Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.C(Cl)Cl>CCOCC>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Temperature: 150 °C
Yield: 62 %

Procedure:
A thoroughly mixed paste of 2-aminobenzenethiol (0.63 g, 5.07 mmol) and 2-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol) in trimethylsilylpolyphosphate (5 ml) was stirred and heated at 150° C. under an atmosphere of argon for 1.5 h. On cooling to room temperature the reaction mixture was a solid mass to which was added DCM (35 ml) and Et2O (50 ml). The solid was broken up and collected by filtration, then recrystallised from AcOH and dried under high vacuum for 18 h to give the title compound (0.90 g, 62%) as a yellow solid.
Reaction SMILES: [N+](=[C:3]([C:10](=[O:21])[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-]>ClCCl.C(#N)C.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:19][C@@H:17]([C@H:16]1[C:15](=[O:20])[N:14]2[C@@H:13]1[C@@H:11]([CH3:12])[C:10](=[O:21])[CH:3]2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH3:18]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCOC(=O)C1C(=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.5 g) in dichloromethane (10 ml) was added rhodium(II) octanoate (13.2 mg) under reflux. After refluxing for 20 minutes, to the solution was added rhodium(II) octanoate (13.2 mg). The mixture was refluxed for 40 minutes. The reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous acetonitrile (10 ml) and then evaporated. This operation was repeated once again and the resulting residue was dried in vacuo to give allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo-[3.2.0]heptane-2-carboxylate. The residue containing the compound obtained above was dissolved in anhydrous acetonitrile (10 ml) and cooled to 0°-2° C. under an atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.53 ml) and N,N-diisopropyl-N-ethylamine (0.47 ml) successively and the solution was stirred at 0°-2° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-1-allyloxycarbonyl-4-mercapto-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.62 g) in acetonitrile (10 ml) and N,N-diisopropyl-N-ethylamine (0.38 ml) successively with stirring at 2°-5° C., and the stirring was continued at the same temperature for 2 hours. To a reaction mixture was added ethyl acetate (30 ml) and water (10 ml) with stirring, and the organic layer was separated. This layer was washed with saturated aqueous sodium chloride solution (30 ml×2), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (50 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give allyl (4R,5S,6S)-3-[(2S, 4S)-1-allyloxycarbonyl-2-{(2-ureidoethyl)oxymethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH:25]1([NH:28][C:18]2[S:19]/[C:15](=[CH:14]\[C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]4[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=2)[CH2:27][CH2:26]1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), cyclopropylamine and DIEA to give 6-[2-Cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 365 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[C:9]=[S:10])=[N:6][CH:7]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:7]=1)[C:9](=[S:10])[N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:9](=[S:10])[N:8]=2
Reactant: S=C=Nc1ccc(Cl)cn1
Solvent: CC#N
Product: S=c1nc2ccc(Cl)cn2c(=S)n1-c1ccc(Cl)cn1
Reaction time: 72 h

Procedure:
1.1 G. of freshly distilled 5-chloro-2-pyridyl isothiocyanate is dissolved in 5 ml. acetonitrile and allowed to stand at room temperature for 3 days. The reaction mixture is filtered and the solid material washed with acetonitrile affording 7-chloro-3-(5-chloro-2-pyridyl) pyrido-(1,2-a) 1,3,5-triazine-2,4-dithione m.p. 131°-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1

Procedure:
To a mixture 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.100 g, 0.22 mmol) and ethanol (3 ml) was added 4-dimethylamino benzaldehyde (0.044 g, 0.29 mmol) and 1M aq. Na2S2O4 (900 μL, 0.9 mmol). The reaction mixture was stirred at reflux for 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate v/v 7:3, and then 0.5% to 2% methanol in ethyl acetate) to give the title compound as an off white solid (0.034 g, 27%); 1H-NMR (250 MHz, DMSO-d6) 2.77 (broad m, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.40 (s, 2H, NCH2CO), 3.67 (broad m, 4H, piperazine N(CH2)2), 6.82 (d, J=8.8 Hz, 2H) and 8.02 (d, J=8.8 Hz, 2H) 2,6-ArH and 3,5-ArH, 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, 1H, J=3.5 Hz) (thiazole 4-H, 5-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.80 (broad s, 1H, CONH), 13.12 (broad s, 1H, imidazo[4,5-b]pyridine NH); LC-MS (ESI, m/z) Rt=6.0 min—541/543 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS Found: 541.1203, calculated for C23H26N8OSBr (M+H+): 541.1134.