Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:5]2[N:22]=[CH:23][CH:24]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[N:5]2[N:22]=[CH:23][C:24]([CH:33]=[O:34])=[C:4]2[N:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3ccnn23)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3c(C=O)cnn23)CC1
Reaction time: 8 h
Yield: 48 %

Procedure:
To tert-butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (1.7 g, 4.8 mmol) in DMF (36 mL), POCl3 (7.7 mL, 82.9 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 8 hours. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, tert-butyl 4-(5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was collected as a solid in 48% yield. LCMS (M+1=380)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(OC)nc1C
Yield: 64 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Pd]>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)C1CCCC(=O)C1
Reaction time: 21 h
Yield: 75.2 %

Procedure:
300 g (2 mol) of 3-tert.butylphenol are hydrogenated in the presence of 3 g of palladium-on-active charcoal 5% and 3 g of anhydrous sodium carbonate at 0.15-0.3 bar hydrogen over-pressure and 115° C. In an autoclave for 21 hours. The mixture is then filtered over Celite. The Celite is washed with ether and the solution is evaporated. In this manner there are obtained 310.8 g of crude product, namely 1.5% trans-tert.butylcyclohexanol, 3.5% cis-tert.butylcyclohexanol, 86% 3-tert.butylcyclohexanone and 7.6% 3-tert.butylphenol. This product can be purified by distillation. There are obtained 232 g (75%) of 3-tert.butylcyclohexanone, b.p. 75°-76° C., 2 mbar (olfactorily acceptable, purity 94%) in addition to 11.3 g (3.6%) of impure material (purity 92%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:40][CH2:39][C:34]5(OCC[O:35]5)[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34](=[O:35])[CH2:39][CH2:40]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC5(CC4)OCCO5)c3)cc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
1,4-Dioxa-8-aza-spiro[4.5]decan-8-carboxylic acid(4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (564 mg, 1.04 mmol) in acetone (35 mL), was cooled to 4° C. and treated dropwise with aqueous hydrochloric acid (4 N, 9 mL). The reaction was warmed to rt and stirred overnight. The reaction was made basic by the addition of saturated aqueous sodium hydrogencarbonate and extracted with EtOAc. The organic phase was washed with brine, dried, filtered and concentrated in vacuo to give 4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (467 mg, 90%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.36 (1H, s), 8.25 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.96 (1H, t), 7.86 (1H, s), 7.72 (1H, d), 7.64 (1H, d), 7.23-7.32 (2H, m), 6.96-6.98 (1H, m), 6.66 (1H, t), 6.55 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 3.72-3.76 (4H, m), 2.36-2.40 (4H, m); m/z (ES+) 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by a method analogous to that of Example 1(b) from 15.0 g (26 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(6-phthalimidohexyloxy)carbonyl-pyridine and 3.9 ml (80 mmol) of hydrazine hydrate. 11.2 g (97%) of an orange coloured oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[N:9]=1
Reactant: Clc1nccn2cnc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Clc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 2 h

Procedure:
To a solution of 8-chloro-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazine (2.10 g, 6.5 mmol) in DMF (12 mL) at 0° C. was added NBS (1.40 g, 7.84 mmol) and stirred for 2 h. DMF was removed under pressure and added water (75 mL). Solid formed was extracted with EtOAc (3×50 mL), washed with water (40 mL) and dried (Na2SO4). Evaporation of solvent gave crude material, which was purified by column chromatography on silica gel using CH2Cl2/MeOH (98:2). Yield: 2.05 g (77%); 1H NMR (CDCl3, 300 MHz) δ 7.11-7.21 (m, 5H), 7.28-7.32 (m, 3H), 7.61-7.64 (m, 2H), 7.70 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[C:5]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethyl-1-ethoxycarbonylcyclopropane carboxylate (5.0 g.), sodium chloride (0.95 g.), and `wet` dimethylsulphoxide (6.0 ml.) was heated at a temperature of 175 ° to 180° C. under a nitrogen atmosphere for a period of 6 hours, after which it was cooled to the ambient temperature poured into water and extracted with petroleum ether (boiling range 60 ° to 80° C.). The extracts were dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield a residue comprising about 60% of the cis-isomer and 40% of the trans-isomer of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylate in about 80% yield, identification of which was confirmed by comparison with authentic samples using infra-red spectroscopy and gas-liquid chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[O:8])=[CH:18][CH:19]=1)#[N:2]
Reactant: CCOC(=O)CCCNC(=O)c1ccc(C#N)cc1
Reactant: COCCCBr
Product: COCCCN(CCCC(=O)O)C(=O)c1ccc(C#N)cc1

