Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Na].Cl.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: OCCCCCCCO
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCCCCCCOCc1ccc2ccccc2n1

Procedure:
1,7-Heptanediol (ex Lancaster) (1.7 g) was reacted with sodium (0.24 g) in toluene (50 ml) as in Stage A(ii). 2-Chloromethylquinoline hydrochloride (ex Aldrich) was added followed by triethylamine (0.7 ml). After heating under reflux for 6 hours, the reaction mixture was partitioned between water and diethyl ether and the organic phase washed with brine and dried. The crude material was purified by chromatography on silica (eluting with ether-hexane) to give 7-(2-quinolinylmethoxy)heptan-1-ol (0.43 g) which was used in Stage b.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 7-bromo-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.10 mmol) in concentrated H2SO4 (0.5 mL) at 0° C. was added KNO3 (11 mg, 0.109 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 12 h and it was poured into ice water (2 g). The precipitate was collected by filtration, affording 32 mg (91.4%) of crude title compound. It was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH 2 with 4N HCl to give a brown precipitate, which was collected by filtration, and dried at 50° C. for 4 h, affording pure title compound (28 mg, 79.3%) as a yellow powder. Mp: 292°-94° C., IR (KBr, cm-1): 3412, 3068, 3937, 1718, 1556, 1387. 1H NMR (DMSO-d6): δ7.644 (s, 1H), 11.721 (s, 1H), 12.423 (s, 1H). HRMS: calcd for C9H3CIF3N3O4 (M+) m/z: 352.9258, found: 352.9259.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH:14]1[C:19](O)=[O:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].P(C#N)([O-])(OCC)=O.O>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH:14]1[C:19]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:20])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Reactant: C1CCNC1
Agent: CCOP(=O)([O-])C#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSCC1C(=O)N1CCCC1
Yield: 74 %

Procedure:
followed by a solution of pyrrolidine (2.0 ml) in 10 ml of tetrahydrofuran, was added at 0° C. under a stream of nitrogen to a solution of 5.0 g of 4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid in 100 ml of tetrahydrofuran. After the mixture had been stirred for I hour, a solution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuran was added to the mixture and the mixture was stirred for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield 461 g (74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50].C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:52]([O:51][C:49](=[O:50])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:53]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol) in DCM (1 ml) was added pyridine (0.1 ml) followed by ethyl chloroformate (10.70 μl, 0.111 mmol). The vial was capped and the contents stirred at room temperature for 16 h. Un-reacted chloroformate was quenched by adding MP-Trisamine (91 mg, 0.186 mmol) and tumbling the vial for an additional 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-ethyl(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:33])[C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>>[CH3:1][O:2][N:3]([CH3:33])[C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:42])=[CH:20][C:19]=2[N:18]=[C:17]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)N(C)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCCCCCCCC(=O)N(C)OC

