Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH2:12])C=C>ClCCCl>[CH2:5]1[CH:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:12][CH2:1][O:4]1
Reactant: C=CCOCC1CCCCC1=C
Solvent: ClCCCl
Product: C1=C2CCCCC2COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2-methylidenecyclohexyl)methyl prop-2-en-1-yl ether (0.104 g, 0.626 mmol) in DCE (6.5 mL) was degassed 3×N2/pump, then Zhan-1b (0.023 g, 0.031 mmol) was added and the reaction was degassed again The mixture was stirred at rt for 2 hr. It was concentrated and purified by silica gel chromatography to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.39 (t, 1H, J=2.4 Hz), 4.04-4.10 (m, 2H), 3.92 (dd, 1H, J=5.7 Hz, 11.2 Hz), 3.24 (dd, 1H, J=8.2 Hz, 11.2 Hz), 2.15-2.27 (m, 2H), 1.92-2.02 (m, 1H), 1.74-1.83 (m, 2H), 1.64-1.72 (m, 1H), 1.18-1.45 (m, 2H), 0.93-1.06 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:4].[Na+].C(=O)([O-])O.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:19])[S:10][C:9]=12)=[O:4]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H]1C(c2cn3cnc(C(=O)N(C)C)c3s2)=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cnc(C(=O)N(C)C)c4s3)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 50 mg of sodium (1R,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-carbapen-2-em-3-carboxylate in 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. The reaction mixture was added with 43 mg of pivaloyloxymethyl iodide, stirred for 1 hour, extracted with 20 ml of ethyl acetate, and the organic layer was washed with 12 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=95:5) to give 55 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:18]=[C:17]([B:19]2[O:23]C(C)(C)C(C)(C)[O:20]2)[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH3:4].O.C(OCC)(=O)C>C(O)C>[C:10]([CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:17]([B:19]([OH:23])[OH:20])=[CH:18][C:6]=1[O:5][CH2:3][CH3:4])([OH:12])=[O:11]
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(B(O)O)ccc1OCC(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (2.14 mL) was added to a solution of ethyl [2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (0.15 g) in ethanol (10 mL), and the resulting mixture was stirred at 60° C. for 3 hrs. Water and ethyl acetate were added to the reaction mixture. The aqueous layer was separated, washed with ethyl acetate, made acidic with the addition of 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.066 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:26]=[CH:25][C:23](=S)[NH:22][C:20]1=[S:21].O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:26]2[CH:25]=[CH:23][NH:22][C:20](=[S:21])[N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: S=c1cc[nH]c(=S)[nH]1
Solvent: c1ccncc1
Solvent: O
Product: S=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)cc[nH]1

Procedure:
3-(3-(Piperidinomethyl)phenoxy)propylamine (11.0 g) and dithiouracil (5.8 g) were refluxed in pyridine (100 ml; dried over potassium hydroxide) for approximately 72 hours. The solution was cooled and evaporated under reduced pressure to afford a residue. This residue was treated with water, evaporated under reduced pressure, and azeotroped thoroughly with n-propanol in an effort to remove pyridine. To the resultant residue was added further n-propanol to give the title compound as a solid which was collected by filtration and dried (13.88 g).
Reaction SMILES: C1([Mg]Br)CC1.[Mg].C1(Br)CC1.C[N:12]1[C:18](=O)[C:17]2[CH:20]=[N:21][CH:22]=[CH:23][C:16]=2[N:15]2C=NC(C=O)=[C:14]2[CH2:13]1.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)P(N(C)C)(N(C)C)=O>[NH:15]1[C:16]2[CH:23]=[CH:22][N:21]=[CH:20][C:17]=2[CH:18]=[N:12][C:13]([CH:33]([CH:32]2[CH2:30][CH2:31]2)[OH:29])=[CH:14]1
Reactant: CN1Cc2c(C=O)ncn2-c2ccncc2C1=O
Reactant: C1CCOC1
Agent: BrC1CC1
Agent: Br[Mg]C1CC1
Agent: [Mg]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OC(C1=CNc2ccncc2C=N1)C1CC1
Reaction time: 1 h

