Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH:31]=O)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.O>O1CCCC1>[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH3:31])[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenoxy-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hq) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10]Cl>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Cl:10]
Reactant: Cc1ccc(Cl)cc1Cl
Reactant: ClCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
1 Mol of 2,4-dichloro-methylbenzene and 322 g of carbon tetrachloride are heated to reflux. 0.8 g of azobisisobutyronitrile is added and chlorine gas is introduced in a slight excess. After 0.5 hours, 0.75 mol of product is obtained according to gas-chromatographic analysis.
Reaction SMILES: Cl.C[NH:3][C:4]([CH3:9])([C:6](O)=[O:7])[CH3:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:39])OC4C=CC=CC=4)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+].O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([N:30]4[C:6](=[O:7])[C:4]([CH3:9])([CH3:5])[NH:3][C:31]4=[O:39])=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CNC(C)(C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(C)(C)C4=O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A mixture of 23 parts of methyl 2-methylalanine hydrochloride, 55 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate. 12.45 parts of sodium hydrogen carbonate, 10 parts of N,N-dimethyl-4-pyridinamine and 300 parts of 1,4-dioxane was stirred overnight at reflux temperature. Water was added till saturation. After stirring for another hour at reflux temperature, the mixture was cooled to room temperature. The product was filtered off, washed with water and 2,2'-oxybispropane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried. yielding 45.33 parts (84.4%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4-imidazolidinedione; mp. 255.0° C. (intermediate 19).
Reaction SMILES: C1N(CCO)CCN(CCS(O)(=O)=O)C1.[Na+].[Cl-].[Cl-].[Cl-].[Ca+2].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].NCC(N1CCC[C@H]1C(N[C@H](C(O)=O)CCCCN)=O)=O.NC[C:74]1[C:75](=[O:84])[O:76][C:77]2[C:82]([CH:83]=1)=[CH:81][CH:80]=[CH:79][CH:78]=2>>[O:76]1[C:77]2[C:82](=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:83]=[CH:74][C:75]1=[O:84]
Reactant: NCc1cc2ccccc2oc1=O
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Product: O=c1ccc2ccccc2o1

Procedure:
Identification of functional placental bikunin was achieved by measuring its ability to inhibit bovine trypsin and human plasma kallikrein. Trypsin inhibitory activity was performed in assay buffer (50 mM Hepes, pH 7.5, 0.1 M NaCl, 2.0 mM CaCl2, 0.1% Triton x-100) at room temperature in a 96-well microtiter plate (Perkin Elmer) using Gly-Pro-Lys-Aminomethylcoumarin as a substrate. The amount of coumarin produced by trypsin was determined by measuring the fluorescence (ex=370 nm, em=432 nm) on a Perkin-Elmer LS-50B fluorimeter equipped with a plate reader. Trypsin (23 μg in 100 μl buffer) was mixed with 20 μl of the sample to be tested and incubated for 10 minutes at 25° C. The reaction was started by the addition of 50 μl of the substrate GPK-AMC (33 μM final) in assay buffer. The fluorescence intensity was measured and the % inhibition for each fraction was determined by: % inhibition=100×[1−Fo/F1] where Fo is the fluorescence of the unknown and F1 is the fluorescence of the trypsin only control. Kallikrein inhibitory activity of the fractions was similarly measured using 7.0 nM kallikrein in assay buffer (50 mM Tris, pH 8.0, 50 mM NaCl, 0.1% triton x-100) and 66.0 μM Pro-Phe-Arg-AMC as a substrate. Determination of the In Vitro Specificity of Placental Bikunin
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:3].F>C(OCC)C>[CH3:3][C:2]1([CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1
Reactant: C=C(C)CCOc1ccccc1
Agent: F
Solvent: CCOCC
Product: CC1(C)CCOc2ccccc21
Reaction time: 72 h
Yield: 92.2 %

Procedure:
A mixture of 19.2 g 2-methyl-4-phenoxy-1-butene and 50 ml of anhydrous hydrogen fluoride was stored at room temperature for 3 days. The mixture was then diluted with 500 ml of diethyl ether and the resulting mixture was washed with saturated sodium bicarbonate solution (2×500 ml). It was then dried (MgSO4) and concentrated in vacuo to give 17.7 g of the title compound as an oil. Yield 92%.