Procedure:
Using ethyl 4-(4-cyanobenzamido)butanoate and 1-bromo-3-methoxypropane, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 28, 4-(4-cyano-N-(3-methoxypropyl)benzamido)butanoic acid was obtained.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(CC(C)C)=NN(CC(O)=O)C1=O.[C:67]([O:71][C:72](=[O:82])[N:73](C1C=CC=C(N)C=1)[CH3:74])([CH3:70])([CH3:69])[CH3:68].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:67]([O:71][C:72](=[O:82])[N:73]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:74])([CH3:70])([CH3:69])[CH3:68]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)CC1=NN(CC(=O)O)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [1-(3,3-dimethyl-2-oxo-butyl)-5-isobutyl-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 11, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. The compound was further characterised as the hydrochloride salt. 1H NMR (DMSO-d6) 10.03 (1H, br s), 7.56-7.46 (3H, m), 7.28-7.20 (3H, m), 7.13 (1H, d), 6.89 (1H, d), 4.73 (2H, br s), 4.10 (2H, br), 3.85 (1H, br m), 2.78 (3H, s), 2.30 (1H, br m), 1.74 (1H, m), 1.15 (9H, s), 0.86 (6H, br m). Found: C, 61.02; H, 7.35; N, 13.18%; C27H35N5O3.H2O.HCl requires C, 60.95, H, 7.20, N, 13.16%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
7-{[2-(4-Trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid ethyl ester (160 mg, 0.34 mmol) was dissolved in 5 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (29 mg, 0.69 mmol) was added. After 2.5 h at room temperature, the volatiles were removed under vacuum and 5 ml of water was added to the mixture, which was brought to pH 4 with 1N HCl. The resulting slurry was filtered to provide 147 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.P(Br)(Br)[Br:14]>>[CH3:1][C:2]1[C:7]2[C:8]([Br:14])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(C)c2c(c1)OCC2=O
Product: Cc1cc(C)c2c(Br)coc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
4,6-dimethyl-3-benzofuranone (0.90 moles) was slowly added in phosphorus tribromide (30 ml), previously heated to 100° C. The mix is cautiously treated with ice, extracted with methylenechloride. The organic phase is made anhydrous (Na2SO4) and freed from the solvent under reduced pressure to produce 4,6-dimethyl-3-bromobenzofuran (60% yield).
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[C:14]=2[C:15]=1[NH2:16])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CC(O)=O.OP(O)(O)=O>[Cl:23][C:17]1[C:14]2[C:15]3[NH:16][CH:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:2][C:1](=[O:10])[C:11]=3[O:12][C:13]=2[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc2oc(C(=O)C=Cc3ccccc3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1ccccc1)CC3=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A mixture of 8A (1.9 g, 5.8 mmol) in AcOH (10 mL) and H3PO4 (10 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids were precipitated out, collected by filtration and dried to give product 8B (1.78 g, 93.68% yield).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C@H:11]([NH:15][C:16]([N:18]2[C:24](=[O:25])[C@@H:23]([CH2:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[CH2:22][NH:21][C:20](=[N:36][O:37][CH2:38][CH3:39])[CH2:19]2)=[O:17])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.O.C(O)(=O)C.O>C(OCC)(=O)C>[C:4]([OH:6])(=[O:5])[CH3:3].[NH2:1][C:2]1[CH:10]=[C:9]([C@H:11]([NH:15][C:16]([N:18]2[C:24](=[O:25])[C@@H:23]([CH2:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[CH2:22][NH:21]/[C:20](=[N:36]\[O:37][CH2:38][CH3:39])/[CH2:19]2)=[O:17])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCC[C@@H](NC(=O)N1C/C(=N/OCC)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.8 %