Procedure:
To a solution of cyclopropyl magnesium bromide in dry tetrahydrofuran (prepared from 72 mg (3 mmole)) of magnesium and 362 mg (3 mmole) of cyclopropyl bromide in 4 ml of tetrahydrofuran was added at room temperature in one portion a suspension of 240 mg (1 mmole)of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a]-pyrido [3,4-f][1,4]-diazepine-3-carboxaldehyde suspended in a mixture of 1 ml of tetrahydrofuran and 1 ml of hexamethyl-phosphoramide. After 1 hour, the reaction was quenched with aqueous ammonium chloride and extracted with dichloromethane. Column chromatography (SiO2 -5% methanol in dichloromethane) yielded 120 mg of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,5-a]-pyrido-[3,4-f][1,4]-diazepin-3-yl cyclopropyl carbinol as an oil, (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:13]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N+:11]=1[O-:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)[n+]([O-])c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 15.3 g (0.073 mole) of methyl 2,6-dichloroisonicotinate in 180 ml of trifluoroacetic acid was heated at 90° C. During a six hour period 34 ml of 30% hydrogen peroxide was added to the hot reaction mixture in four to five ml aliquots. After complete addition the reaction mixture was stirred at 90° C. for two hours. The solvent was distilled from the mixture under reduced pressure to leave a solid. The solid was triturated with water, and the mixture was then filtered. The filter cake was recrystallized from acetone to yield 8.75 g of methyl 2,6-dichloroisonicotinate N-oxide.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([N:36]=[N+]=[N-])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([NH2:36])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: [Pd]
Solvent: O=CO
Product: NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-azidoacetate (2.856 g.) and 10% palladium on carbon (600 mg.) in formic acid (27 ml.) was stirred at room temperature under hydrogen atmosphere. After stirring for an hour, to the mixture wass added 5% palladium on carbon (600 mg.) in formic acid (8 ml.) and stirred under hydrogen atmosphere for additional 2.5 hours. The resultant mixture was filtered through a pad of Celite and the filter cake was washed with methylene chloride. The filtrate and washings were combined and concentrated in vacuo to a volume of 15 ml. A part of this concentrate was evaporated to dryness to give benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-aminoacetate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: BrCCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCn1ccnc1
Yield: 37.5 %

Procedure:
Using General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (91.3 mg, 0.341 mmol), 1-(3-bromo-propyl)-1H-imidazole (129 mg, 0.680 mmol), KI (5.6 mg, 0.034 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.4 mL) were stirred at 60° C. overnight. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) followed by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (48 mg, 38%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:6]2[O:5][C:4]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:3][C:2]=2[C:26]([OH:28])=[O:27])=[CH:9][CH:10]=1
Reactant: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a dry flask was added 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (50 mg, 0.133 mmol) and THF (2669 μl), and the reaction mixture was cooled to −78° C. nBuLi (92 μl, 0.147 mmol) was added slowly and the reaction mixture was stirred at −78° C. for 30 min. Crushed dry ice was added, the reaction mixture was stirred at −78° C. for 20 min, quenched with 10% KHSO4, and allowed to warm to RT. The reaction mixture was extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylic acid (47 mg crude) to be used as is in the next step. MS: M+H=340.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:13]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[N:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][C:30]3[CH:29]=[CH:28][C:27]([C:24]4[N:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][N:25]=4)=[CH:32][CH:31]=3)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc4c(c3)OCO4)cc2)nc1
Reaction time: 18 h