Reaction SMILES: C(OC([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[C:10]1=[O:38])=O)(C)(C)C.Cl>C(Cl)(Cl)Cl>[NH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[C:10]1=[O:38]
Reactant: COC(=O)c1cccnc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccnc1CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methoxycarbonylpyridin-2-yl) methyl-1H-1,4-benzodiazepin-2-one (0.80 g) in chloroform (10 ml) was treated with hydrogen chloride at room temperature and the mixture was stirred for 1 hour under the same condition. The mixture was concentrated in vacuo and the residue was taken up with chloroform. The organic layer was washed with a saturated sodium carbonate aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo to give (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-methoxycarbonylpyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one (0.64 g) as a colorless form.
Reaction SMILES: CC1C=CC(C)=CC=1.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][O:24][CH3:25])[CH:21]=1)[C:16](Cl)=O.[C:26]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=C)=[CH:32][CH:31]=1)(=[O:28])[CH3:27].CN1CCOCC1>[Pd].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:26]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:16][C:15]2[CH:14]=[C:13]([O:12][CH2:11][O:10][CH3:9])[CH:21]=[C:20]([O:22][CH2:23][O:24][CH3:25])[CH:19]=2)=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: COCOc1cc(OCOC)cc(C(=O)Cl)c1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccc(C)cc1
Product: COCOc1cc(C=Cc2ccc(OC(C)=O)cc2)cc(OCOC)c1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 58.6 %

Procedure:
A 50 mL round bottom flask was charged with p-xylene (20 mL), Pd II catalyst (22.5 mg, 0.1 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (42.7 mg, 0.1 mmol), 3,5-bis(methoxymethoxy)benzoyl chloride (2.42 g, 10 mmol), 4-acetoxystyrene (1.94 g, 12 mmol), and N-methyl morpholine (1.38 g, 12 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (2.1 g, 59%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.48 (d, 2H), 7.08-6.93 (m, 4H), 6.86 (d, 2H), 6.66 (t, 1H), 5.19 (s, 4H), 3.50 (s, 6H), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 169.5, 158.7, 150.3, 139.5, 135.0, 128.7, 128.5, 127.6, 121.9, 108.0, 104.5, 94.6, 56.2, 21.2; HRMS (EI+) found 358.1409 M+, calcd 358.1416 for C20H22O6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11]Cl)[C:6]=1[C:7]([F:10])([F:9])[F:8].[O-:22][CH2:23][CH3:24].[Na+].C(O)C>O1CCCC1.[O-]CC.[Na+].O>[Cl:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11][O:22][CH2:23][CH3:24])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CC[O-]
Reactant: N#Cc1c(Cl)c(C(F)(F)F)n(CCl)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-chloro-1-(chloromethyl)-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.6 g, 0.0074 mol) in tetrahydrofuran is treated with sodium ethoxide as a 21% wt/wt solution in denatured ethanol (3.6 mL, 0.0096 mol), stirred at room temperature for 1 hour, treated with an additional 2-3 drops of the sodium ethoxide solution, heated at reflux temperature for 1 hour, cooled and poured in water. The resultant precipitate is filtered, dried and recrystallized from isopropanol to afford the title product as a white solid, 1.6 g (60% yield), mp 104.0-104.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=O)[CH2:3]1.C(N(C(C)C)CC)(C)C.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O.S(Cl)(Cl)=O>C(Cl)Cl.C(O)C>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4](=[O:6])[N:20]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)[C:7](=[O:9])[CH2:8]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(CCN2C(=O)CC(C)(C)CC2=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of 3,3-dimethylglutaric anhydride (0.3 mmol), diisopropylethylamine (0.30 mmol) and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol) in CH2Cl2 (3 mL) was stirred 1 h at rt. Thionylchloride (3 mmol) was added and the mixture was stirred for 2 h at rt. Addition of ethanol (5 mL) followed by evaporation to dryness gave a crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:1). This gave the title compound in 23% yield as crystals. Furthermore 3,3-dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid ethyl ester could be isolated in 27% yield as an oil (see characterization below)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>CN(C=O)C.CCCCCC>[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14])(=[O:11])[NH2:16]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (1.01 g, 4.99 mmol) in DMF (5 mL) at −20° C. was added NMM (1.10 mL, 9.99 mmol) and isobutyl chloroformate (1.30 mL, 9.99 mmol). The reaction was stirred for 10 min at −20° C. The precipitate was removed by filtration. 