Procedure:
The general methods described in Steps 9 and 10 of Example 1 and Step 7 of Example 16 was used to aminate N-methoxy-N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide (4.01 g, 8.86 mmol) by reaction with m-CPBA (6.13 g) to provide N-methoxy-N-methyl-12-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide followed by reaction with p-toluenesulfonyl chloride (2.53 g, 13.3 mmol) and ammonium hydroxide solution (40 mL) to provide 2-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methyldodecanamide hydrochloride as an off-white solid after recrystallizationof the hydrochloride salt from isopropanol, mp 156-158° C.
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH:3]([N:14]=[O:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH2:25]C.CCN(C(C)C)C(C)C>C(#N)C>[CH3:16][C:2]([CH3:17])([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH3:25])[C:3](=[N:14][OH:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cn(CC(N=O)C(C)(C)Cl)c([N+](=O)[O-])n1
Reactant: CCC(=NO)C(C)(C)NCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCCCNC(C)(C)C(Cn1cc(C)nc1[N+](=O)[O-])=NO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Chloro-3-methyl-2-nitroso-1-(4-methyl-2-nitro-1H-imidazol-1-yl) butane (3.41 g, 13.09 mmol) was added in portions to a stirred solution of N-(3-aminopropyl)-1-amino-1,1-dimethyl-2-butanone oxime (2.0 g, 11.56 mmol, Example 1) and (i-Pr)2NEt (1.64 g, 13.09 mmol) in dry acetonitrile (20 mL) at 50° C. under a nitrogen atmosphere. After the addition the reaction mixture was stirred for an additional 2 hours at 50° C. and cooled to room temperature. The solid which formed was filtered and recrystallized from acetonitrile to provide the title product as a light yellow colored solid. Yield: 3.08 g (59.4%); mp. 140-141° C.; 1H NMR (DMSO-d6) δ 1.12 & 1.19[2s, 6H, C(CH3)2], 1.33(m, 2H, CH2CH2CH2), 1.70[s, 3H, C(=N)CH3], 1.79 (bs, 2H, NH) 2.15(s, 3H, imi-CH3), 2.19(m, 4H, NHCH2), 5.19[s, 2H, NCH2C(=N)], 7.05 (s, 1H, imi-CH) and 10.33 & 11.36 (2s, 2H, NOH). MS m/e 398 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[C:20](=[O:36])[NH:21][C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[C:24]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:18][C:19]1[C:20](=[O:36])[N:21]([CH2:8][C@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])[C:24]=1[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 11a (638 mg, 2.62 mmol) in THF (10 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methylpyrimidine-2,4(1H,3H)-dione 4d.1 (869 mg, 2.62 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (906 mg, 3.93 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 hours and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 11b (1.39 g, 95.4%). MS (CI) m/z 456.1, 458.1 (MH+−Boc).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C(OC(C)(C)C)=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(C(=O)OC(C)(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(O)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 4-[tert-butoxycarbonyl-(5-tert-butoxycarbonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (6.75 g, 13.7 mmol, 1.0 equiv) in a mixture of THF/methanol (1:1) (100 mL) at 3° C. was added drop by drop a solution of 1 M LiOH (34.2 mL, 34.5 mmol, 2.5 equiv) and after the addition was completed the mixture warmed up to rt. After 18 h, the reaction mixture was poured into cold water and extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 4.31 g (80%) of the title compound as orange foam. MS (ISP):=394.1 [M+H]+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)([CH3:16])[C:11]([O:13]CC)=[O:12])=[O:8]>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)([CH3:16])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CCOC(=O)C(C)(NC(=O)c1cccc(Cl)c1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)(NC(=O)c2cccc(Cl)c2)C(=O)O)cc1
Yield: 90.2 %

Procedure:
1.2 g (0.02M) of potassium hydroxide was dissolved in a mixed solution of 30 ml of ethanol and 5 ml of H2O. To this solution, 3.5 g (0.01M) of ethyl 2-(m-chlorobenzamido)-2-(p-tolyl)propionate obtained in Example I was added. The resulting solution was heated for 1 hr with reflux, cooled and distilled in vacuo to remove ethanol. The remainder was adjusted into pH 2 with 2 N HCl solution and extracted with methylene dichloride. Thereafter, the extract was distilled in vacuo, to give 2.9 g of the titled compound: 92 % Yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cccc2c(=O)[nH]ncc12
Yield: 100450.6 %

