Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[C:25]([C:24]1[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2[CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)#[N:26]
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: N#Cc1cccnc1-n1c(C=Cc2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloro-3-Cyanopyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate to give the titled compound. MW: 334.38; mp: 171.5-172.5° C.; 1H-NMR (CDCl3) δ: 8.98 (1H, dd, J=4.8, 1.8 Hz) 8.32 (1H, dd, J=7.7, 1.8 Hz), 7.98 (1H, d, J=16.1 Hz), 7.89-7.85 (1H, m), 7.67 (1H, dd, J=7.7, 4.8 Hz), 7.52-7.47 (2H, m), 7.42-7.26 (5H, m), 7.23-7.19 (1H, m), 6.83 (1H, d, J=16.1 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:6]=1)=[N+]=[N-]>CO.[Pd]>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:7]1[N:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCc1cccc(OCC(F)(F)F)n1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
A mixture of 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.44 g, 1.90 mmol, Step-5) and palladium 10% on carbon (0.070 g) in methanol (12 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure to give 0.27 g (68% yield) of the title compound as dark brown oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7].O[NH:21][CH2:22][CH:23]([CH3:25])[CH3:24].[OH2:26]>CN(C)C=O.C(O)C>[CH3:24][C:23]([CH3:25])([OH:26])[CH2:22][NH:21][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: CC(C)CNO
Reactant: O
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 60 °C

Procedure:
Phosphorus oxychloride (4 mL, 43 mmol) was reacted with N,N-dimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.9 g, 36.1 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was warmed in an oil bath to 60° C. After 3 hours the reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The wet crude 5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine was added followed by the slow addition of hydroxyisobutylamine (3.4 g, 40 mmol). The reaction mixture was refluxed for 2 hours and then combined with water (˜100 mL). The resulting precipitate was isolated by filtration to provide 7.2 g of 1,1-dimethyl-2-[(3-nitro[]1,5]naphthyridin-4-yl)amino]ethanol. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 184.5–186° C. Analysis: Calculated for C12H14N4O3: % C, 54.96; % H, 5.38; % N, 21.36; Found: % C, 54.63; % H, 5.36: % N, 21.51.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:23]=[CH:22][C:19](C#N)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:24][Mg]Br.Cl.[C:28]([O-:31])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:28](=[O:31])[CH3:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: O=C([O-])O
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)nn2)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc(N3CCN(C(C)C)CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 4-[6-(4-isopropylpiperazin-1-yl)pyridazin-3-yl]benzonitrile (0.36 g, 1.17 mmol, prepared by a similar procedure to that described in Example 1) in dry THF (5 mL) was added a 1.4 M methylmagnesium bromide solution in toluene/THF. The reaction mixture was stirred at room temperature for 24 h, 1 M hydrochloric acid (7 mL) was added and the solution stirred for 1 h. The mixture was made alkaline by addition of excess NaHCO3 solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, the solvent was removed and the solid was re-crystallized from ethanol to give the title compound, 163 mg (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O:26][CH2:27][CH3:28])(=[O:25])[C:22]([CH3:24])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:21]([O:26][CH2:27][CH3:28])=[O:25])[CH3:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the same manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and ethyl pyruvate gives 7-chloro-2-[[1-(ethoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oily product. NMR (CDCl3) δ1.20 (t, 3, CH2CH3), 2.25 (2, 3, CH3), 4.23 (q. 2, CH2CH3), 4.50 (broad s, 2, 3-CH2), between 6.95 and 7.6 (m, 9, NH and arom H's).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
5-bromo-2-iodopyrimidine (0.320 g), 4-(trifluoromethyloxy)phenylboronic acid (FRONTIER SCIEN., 0.231 g), tetrakis(triphenylphosphine)palladium(0) (ALDRICH, 0.026 g) and sodium carbonate (1.6 ml, 2M in H2O) in dry toluene (2.8 ml) was refluxed for 24 hours under argon atmosphere. After cooling to room temperature, H2O (5 ml) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, concentrated under vacuum and purified by column chromatography on silica gel, eluting with EtOAc-hexane 1:20 to give 0.248 g of the desired product as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[CH2:24](I)[CH3:25].CO>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:6][CH:5]=1