26% NH4OH (aq) solution (0.39 mL, 9.99 mmol) was added and the reaction was stirred at −20° C. for 3 h. The volume was reduced under vacuum and hexane was added. A white precipitate was formed after a few minutes. The precipitate was collected in a filter and washed with additional hexane. The precipitate was recrystallised from EtOAc and hexane to give the title compound (0.811 g, 80%) as white solid.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH:12]([OH:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)=O)C>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:10]1[CH2:9][CH:8]([CH2:6][OH:5])[CH:12]([OH:13])[CH2:11]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C(CO)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (0.305 g, 13 mmol) in anhydrous tetrahydrofuran (25 mL) was added a solution of ethyl ester 73 (2.69 g, 9.2 mmol) in THF (25 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.3 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (40 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×75 mL) The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 74 was purified by column chromatography first by eluting with dichloromethane/methanol (5%) (1.98 g, 85%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C(O)(=O)/C=C\C(O)=O.[BrH:18].C(O)(=O)C>>[Br:18][CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: Br
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(=O)O
Product: COC(=O)C(Br)CC(=O)O
Temperature: -2 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methyl hydrogen (2Z)-2-butendioate (also known as the monomethyl ester of maleic acid) (50 g, 0.385 mol) was added dropwise to a solution of hydrogen bromide in acetic acid 141.43 g, 33%, 0.577 mol) at 0° C. over 1 h. The reaction mixture was stored at about 5° C. overnight. The solvent was then removed under reduced pressure. Toluene (100 mL) was added, and the mixture was evaporated under reduced pressure. The process was repeated three times using more toluene (3×100 mL). Then toluene (50 mL) was added, and the mixture was cooled to −2° C. Hexanes (50 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred about 30 minutes while the product crystallized. The product was then isolated by filtration and dried in vacuo to provide the title compound as a white solid (63.37 g, 81.8% yield). A sample recrystallized from toluene/hexanes melted at 38-40° C.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([CH2:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-])=O)[CH:4]=1)[CH3:2]>C(OCC)(=O)C>[CH2:10]([C:9]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([NH2:12])=[C:6]([NH2:7])[CH:8]=1)[CH3:11]
Reactant: CCc1cc(N)c([N+](=O)[O-])cc1CC
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(N)cc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
4,5-Diethyl-2-nitroaniline (23) (567 mg, 2.92 mmol) was dissolved in ethyl acetate (20 mL). To this solution was added 10% Pd--C (142 mg, 20%; Aldrich). The mixture was agitated at room temperature under a pressure of 35 psi (H2) for 5 h. The catalyst was removed through a column of Celite (5 g) and washed with ethyl acetate (3×20 mL). The filtrates were combined and evaporated in vacuo to give 4,5-diethyl-1,2-diaminobenzene 24 (459 mg, 96%)as a colorless solid; mp 114°-116° C. (lit. mp 114°-115° C.; Lambooy, J. P., J. Am. Chem. Soc. 71:3756 (1949)); 1H NMR (CDCl3, 300 MHz) δ1.158 (t, 6H, J=7.5 Hz), 2.498 (q, 4H, J=7.5 Hz), 2.908 (br, s, 4H), 6.555 (s, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44]O)[CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][NH:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49])[CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4cccc(OCCO)c4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: OCC(CO)NCCOc1cccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[3-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-1,3-propanediol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[S:14][CH:15]=[C:16]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH:22]=2)[N:17]=1)[C:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:7].C(N(CC)C(C)C)(C)C.[C:36]([N:39]1[CH2:47][CH2:46][CH:42]([C:43](Cl)=[O:44])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([N:39]1[CH2:40][CH2:41][CH:42]([C:43]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)[N:17]=2)[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[O:44])[CH2:46][CH2:47]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)NCCCN(C(=O)c2cccs2)c2nc(-c3cc4ccccc4o3)cs2)CC1