Procedure:
980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine, and it is hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 830 g of 5-amino-phthalazin-1-one as a solid is obtained as a crude product.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH:34]1([CH:12]([N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][CH:6]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(CCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(CCc2ccc(C(=O)O)cc2)C2CCCCC2)c(OC)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 180 mg (0.327 mmol) 4-{3-cyclohexyl-3-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-propyl}-benzoic acid methyl ester in 3 ml dioxane was added 3 ml water and 41 mg (0.98 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 4 h at 100° C. and then poured on 30 ml aqueous 1M hydrochloric acid and 30 ml ethyl acetate. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5) to give the title compound as a light yellow solid (78%). MS (Turbo Spray): m/z=536.236 [M+H].
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:22])[C:13]([CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=2)=[C:12]3[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[F:63][C:64]([F:70])([F:69])[S:65]([NH2:68])(=[O:67])=[O:66].C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[O:34][CH2:33][C:13]1[N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([NH:68][S:65]([C:64]([F:70])([F:69])[F:63])(=[O:67])=[O:66])=[O:28])[CH:25]=2)[C:15]2[C:11]([C:12]=1[C:45]([N:47]1[CH2:48][CH2:49][CH2:50][CH2:51]1)=[O:46])=[CH:10][C:9]([NH:8][C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:7])=[CH:17][CH:16]=2
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The compound of Example 55 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) followed by anhydrous THF (0.04 M) and the reaction mixture was then stirred at 25° C., overnight. Worked up with ethyl acetate/water followed by washing the organic layer with 1N HCl, saturated bicarbonate and brine. Trituration with CH2Cl2/hexane (8:2) afforded the desired product in 84% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]([C:34]([O:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].O>CN(C)C=O.C(OCC)(=O)C>[NH:25]([C:34]([O:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[O:12])=[CH:41][CH:40]=1)=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28]
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(N)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (557.3 mg, 2.993 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added 1,1′-carbonyldiimidazole (531.7 mg, 3.279 mmol), and the mixture was stirred at 50° C. for 2 hr. 2-(4-Aminophenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (1.065 g, 3.607 mmol) was added, and the mixture was stirred at room temperature for 16 hr. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred, stood still and partitioned. The organic layer was washed with 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in tert-butyl methyl ether (30 ml), filtered, washed 3 times with tert-butyl methyl ether, and dried under reduced pressure to give 2-[(4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (1.098 g, 2.368 mmol, yield 79.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O.C(O)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
4-chlorobenzaldehyde (50 g; 0.36 mol), sodium formate (48.4 g; 0.71 mol), and hydroxylamine hydrochloride (24.7 g; 0.36 mol) were added to 400 ml formic acid (98 wt.%). The reaction mixture was refluxed for 1 hour at l30.C, cooled to room temperature and poured into 1 liter cold water to produce a white precipitate, which was filtered and air-dried to yield 43 g 4-chlorobenzonitrile (m.p.=91°-92° C). The yield for this step in the reaction sequence was about 88%.
Reaction SMILES: [CH3:1]O.B(F)(F)F.[Br:7][C:8]1[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1>CO>[Br:7][C:8]1[O:12][C:11]([C:13]([O:15][CH3:1])=[O:14])=[CH:10][CH:9]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)o1
Agent: FB(F)F
Product: COC(=O)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Boron trifluoride methanol (6.3 ml, 7.6 g) was added to a stirred solution of 5-bromofuran-2-carboxylic acid (10 g) in methanol (90 ml) and heated under reflux under nitrogen for 5 hours. More boron trifluoride methanol (5 ml) was added and the mixture heated under reflux for 5 hours, allowed to cool to room temperature and stand for 10 hours before the solvent was removed in vacuo and the residue poured into saturated sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×200 ml). The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml), dried over MgSO4, and the solvent removed in vacuo to give methyl 5-bromofuran-2-carboxylate, m.p. 62° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1([C@H:14]2[NH:17][C:16](=[O:18])[C@@H:15]2[O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:1]1([C:5]([N:17]2[C@H:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@@H:15]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:16]2=[O:18])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: O=C(Cl)C1CCC1
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)C2CCC2)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using cyclobutylcarbonyl chloride, (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one was converted to the title product: 1H NMR (CDCl3) δ 0.18-0.61 (m, 15H), 1.66-2.22 (m, 6H), 3.61 (m, 1H), 4.89 (d, 1H, J=5.7 Hz), 4.94 (d, 1H, J=5.7 Hz), 7.03-7.18 (m, 5H).
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19]OC(=O)CCC(O)=O)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[SH:33][C:34]1[N:38]([CH3:39])[N:37]=[N:36][N:35]=1.C(=O)([O-])O.[Na+:44]>O>[Na+:44].[C:1]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([O-:30])=[O:29])=[C:16]([CH2:19][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
In water (5 ml) was dissolved 7β-(D-mandelamido)-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (0.46 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.25 g). The solution was stirred at 60° C. for 1 hour and a half. After cooling in the air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, elution being carried out with water and, then, with a solvent mixture of water and methanol. The fractions containing the desired compound are pooled, concentrated and lyophilized. The procedure provided 7β-(D-mandelamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (0.31 g)
Reaction SMILES: [Cl-].[CH:2]1([NH2+:10][CH2:11][CH2:12]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:10]([CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:26]1
Reactant: ClCC[NH2+]C1CCCCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.