Procedure:
5 mmol of benzo[1,3]dioxole-5-carboxylic acid and 4.8 mmol of 4-(5-octylpyrimidin-2-yl)phenol are dissolved in 50 ml of CH2Cl2, and 5 mmol of DCC and 0.05 mmol of DMAP are added. The mixture is stirred for 18 hours with exclusion of light, the solvent is stripped off vacuo, and the product is purified by column chromatography on silica gel, giving 4-(5-octylpyrimidin-2-yl)phenyl benzo[1,3]dioxole-5-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:12](=[O:13])([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-nitrophenol (1.00 g) in dichloromethane (20 ml) were added dropwise ethyl chloroformate (0.70 ml) and pyridine (0.70 ml) under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. To the residue obtained was added ethyl acetate, and the organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, a saturated aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residual solid obtained was collected by filtration using hexane to afford ethyl 4-nitrophenyl carbonate (1.44 g, yield: 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](=[CH2:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C[N+]1([O-])CC[O:36]CC1.[O-]S([O-])=O.[Na+].[Na+].C1COCC1.[OH2:51]>CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29]([CH2:31][OH:36])([OH:51])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O
Reactant: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1(O)CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C

Procedure:
To a solution of 7-[8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline (3.2 g, 7.6 mmol) in THF-water mixture (100 mL, 3:1) were added NMO (1.94 g, 8.3 mmol) and potassium osmate dihydrate (0.14 g, 0.4 mmol). The reaction mixture was stirred at rt. After 20 h the reaction was quenched with Na2SO3 (4.8 g, 38 mmol). The reaction mixture was diluted with EtOAc (250 mL) and washed with brine (2×100 mL). Part of the solvent was removed and the organic phase was passed through celite, dried over anhydrous Na2SO4 and concentrated in vacuo. The material was carried on to the subsequent oxidation without further purification.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36]C1CCN(S(C2C3C(Cl)=CN=C(N)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Product: Cl
Product: Nc1ncc(Br)c2c(S(=O)(=O)N3CCC(N)C3)cccc12

Procedure:
Intermediate 29 is used in the method of Example 39, Step B instead of Intermediate 28 to obtain the title compound as hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:35](=[O:36])[N:11]2[C:12]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:13]([CH2:17][I:18])[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(OCC)(=O)C>CN(C)C=O>[I-:18].[C:1]([O:5][C:6]([NH:8][CH:9]1[C:35](=[O:36])[N:11]2[C:12]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:13]([CH2:17][N+:38]3([CH3:37])[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12
Reactant: CN1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[N+]3(C)CCCC3)CS(=O)[C@H]12
Product: [I-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of benzhydryl 7-tert-butoxycarbonylamino-3-iodomethyl-3-cephem-4-carboxylate-1-oxide (4.3 g) in dimethylformamide (70 ml) was added 1-methylpyrrolidine (0.63 g) at 0° C. The mixture was stirred for 1.5 hours under ice-cooling and poured into a mixture of ethyl acetate (700 ml) and ice-water (350 ml). The separated organic layer was washed with water, brine and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized in diisopropyl ether, collected by filtration and dried in vacuo to give powdery benzhydryl 7-tert-butoxycarbonylamino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate-1-oxide iodide (4.3 g).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH3:22])[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH3:22])[C@@H:17]2[C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)OC(C)(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To 280 mg of t-butyl ester from Step A was added 2 drops of anisole and 4 mL of TFA. After 75 min the volatiles were removed in vacuo followed by evaporation of two portions of methylene chloride. The residue was used directly in the Step C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=[C:27]([NH:33]C(=O)OCC3C=CC=CC=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Si:1]([O:18][CH:19]1[CH2:20][CH:21]2[CH:23]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:31])[CH3:32])[N:28]=[C:27]([NH2:33])[CH:26]=2)[CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)n1nc(NC(=O)OCc2ccccc2)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: [Pd]
Solvent: CO
Product: CC(C)n1nc(N)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reaction time: 16 h