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:17][C:18]2([OH:62])[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:31]=[C:30]4[C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[O:26])[CH2:19]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1>C([SiH](CC)CC)C>[N:8]1([CH2:17][C@@:18]2([OH:62])[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][N:31]=[C:30]4[C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[O:26])[CH2:19]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(Cn5ncc6ccccc65)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)N[C@@H]4CCC[C@](O)(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to N-(-3-((1H-indazol-1-yl)methyl)-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (0.1 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (1 drop) was added to the reaction and stirred for an additional 5 minutes. The crude product purified using prep HPLC.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:39][N:40]1[C:44]([C:45]2[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=2)[NH2:48])=[CH:43][N:42]=[C:41]1[CH3:52]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:52][C:41]1[N:40]([CH3:39])[C:44]([C:45]2[CH:46]=[C:47]([NH:48][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:49]=[CH:50][CH:51]=2)=[CH:43][N:42]=1
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccccc34)c2)n1C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (106 mg) and 1-hydroxybenzotriazole (81 mg) in dichloromethane (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and the mixture was stirred for 15 minutes. After adding 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and 4-dimethylaminopyridine (92 mg), the mixture was stirred for 60 hours. The residue was evaporated under reduced pressure and purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-imidazol-4-yl)-phenyl]-9H-carbazole-1-carboxamide (101 mg, 53.2%).
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a cooled (0° C.) solution of 0.230 g (0.80 mmol) of the product of Step D dissolved in 4 mL of CH2Cl2 was added 0.263 g (1.00 mmol) of carbon tetrabromide and 0.333 g (1.00 mmol) of triphenylphosphine. After 15 minutes at 0° C., the reaction mixture was allowed to warm to room temperature and was stirred for an additional 6 hours. The reaction was then concentrated in vacuo and purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 097 g (35%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]2[O:21][CH2:22][CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:6][CH:5]=1.N12CCCC=C1CCCNC2.O>C(#N)C.C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[F:30][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1COC(c2ccc(OC(F)F)c3oc4ccc([N+](=O)[O-])cc4c23)=N1
Agent: C1=C2CCCNCN2CCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc([N+](=O)[O-])cc4c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of ethyl 2-(4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan-1-yl)-4,5-dihydrooxazole-4-carboxylate (0.8 g, 1.90 mmol) in acetonitrile (8 mL), CCl4 (5 mL) and pyridine (8 mL) were added. To this mixture 1,3-diaza bicyclo[5.4.0]undec-7-ene (DBU) (1.6 mL, 10.72 mmol) was added. The reaction mass was stirred at room temperature for 1 hour. The reaction mixture was poured into the cold water (50 mL) and extracted with dichloromethane (2×50 mL). The organics were dried over sodium sulphate and filtered. The organics were evaporated under reduced pressure to give the crude product. The product was purified by column chromatography by using gradient of ethyl acetate in hexane (0-5) %. Yield—94%. 1H-NMR (CDCl3) δ: 1.52-1.55 (m, 3H), 4.54-4.60 (m, 2H), 6.72-6.90-7.08 (brs, 1H), 7.51 (d, 1H), 7.77 (d, 1H), 8.14 (d, 1H), 8.46 (s, 1H), 8.52-8.55 (m, 1H), 10.66 (d, 1H); HPLC (purity): 97.4%; Mass calculated for C19H12F2N2O7-418.3, observed—419.1; Rf—0.49 (Ethyl acetate:Hexane (3:7).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:18]I>CN(C)C=O.O.[Cl-].[Na+].O>[CH3:18][O:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% dispersion on mineral oil) (198 mg, 4.95 mmol) was added portionwise to tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (21) (710 mg, 3.30 mmol) in N,N-dimethylformamide (12 mL) at ambient temperature over a period of 30 seconds under an air atmosphere. The resulting suspension was stirred at 25° C. for 20 minutes. Methyl iodide (0.411 mL, 6.60 mmol) was then and the resulting suspension was stirred at 25° C. for 18 hours. The reaction mixture was diluted with water (150 mL) and saturated brine (25 mL), then washed sequentially with dichloromethane (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was used directly in the next stage.