Reactant: CCCCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCC(Cn1cncn1)(C(=O)OCC)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a 250 mL 3 neck flask stirring under N2 was charged 1.0 g of 60% sodium hydroxide (prewashed with hexanes) in 50 mL of dimethyl formamide (DMF). To the slurry was charged 6.14 g (0.020 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1yl)methyl]hexanoic acid in 50 mL of dimethyl formamide. The mixture was stirred at room temperature and 3.74 g (0.024 mole) of ethyl iodide was added. The reaction was monitored by thin layer chromatography (TLC) in a one to 19 mixture of methanol and ethyl acetate. Upon completion the reaction was quenched with water extracted with ether, and washed with saturated sodium bicarbonate. After drying and removal of the solvent, 5.9 g (88% yield) of a thick oil remained, Example 18 of Table 1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH3:38])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:38][N:28]([CH3:27])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@@H:9]1[C@@H:10](I)[CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[SnH](CCCC)CCCC.[CH:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C:13]2([NH:8][C:6]([O:5][CH2:1][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:7])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@@H]1[C@@H](I)C[C@@H]2NC(=O)OCc1ccccc1
Reactant: c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(C)(C)OC(=O)N1C(=O)C2(NC(=O)OCc3ccccc3)CCCC1C2
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1

Procedure:
A sample of (1R,2S,4S,5R)-2-benzyloxycarbonylamino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (43.3 g) was dissolved in benzene (580 mL) prior to the addition of Bu3SnH (27.8 g) and AIBN (0.7 g). The resulting mixture was warmed to a gentle reflux for 3 h. After cooling, the solvent was removed and hexane was added. The resulting white solid was collected by vacuum filtration to give the title compound, (1R,2S,5R)-2-Benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (29.5 g). MS found: (M+Na)+=397.4.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH3:20].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1Cc2cc(-c3ccccc3)ccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
A mixture of 2.5 g of 1D, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for seven hours, with removal of water as it formed. The resulting mixture was concentrated, and the residue dissolved in ether. The solution was washed with saturated sodium bicarbonate solution and water. The aqueous portion was extracted with ether. The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was distilled to give ethyl 2,3-dihydro-5-phenylbenzofuran-2-carboxylate (1E), as a colorless liquid, bp: 180°-181° C., 0.35 Torr.
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2([CH3:22])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1.[ClH:25].N([O-])=O.[Na+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32]>O.CC(C)=O>[Cl:25][CH:31]([CH2:32][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2([CH3:22])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1)[C:30]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Cc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Reactant: C=CC(=O)OCC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(C)c(C)c(C)c3O2)cc1

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 734 mg of 2-(4-aminophenoxymethyl)-2,5,6,7,8-pentamethylchroman (prepared as described in Preparation 32), 1 ml of concentrated aqueous hydrochloric acid, 190 mg of sodium nitrite, 1.2 ml of ethyl acrylate, 70 mg of cuprous oxide, 10 ml of acetone and 2 ml of water were reacted, to afford 390 mg of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12]2)=[O:10])=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:13]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)N1CCC(c2ccc(Cl)cc2)=N1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To 3.2 g of N,3-bis-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide dissolved in 20 ml of tetrahydrofuran and cooled in an acetone bath maintained at -20° C., was added 1.5 ml of diisopropyl amine and 8.0 ml of a 2.7 molar solution of butyllithium in hexane. The resulting solution was stirred for 20 minutes and then cooled to -70° C. To this solution was added 0.5 ml of ethyl chloroformate. The reaction was allowed to stir for 10 minutes and then allowed to warm to room temperature over 10 minutes. The reaction was quenched with 1.0 ml of acetic acid and the reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 3.3 g of N,3-bis-(4-chlorophenyl)-4-carboethoxy-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR and IR data were consistent with the structure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@@:11]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][C@@H:16]([OH:18])[C@@H:15]2[C@@H:13]([O:14]2)[CH2:12]1.C(N(CC)CC)C>ClCCl>[C:1]([O:18][C@H:16]1[C@@H:15]2[C@@H:13]([O:14]2)[CH2:12][C@:11]([OH:10])([C:19]([O:21][CH3:22])=[O:20])[CH2:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@]1(O)C[C@@H](O)[C@H]2O[C@H]2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Benzoyl chloride (0.216 mL, 1.86 mmol) was added dropwise to a 0° C. solution of Example 17C (0.35 g, 1.86 mmol) and triethylamine (0.52 mL, 3.74 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at room temperature, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash column chromatography using hexanes/ethyl acetate (3/2) to afford 495 mg (91%) of the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][C:3]=1[Cl:15].CO.