O)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg) was dissolved in dichloromethane (2 ml) to prepare a solution. Trifluoroacetic acid (2 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 4 hr. The reaction solution was made alkaline by the addition of 1 N sodium hydroxide, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, yield 29%).
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:14]=2[CH:42]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:18]([C:16]1[N:15]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:14]2[CH:42]=[C:10]([NH:9][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=[CH:12][C:13]=2[N:17]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
2.0 g (15 mMol) of pyrrolidinocarbonyl chloride are placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate dissolved in 50 ml of dry pyridine are added dropwise for one hour. The reaction solution is stirred for a further 24 hours and then concentrated by rotary evaporation. The oily residue is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution, the organic phase is separated off and, after drying with magnesium sulphate, concentrated by rotary evaporation. Purification is carried out using a silica gel column (particle size: 0.063-0.2 mm), eluting with petroleum ether/ethyl acetate=3:7. The corresponding column fractions are concentrated by rotary evaporation and dried in vacuo at 50° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13].[OH-].[K+].I[CH3:17]>C(O)C>[CH3:17][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13]
Reactant: COc1cccc2cc(O)cnc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cnc2c(OC)cccc2c1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
175 mg of 3-hydroxy-8-methoxy quinoline [compound (V)] prepared in example 6 and 66 mg of potassium hydroxide were added to 3 ml of ethanol, and the solution was agitated for 30 minutes. To the solution was added 284 mg of iodomethane, and the solution was agitated for 24 hours. The solvent was removed, and the solution was extracted with dichloromethane. The dichloromethane layer was washed with water and aqueous sodium hydroxide, and dried with anhydrous magnesium sulfate. The dichloromethane was removed by vacuum distillation to give 165 mg of 3,8-dimethoxy quinoline.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)c1
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(O)c2)nc2ncn(Cc3ccccc3)c12
Temperature: 100 °C
Reaction time: 35.5 h
Yield: 66.8 %

Procedure:
1.00 g (3.01 mmol) of 7-benzyl-2-(3-methoxyphenyl)hypoxanthine prepared according to the same method as in Example 16 was dissolved in 20 ml of acetic acid. 3 ml of hydrobromic acid was added to the solution, followed by stirring for 35.5 hours at 100° C. Crystals obtained by cooling was separated by filtration and washed with distilled water and ethanol. The resulting crude crystals were purified by recrystallization from ethanol to obtain 0.64 g of 7-benzyl-2-(3-hydroxyphenyl)hypoxanthine (yield 67%).
Reaction SMILES: [N:1]([O-])=[O:2].[Na+].C(O)(=O)C.[N+:9]([C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([N:1]=[O:2])[CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:29][CH:30]=1)([O-:11])=[O:10]
Reactant: O=N[O-]
Reactant: O=C(O)C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1C(=O)O
Reaction time: 1 h

Procedure:
The H2O (300 mL) solution of NaNO2 (cont. 98.5%) (6.66 g) was added to the acetic acid (864 mL) solution of piperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester (26.72 g) under a nitrogen atmosphere at 0° C. for 0.5 h and stirred for 1 h. In addition, the H2O (132 mL) solution of NaNO2 (cont. 98.5%) (2.41 g) was added to the solution at 0° C. for 0.5 h and stirred for 1 h. The solution was concentrated under reduced pressure and H2O (500 mL) was added to the residue. The solution was extracted with AcOEt (5 times) and organic layer was washed with brine. The mixture was dried over MgSO4, filtered and concentrated under reduced pressure to afford crude 4-nitrosopiperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester as pale brown amorphous (27.83 g (gross), 25.77 g (net), 88.2%).
Reaction SMILES: [F:1][CH:2]([C:21]1[O:22]CC(C)(C)N=1)[CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH2:28]>Cl>[F:1][CH:2]([CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:21]([OH:22])=[O:28]
Reactant: O
Reactant: CCCCCC=CCCCCC#CCC#CCCC(F)C1=NC(C)(C)CO1
Agent: Cl
Product: CCCCC/C=C\CCCCC#CCC#CCCC(F)C(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A suspension of 2-(1-fluorononadec-13-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole (86 mg) in 3 ml of 3N HCl was refluxed wih stirring under argon for 15 min. It was cooled to about 23° C., diluted with 3 ml of water, and extracted three times with ether. The ether extracts were combined, washed with brine, and dried over MgSO4. Concentration of ether at 35° C./35 mmHg gave the crude acid which was purified by flash chromatography on silica gel (8 g, 230-400 mesh). Elution with HOAc-CH3OH-CHCl3 under nitrogen afforded 49 mg (66% yield by weight) of (Z)-2-fluoro-14-eicosene-5,8-diynoic acid as a colorless oil.
Reaction SMILES: [C-]#N.[Na+].[Cu][C:5]#[N:6].Br[C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14]>CN(C)C=O>[C:5]([C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14])#[N:6]
Reactant: N#C[Cu]
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2cc(Cl)cc(Cl)c2Cl)c(N)nc1N
Temperature: 130 °C