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a suspension of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (9.2 g: 9 mMol.) in a mixture of anisole (18 ml) and nitromethane (72 ml) is added dropwise a solution of aluminum chloride (9.6 g: 72 mMol.) in anisole (31 ml) at -30° C. After stirring for 1 hour at the same temperature, the reaction mixture is quenched with ethanol (25 ml), stirred for several minutes, diluted with 1N-hydrochloric acid (75 ml) and water (500 ml), and washed with ethyl acetate. The aqueous layer was separated, concentrated to remove the organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with a mixture of methanol and water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (4.19 g). Yield: 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][C:30]#[N:31])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:33])[CH:20]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:25]([CH3:26])[CH3:27])[CH:22]=1)[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A solution of (2-{3-chloro-5-[(-cyano-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4yl-carbamic acid tert-butyl ester (0.200 g) in methanol (2 ml) at 0° C. was treated with cobalt (II) chloride hexahydrate (0.195 g) and sodium borohydride (0.078 g) and stirred overnight at room temperature. Silica was added and the mixture was evaporated under reduced pressure, the residue was subjected to flash chromatography eluting with methanol:chloroform:ammonia(0.88) (10:89:1 v/v/v). The required fractions were evaporated under reduced pressure to give the title compound as a pale straw coloured oil (0.128 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[N:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.5 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.06 g) and 5-amino-2-isopropylpyridine (0.50 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.08 g) was obtained. melting point: 157.4° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH2:29][CH3:30])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:24]=[N:25][N:26]([CH2:29][CH3:30])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A small screw cap test tube was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 192 mg, 0.4611 mmol) and THF (4.6 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (87.9 mg, 0.46 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (CHCl3:MeOH mix eluant with gradient of 1% MeOH to 15% MeOH) to afford the title compound in 16% yield (0.041 g, 0.072 mmol).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12]C[C@H:10]1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:10]1[NH:15][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@@H]1CCC[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of (1R,2R)-2-benzyloxycyclohexylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×35 mL). The solid was suspended in 80% acetone/EtOH (200 mL). The suspension was stirred at reflux for 30 seconds before the solid was filtered and dried in the vacuum oven (50° C.), affording the title compound (844 mg. 55%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.60 (d, 1H, J=11.2 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.39 (m, 1H), 2.94 (m, 2H), 2.85 (m, 1H), 2.74 (t, 2H, J=6.5 Hz), 2.24 (m, 1H), 1.90 (m, 3H), 1.64 (m, 2H), 1.14 (m, 4H). 13C NMR (D2O, 125 MHz) δ ppm 137.35, 129.28, 129.19, 128.90, 76.90, 70.35, 60.97, 48.12, 42.90, 29.59, 26.53, 23.64, 23.09, 21.63. [α]D=−68.9° (c=0.0026 in water). ES-MS 326 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[F:10].[N+]([C:14]1[CH:19]=CC=C[CH:15]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[C:5](=[CH:4][C:3]=1[F:10])[N:9]=[CH:19][CH:14]=[CH:15]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1cc(F)c(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc2ncccc2c(F)c1Br

Procedure:
A mixture of 4-bromo-3,5-difluoro-phenylamine (6.0 g, 28.8 mmole), ferrous sulfate (1.82 g), glycerol (8.6 mL), nitrobenzene (1.79 mL) and 5.0 ml of concentrated sulfuric acid (5 mL) was heated gently. After the first vigorous reaction, the mixture was heated to reflux for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return the title compound as a white solid (3.5 g, 49.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=O)[NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.P(Cl)(Cl)(OCC)=O.[NH4+].[Cl-]>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[N:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(N)=O)CC1
Agent: CCOP(=O)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl((trans-4-carbamoylcyclohexyl)methyl)carbamate (1.7 g, 6.6 mmol) in CH2Cl2 (33 mL) was added DBU (3 g, 19.8 mmol) at room temperature. After stirring for 10 min, ethyl dichlorophosphate (2.2 g, 13.2 mmol) was added. The mixture was stirred at room temperature for 50 min. TLC (CH2Cl2:MeOH=10:1) showed the reaction was complete. The mixture was poured into sat. NH4Cl (aq., 150 mL) and extracted with CH2Cl2 (100 mL*2). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by combi flash to give tert-butyl((trans-4-cyanocyclohexyl)methyl)carbamate (1.4 g, 88%) as a white solid.