[OH-].[Na+]>O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: CON=Cc1cc(C(=O)[O-])cc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 210 g (0.86 moles) of the previously prepared 4-amino-3-chloro-5-methoxyiminomethylbenzoate, 1.7 l of methanol and 462 g (1.73 moles) of 15% aqueous sodium hydroxide. The resulting mixture was refluxed for 3 hours, after which the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated using a rotary evaporator. The crude reaction mixture was dissolved in 2 l of water. The resulting aqueous solution was washed once with 500 mL of ethyl acetate, cooled in an ice bath and acidified to pH=2 with concentrated hydrochloric acid. The expected 4-amino-3-chloro-5-methoxyiminomethylbenizoic acid precipitated as a light yellow solid which was separated by suction filtration. The filter cake was washed with a 1:2 mixture of ethyl ether and hexane yielding after drying 185.2 g (94% yield).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]=[C:21]=[O:23])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CN=C=O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
4t-butylbenzylamine (3.2 g) was dissolved in dichloromethane (10 ml) and to the solution was added triethylamine (2.79 ml), followed by cooling to 0° C. and slowly adding dropwise a solution of triphosgene (1.98 g) in dichloromethane (5 ml). The mixture was stirred at room temperature for 5 hours and water (10 ml) was added thereto. The resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=20/1) to yield 4-t-butylbenzylisocyanate (880 mg) as a solid. The obtained compound (400 mg) and 3-fluorophenethylamine (290 mg) were dissolved in dichloromethane (20 ml) and the solution was stirred at room temperature for 22 hours. The solvent was removed therefrom and the residue was purified by column-chromatography (hexane/ethyl acetate=4/1) to yield the compound 29 (400 mg, 58%) as a solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:44]([Sn](CCCC)(CCCC)CCCC)=[CH2:45].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([CH:44]=[CH2:45])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.4645 g (0.00073 mole) of diphenylmethyl 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem4-carboxylate, 0.279 g (0.00088 mole) of ethenyl tri-n-butylstannane, 0.200 g (0.00146 mole) of zinc chloride and 0.0068 g (0.000029 mole) of tri-(2-furyl)phosphine in 6 mL of dry 1-methyl-2-pyrrolidinone, under an Argon atmosphere, was degassed for 30 seconds. Then 0.0084 g (0 000014 mole) of palladium(0) bis(dibenzylidene acetone) was added all at once. The reaction mixture was stirred at room temperature for 1 hr. The reaction mix was then diluted with ethyl acetate and the organic solution washed with dilute ammonium chloride. The ethyl acetate was removed at reduced pressure and replaced with acetonitrile. The organic phase was washed with n-pentane and the acetonitrile removed at reduced pressure. The residue was crystallized from ethanol/methylene chloride yielding 0.320 g (85%) of diphenylmethyl 7-phenylacetamido-3-ethenyl-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent for the desired structure.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1/[CH:29]=[CH:30]/[CH:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]1[C:31](=[O:32])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C/C=C/c1ccccc1Cl
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccccc1Cl
Yield: 48 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(2-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 14 as a white solid (65 mg, 48%). Analytical data for 14: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=8.0 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.39-7.32 (m, 3H), 7.28-7.22 (m, 2H), 7.10-7.03 (m, 2H), 7.01-6.94 (m, 4H), 4.09 (d, J=6.9 Hz, 1H), 3.58 (ddd, J=9.8, 6.8, 4.9 Hz, 1H), 3.31 (dd, J=14.9, 4.9 Hz, 1H), 2.42 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.3 Hz), 155.4 (d, JCF=240.2 Hz), 148.9, 140.0, 136.8, 136.5, 134.4, 129.9, 129.3, 129.1, 128.5, 127.9, 127.3, 127.0, 118.3 (dd, JCF=13.0, 9.3 Hz), 117.1 (dd, JCF=25.8, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.5 Hz), 114.5 (dd, JCF=26.8, 3.7 Hz), 110.7 (d, JCF=3.8 Hz), 47.0, 38.6, 32.6; IR (film) cm−1 1772, 1636, 1619, 1598, 1529, 1481, 1463, 1172, 1118, 1079, 875, 813, 766, 741, 697; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=20.7, Rt2 (minor)=23.6 min; er=92:8.