Procedure:
A mixture of 97% sodium cyanide (0.064 g, 1.306×10−3 mole) and 90% copper(I) cyanide (0.135 g, 1.306×10−3 mole) in dry dimethylformamide (5 ml) was stirred and heated to 130° C. To the resulting clear solution was added 5-Bromo-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.35 g, 0.95×10−3 mole) in small portions, and the solution was maintained at 140-150° C. for 16 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was extracted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-17% ethyl acetate in cyclohexane as the eluent. Yield 0.152 g (51 %), M.p. 277-279° C.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:11][CH2:10]1)C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:13][CH2:14]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(OCc5ccccc5)CC4)c3n2)cc(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(O)CC4)c3n2)cc(OC)c1OC
Yield: 130.9 %

Procedure:
A solution of (4-benzyloxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (36 mg, 0.070 mmol) and 10% Pd/C (10 mg), in THF (10 ml) and EtOH (8 ml), was hydrogenated for 5 days under a 60 psi H2 atmosphere. The reaction mixture was vacuum purged with argon (3×), and filtered through a plug of celite using THF and DCM. The filtrate was concentrated giving an opaque oil which was purified by silica gel chromatography using 0-10% MeOH in EtOAc as eluant provided 39 mg (36%) of (4-hydroxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a pale yellow solid. MP 242-244° C. M+H=426.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
3,4-Dihydroxy benzoic acid, benzyl bromide, and potassium carbonate were dissolved in acetonitrile, and the solution was refluxed for 18 hours. The reaction solution was then cooled to room temperature and filtered. The solution was then concentrated and diluted with hexanes, resulting in a solid that was collected by filtration. The solid was then recrystallized in the mixture of THF and hexanes, giving rise to a pure product.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 113.1 %

Procedure:
To a 250 mL round-bottomed flask were added a stir bar, 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (15.0 g, 40 mmol) and 4-bromobenzyl amine hydrochloride (11 g, 50 mmol), DMA (130 mL), and DIPEA (22 mL, 125 mmol). The resulting mixture was heated to 100° C. After 24 h, the mixture was cooled and concentrated to dryness. The residue was triturated with IPA (200 mL) and the orange solid was collected by vacuum filtration. The collected solid was washed with IPA (2×50 mL) and hexanes (2×50 mL) to afford the title compound (21 g, 84%). MS (ESI): mass calcd. for C23H18BrN3O3, 463.05; m/z found 464.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.34-8.27 (m, 1H), 8.21 (d, J=8.4, 1H), 8.12-8.06 (m, 1H), 7.87-7.81 (m, 2H), 7.75 (ddd, J=8.4, 6.9, 1.4, 1H), 7.63 (d, J=8.5, 1H), 7.58-7.53 (m, 1H), 7.49-7.46 (m, 2H), 7.25-7.18 (m, 3H), 6.71 (d, J=9.4, 1H), 5.34 (s, 2H), 4.49 (d, J=5.8, 2H).
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C(C)(C)C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:24][NH:25][CH:26]([CH2:34][O:35]COC)[CH:27]([OH:33])[CH2:28][O:29]COC)=[CH:11]1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:35][CH2:34][CH:26]([NH:25][CH2:24][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)[CH:27]([OH:33])[CH2:28][OH:29]
Reactant: COCOCC(O)C(COCOC)NCc1cn(COCc2ccccc2)c2c(OC(C)(C)C)ncnc12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cnc2c(CNC(CO)C(O)CO)c[nH]c12
Reaction time: 0.17 h