Procedure:
The reaction mixture was diluted with ethyl acetate (10 ml) and filtered by a glass filter spread with Celite®, and further the residue was washed with ethyl acetate (20 ml). The filtrate and the washings were combined, then successively washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, then concentrated. The concentrated residue was purified by flash column chromatography to obtain 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (compound 12) (698 mg). To the compound 12 (558 mg) thus obtained, acetic acid (1.1 ml) was added and the mixture was stirred at room temperature for 30 minutes. Then water (2.75 ml) was added, and the mixture was stirred for 10 minutes. Further, acetic acid/water (2/5, 2.5 ml) was added, and the mixture was stirred for 15 minutes, then the mixture was cooled to 0° C. and stirred for 30 minutes. The precipitated crystals were collected by filtration to obtain the title compound (543 mg) as a light yellow crystals.
Reaction SMILES: Cl.C([NH:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH3:37])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1)=O>CO>[NH2:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH3:37])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
Conc. hydrochloric acid (127.4 mg.) was dropwise added to a suspension of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 930 mg.) in methanol (15 ml.) and stirred at room temperature for 40 minutes. After methanol was removed under reduced pressure from the resultant solution, water (100 ml.) was added to the residue and the solid substance was dissolved by adding 10% hydrochloric acid. After the insoluble material was filtered out, the filtrate was adjusted to pH 3 with an aqueous sodium bicarbonate. The solution was purified by column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), with an eluent of aqueous methanol. The eluate was lyophilized to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (605 mg.), mp. 150° to 154° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([NH2:6])=[O:5].C[Si](C)(C)[O-:17].[K+].Cl>COCCOCCOC>[OH:17][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(F)cccc1C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOCCOC
Product: NC(=O)c1c(O)cccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-6-(trifluoromethyl)benzamide (500 mg, 2.41 mmol) in diglyme (8.05 mL) was added potassium trimethylsilanolate (1.08 g, 8.45 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mixture was acidified with 1N HCl (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% solution of LiCl in water, dried with MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by Combiflash™ chromatography (SiO2, 12 g, elution with 20-40% EtOAc/hexanes over 40 min) to afford the title compound as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[CH2:37][NH2:38].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:38][CH2:37][CH:29]3[CH2:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC4Cc5ccccc5C4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 99.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol), suspended in 1.3 ml of dichloromethane, was treated sequentially with (2,3-dihydro-1H-inden-2-yl)methanamine hydrochloride (26.8 mg, 0.146 mmol), N-ethyl-N-isopropylpropan-2-amine (32.4 μl, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 16 hours, the reaction was applied directly to a silica gel column and eluted with a gradient (20% to 80%) of ethyl acetate-hexanes to provide the title compound (67 mg, 0.132 mmol, 99.8% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[Cl:32].CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[Cl:32][C:3]1[C:4](=[O:31])[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:6]2[C:11]([C:2]=1[N:1]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:10][C:9]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[N:7]=2
Reactant: COC(OC)N(C)C
Reactant: CC(C)Cn1c(=O)c(Cl)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Product: CC(C)Cn1c(=O)c(Cl)c(N=CN(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
The product of EXAMPLE 61 (50 mg) was combined with N,N-dimethylformamide dimethylacetal (4 mL). The reaction was heated to 95° C. and stirred for 90 minutes at which the solution was concentrated in vacuo. Purification by flash chromatography on silica eluted with 0-30% EtOAc in hexane afforded the title compound (E/Z mixture of isomers). HPLC/MS: 560.9 (M+1), 562.9 (M+3); Rt=4.48 min.