Procedure:
To a solution of benzyl (5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)carbamate (28 g, 47 mmol) in methanol (200 mL) was added 10% palladium on carbon (2.8 g). The reaction mixture was stirred at room temperature under 1 atm of hydrogen. After 16 h, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to provide crude 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-amine which was dissolved in acetonitrile (200 mL). A solution of 4-methylbenzenesulfonic acid monohydrate (22.34 g, 117.5 mmol) in water (25 mL) was added at room temperature. After 30 min at room temperature, the reaction mixture was cooled to 0° C. A solution of sodium nitrite (5.4 g, 78 mmol) and sodium iodide (1174 g, 78.31 mmol) in water (25 mL) was added dropwise to the reaction mixture.
Reaction SMILES: NC1C(Cl)=CC(F)=C([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)C=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:17][CH2:16][CH2:15][CH2:14][N:11]1[C:12](=[O:13])[N:8]=[N:9][NH:10]1
Reactant: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=c1nn[nH]n1CCCF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.0 g (0.0034 mole) of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3- fluoropropyl)-5H-tetrazol-5-one in 30 ml of methylene chloride was added 0.20 g (0.0017 mole) of 4-(N,N-dimethyl)aminopyridine, 0.50 g (0.0017 mole) of trifluoromethylsulfonyl anhydride, and an additional 0.20 g (0.0017 mole) of 4-(N,N-dimethyl)aminopyridine. This mixture was stirred at room temperature for 0.5 hour. The resultant solution was extracted with 100 ml of a dilute, aqueous, sodium hydroxide solution. The extract was washed with 50 ml of methylene chloride and was neutralized with concentrated hydrochloric acid. This aqueous solution was extracted several times with ethyl acetate and the extracts were combined. The combined extract was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a thick oil. This oil was purified by column chromatography on silica gel, eluted with methylene chloride'acetone (95:5) to yield 1.0 g of 1-[4-chloro- 2-fluoro-5-(N-trifluoromethylsulfonylamino)phenyl]-1,4-dihydro-4-(3-fluoropropyl-5H-tetrazol-5-one as a solid, m.p. 111°-113° C.
Reaction SMILES: O[C:2]1([CH:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:9]#[N:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>CN(C=O)C>[O:5]1[CH2:4][CH2:3][C:2](=[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:9]#[N:10])[CH2:7][CH2:6]1
Reactant: N#CC(c1ccc(C(F)(F)F)nc1)C1(O)CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC(=C1CCOCC1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Yield: 97 %

Procedure:
(4-Hydroxy-tetrahydro-pyran-4-yl)-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.15 g, 4.02 mmol) was dissolved in thionyl chloride (50 mL, 600 mmol). One drop of DMF was added and the mixture was heated at reflux for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting crude product was purified by flash chromatography to yield 2-(dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.04 g, 3.9 mmol, 95%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11])=O.[O-:12][C:13]#[N:14].[K+]>>[F:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:11][C:13](=[O:12])[N:14]=[C:2]2[CH3:1]
Reactant: CC(=O)c1cc(F)ccc1N
Reactant: N#C[O-]
Agent: [K+]
Product: Cc1nc(=O)[nH]c2ccc(F)cc12

Procedure:
6-Fluoro-4-methyl-2(1H)-quinazolinone is prepared by treatment of 2-amino-5-fluoroacetophenone with potassium cyanate as in Example 18 and is isolated as the 1/4 hydrate, (mp 294°-296° C.).
Reaction SMILES: [CH2:1]([NH2:8])C1C=CC=CC=1.CN.[C:11]([C:14]1[S:18][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[C:20]2=[O:34])=[N:16][C:15]=1[CH3:35])(=[O:13])[CH3:12]>>[C:11]([C:14]1[S:18][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:8][CH3:1])=[O:31])=[CH:32][CH:33]=3)[C:20]2=[O:34])=[N:16][C:15]=1[CH3:35])(=[O:13])[CH3:12]
Reactant: NCc1ccccc1
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)nc1C
Agent: CN
Product: CNC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with methylamine to react with 4-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 43% yield: nip 173-175° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.12 (br s, 1H), 4.52 (s, 2H), 4.12-4.06 (m, 2H), 3.49-3.43 (m, 2H), 3.00 (d, J=4.2 Hz, 3H), 2.67 (s, 3H), 2.46 (s, 3H); MS (ES+) m/z 373.2 (M+1).