Procedure:
The product from Example 1.5 (104 mg, 0.195 mmol) was stirred in DCM (10 ml) at −78° C. and boron tribromide (1.0M in DCM, 1.95 ml) added dropwise. The reaction was stirred at −78° C. for 45 minutes before addition of methanol (10 ml). The solvents were evaporated and the residue co-evaporated with methanol (2×). The residue was partitioned between water and DCM and the aqueous layer evaporated. The residue was stirred in methanolic ammonia for 10 minutes and then evaporated on to silica and purified by flash silica chromatography, eluting with 5:4.5:0.5 DCM:methanol:ammonia giving the title compound as a white solid (27 mg, 52%). 1H NMR (300 MHz, CDCl3) 2.76 (1H, q, J 5.2 Hz), 3.48 (1H, dd, J 6.3, 11.9 Hz), 3.60 (2H, m), 3.70 (2H, m), 3.85 (2H, ABq), 7.34 (1H, s), 7.78 (1H, s); 13C NMR (75 MHz, CDCl3) 40.2, 59.8, 59.8, 63.5, 71.2, 113.1, 117.5, 129.2, 142.4, 143.5, 155.4; m/z (ES+) 537 (2MH+, 20%), 269 (MH+, 100%); HRMS (ESI+) C11H16N4O4 requires 269.1241. found 269.1250. The product, compound 1.6, is a 1:1 mixture of the enantiomers of Examples 17 and 18 below.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[H][H].C(O)C.P([O-])([O-])([O-])=O>[Pd].O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:43])([F:42])[F:44])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: [H][H]
Reactant: C=CSCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 37.3 %

Procedure:
p-Nitrobenzyl 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylate (syn isomer) (100 mg) was hydrogenated in the presence of 5% palladium on carbon under an atmospheric pressure of hydrogen in a mixture of tetrahydrofuran (6 ml), ethanol (0.6 ml) and 0.025M phosphate buffer solution (pH 6.85, 6.4 ml) at ambient temperature for 1.5 hours. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with diluted hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with diluted hydrochloric acid, washed with ethyl acetate, adjusted to pH 2.4 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diethyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (30.0 mg).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-:32].[Na+].O>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]([NH2:25])=[O:32])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(N)=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (404 mg, 1.00 mmol) obtained in Example 1 was dissolved in ethanol (8 mL), 2 mol/L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 70° C. for 2 days. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with 2 mol/L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (compound 3) (279 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[C:25](=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[CH:25]([OH:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:33][CH:32]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCCC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCCC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Reaction time: 0.5 h

Procedure:
To a cooled solution of 4.2 g of 3,4-dihydro-9-[4,4-bis(4-fluorophenyl)butylamino]acridin-1(2H)-one in tetrahydrofuran was added 5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 0.5 hours at ice bath temperature.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26]Cl)[N:17]=[CH:16]2)[C@@H:6]1[F:29])(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26][N:30]=[N+:31]=[N-:32])[N:17]=[CH:16]2)[C@@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 15, compound (21) is reacted with sodium azide in N,N-dimethylformamide at room temperature for converting the chloro group of compound (21) into azido group, whereby 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-4-azidoacetyl-5-(dimethylaminomethyleneamino)imidazole [compound (22)] is produced.
Reaction SMILES: [CH3:1][C@:2]1([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.I[Si](C)(C)C.Cl>C(Cl)Cl.CO>[CH3:1][C@:2]1([NH2:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: C[C@]1(NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@]1(N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To a solution of (S)-benzyl 3-methyl-1-(4-nitrophenyl)piperidin-3-ylcarbamate (525 mg, 1.421 mmol) in CH2Cl2 (5 ml) cooled at 0° C. was added iodotrimethylsilane (0.290 mL, 2.132 mmol) dropwise. After addition, the orange colored solution was stirred at 0° C. for 15 min, then at rt for 1 hr. The reaction was quenched by addition of 4.3 mmol of HCl (1.1 mL of 4N HCl in dioxane) in MeOH (5 mL). The mixture was concentrated. The dark reddish residue was partitioned between ether and water. The ether phase was extracted with 0.2 N aqueous HCl. The combined acidic aqueous solution was extracted with ether (1×), then basified at 0° C. with 1N aqueous NaOH to pH=10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the desired product, (S)-3-methyl-1-(4-nitrophenyl)piperidin-3-amine (277 mg, 1.177 mmol, 83% yield) as a dark reddish oil. Anal. Calcd. for C12H17N3O2 m/z 235.2, found: 236.0 (M+H)+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (d, J=9.34 Hz, 2 H), 6.83 (d, J=9.34 Hz, 2 H), 3.62-3.50 (m, 1 H), 3.32 (d, J=12.64 Hz, 1 H), 3.18 (s, 1 H), 3.12 (d, J=13.19 Hz, 1 H), 1.82 (d, J=4.95 Hz, 1 H), 1.75 (s, 1 H), 1.69-1.54 (m, 2 H), 1.18 (s, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6])=[O:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>[Ni]>[OH:12][CH2:11][CH:9]([NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][OH:1]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Ni]
Product: O=C(O)CC[C@H](NC(CO)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-fructose and L-(+)-glutamic acid using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 3 hours to 70° C. The reaction product had a melting point of 149° C. (decomposition) and an RF -value of 0.62 (determined as indicated under Example T).