Temperature: 25 °C

Procedure:
A mixture of the amine prepared above (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (139 μL, 0.8 mmol) was dissolved in chloroform (2 mL), and a portion of the solution (200 μL, 0.02 mmol) was added to a solution of 1-acetyl-isonipecotoyl chloride (7.6 mg, 0.04 mmol) in chloroform (200 μL). The reaction mixture was maintained at room temperature overnight.). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μL) and subjected to HPLC purification (Method Z) to provide the title compound (4.5 mg) as a yellowish solid. LC/MS (ESI) m/z 537.1 [M+H]. HPLC retention time (Method C)=3.44 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:11]([Sn:15]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16]I)[CH2:12][CH2:13][CH3:14].CN(C)C=O>O1CCCC1.O>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH2:16][Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)COC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 73.1 %

Procedure:
To a solution of 4-hydroxy-1-methylpiperidine (802 mg, 6.96 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (50%, 334 mg, 6.96 mmol) at room temperature, and the mixture was stirred at room temperature for 35 minutes. To the reaction mixture were added a solution of tributyl-iodomethyl-tin (2.00 g, 4.64 mmol) in tetrahydrofuran (5 ml), and N,N-dimethylformamide (10 ml) at room temperature, and the mixture was stirred at room temperature for 7 hours and 50 minutes. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=100:1 to 20:1) to obtain the title compound (1.42 g, 3.39 mmol, 73%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:15]([CH3:16])[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(CN1CCN(Cc2ccccc2)CC1)c1ccccc1F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(CN1CCNCC1)c1ccccc1F
Yield: 73.8 %

Procedure:
4-Benzyl-1-[2-(2-fluorophenyl)propyl]piperazine (3.17 g, 0.01 mol), ammonium formate (3.2 g, 0.05 mol) and palladium (II) hydroxide on carbon (10% w/w, 1.6 g) were mixed in methanol (200 ml) and heated under reflux for 18 h. The catalyst was filtered off through celite and the filtrate evaporated. Chromatography on silica gel with dichloromethane-methanol-880 ammonia (80:8:1) yielded 1-[2-(2-fluorophenyl)propyl]piperazine (1.64 g, 73%) as a colourless oil, δH (250 MHz, CDCl3) 1.2 (3H, d, J 7.0, Me), 2.3-2.6 (6H, m, CH2), 2.8-3.0 (4H, m, CH2), 3.1-3.2 (1H, m, MeCH), 6.9-7.4 (4H, m, ArH).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:31]1[N:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=1)[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:26]([O-:28])=[O:27])=[C:13]([CH2:16][N+:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23]C=O)[CH:18]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([O:3][N:4]=[C:5]([C:31]1[N:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=1)[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:26]([O-:28])=[O:27])=[C:13]([CH2:16][N+:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(NC=O)c3)CS[C@H]12)c1nccc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(N)c3)CS[C@H]12)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 7-[2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(3-formamido-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (430 mg) and concentrated hydrochloric acid (0.16 ml) in methanol (4.3 ml) was stirred for 2 hours at room temperature. The mixture was adjusted to pH 4 with aqueous sodium bicarbonate and evaporated under reduced pressure. The residue was dissolved in water (50 ml) and subjected to column chromatography on a non ionic adsorption resin "HP-20" (70 ml). After the column was washed with water, the elution was carried out with 25% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(3-amino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.22 g), mp 140° to 145° C. (dec.).