Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: Cc1cccc(CBr)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C

Procedure:
A mixture of 43.0 g (185 mmol) of 2-(2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 42.9 g (241 mmol) of N-bromosuccinimide, and 0.40 g (3.27 mmol) of AIBN in 1000 ml of acetonitrile was refluxed for 2 h. Then, this mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in 500 ml of hexane. The precipitate was filtered on glass frit (G3), and the filtrate was evaporated to dryness to give yellowish crystalline solid. Yield 37.9 g (66%). Anal. calc. for C14H20BBrO2: C, 54.06; H, 6.48. Found: C, 54.35; H, 6.72. 1H NMR (CDCl3): δ 7.21 (m, 1H, 4-H), 7.15 (m, 1H, 3-H), 7.07 (m, 1H, 5-H), 4.72 (s, 2H, CH2Br), 2.44 (s, 3H, 6-Me), 1.42 (s, 12H, Bpin).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C1C=CC=CC=1)=C.C(C1C=CC=CC=1)(=[O:21])C.[C:28]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[C:7]([O:21][O:37][C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH3:29])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)c1ccccc1
Reactant: CC(C)(O)c1ccccc1
Agent: C=C(C)c1ccccc1
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Yield: 55.1 %

Procedure:
The oily material from the distillate weighed 48.5 g. and consisted of 26% cumene, 56% α-methylstyrene and lesser amounts of acetophenone and cumyl alcohol. This recovered material was used without purification in a subsequent run from which a 55.1% yield of dicumyl peroxide was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:16][C:17]1[C:18]([N:24]2[CH2:25][CH2:26][N:27]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[C:2](=[O:1])[CH2:6][S:5][CH2:4]4)=[CH:15][CH:14]=3)=[O:13])[CH2:28][CH2:29]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: O=C(O)c1ccc(N2CSCC2=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CSCC4=O)cc3)CC2)c(C)c1
Yield: 74.4 %

Procedure:
Using 4-(4-oxothiazolidin-3-yl)benzoic acid (112 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 11, the title compound (148 mg) was obtained.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:32]1[C:33]2[C:29](=[CH:28][CH:27]=[CH:26][C:25]=2[C:22]2[N:21]=[C:20]([C:12]3[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=3)[O:24][N:23]=2)[C:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:31]1
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)cccc12
Reactant: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cnc1OC(C)C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
DABCO (20 mg) was added to a solution of ethyl 3-[7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D119) (188 mg) in dimethyl carbonate (2 mL) and DMF (0.2 mL). The resulting mixture was stirred at reflux for 1 day. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (8 mL) and water (8 mL). Sodium hydroxide (40 mg) was added to the mixture. The resulting mixture was heated at 70° C. for 30 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-7-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E17) (19 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.23 (3H, s), 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 5.40 (1H, m), 7.16 (1H, d), 7.19 (1H, s), 7.43 (1H, d), 7.79 (1H, d), 8.29 (1H, s), 8.84 (1H, d), 12.12 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: [CH:1]([Si:3](OC)([O:6][CH3:7])[O:4][CH3:5])=[CH2:2].[CH:10]([Mg]Br)([CH3:12])[CH3:11].C[O-].[Mg+2].C[O-]>C(OCC)C>[CH:10]([CH:2]=[CH:1][SiH:3]([O:6][CH3:7])[O:4][CH3:5])([CH3:12])[CH3:11]
Reactant: CC(C)[Mg]Br
Reactant: C=C[Si](OC)(OC)OC
Agent: C[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CO[SiH](C=CC(C)C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
206 g (1.39 mol) of vinyl trimethoxysilane and 300 ml of dry diethyl ether were charged in a 2 L four-necked flask equipped with a dropping funnel and a mechanical stirrer in a stream of nitrogen, and cooled to 0° C. 1.67 mol of the above prepared diethyl ether solution of isopropyl magnesium bromide was dropwise added thereto with stirring over a period of 120 minutes, and reaction was carried out at room temperature for 2 hours. After completion of the reaction, magnesium methoxide residue as a by-product was removed by filtration, and the obtained filtrate was distilled under reduced pressure to obtain 141 g (0.882 mol) of isopropylvinyldimethoxysilane as an aimed product. The yield was 63.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>CCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1O
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCC
Product: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Reaction time: 5.5 h

Procedure:
To a stirred solution of (4-methoxyphenyl)-naphth-1-yl carbinol of formula II (5.0 gm, 0.018 mol )and o-cresol (2.4 ml, 0.022 mol) in a mixture of anhydrous benzene, anhydrous pentane (50 ml, 1:1), and AlCl3 (2.5 gm) was gradually added, after addition stirring was continued for 5-6 hrs at 0-4° C. The reaction mixture was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed successively with water, dried over Na2SO4 and concentrated to give an oil, which was chromatographed over silica gel using benzene-hexane as the eluent to give the title compound of formula III, yield 4.5 gm (67.16%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Br:10]N1C(=O)CCC1=O.O>O1CCCC1.N1C=CC=CC=1>[Br:10][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc[nH]c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1c[nH]c(Br)c1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A solution (30 mL) of methyl 1H-pyrrole-3-carboxylate (3.06 g) in tetrahydrofuran was cooled to −78° C., N-bromosuccinimide (4.38 g) and then pyridine (3 drops) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=5:1) to give the title compound as a pale-yellow solid (yield 3.08 g, 62%).
Reaction SMILES: [CH3:1][CH:2]([CH:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C(OC=C)(=O)CCCCCCCCCCC>>[CH3:1][CH:2]([C@@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(O)C(C)C(=O)OC
Agent: C=COC(=O)CCCCCCCCCCC
Product: CC[C@H](O)C(C)C(=O)OC
Temperature: 35 °C
Reaction time: 120 h
Yield: 77.8 %

Procedure:
A mixture of 7.2 g of methyl 2-methyl-3-hydroxypentanoate, 11.1 g of vinyl laurate, and 4.0 g of Lipase P (trade name, Amano Pharmaceutical Co., Ltd.) was stirred at 35° C. for 5 days. After stopping the reaction, the enzyme was removed by filtration and washed with n-heptane on a filter paper. n-Heptane was distilled away from the filtrate and the residue was subject to vacuum distillation to give 5.6 g of methyl (3S)-2-methyl-3-hydroxypentanoate of the following formula, [α]D20 =+3.8° (C=1.26, CHCl3). ##STR96##
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[CH:4]1[C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH2:7][CH2:6][NH:5]1.[Cl:15][C:16]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:15][C:16]1[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:5]1[CH2:6][CH2:7][C:8]2[NH:12][CH:11]=[N:10][C:9]=2[CH:4]1[C:3]([F:2])([F:13])[F:14])=[O:19]
Reactant: FC(F)(F)C1NCCc2[nH]cnc21
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2[nH]cnc2C1C(F)(F)F
Yield: 34.3 %

Procedure:
A solution of 4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride (0.10 g, 0.44 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.10 g, 0.44 mmol), HATU (0.18 g, 0.48 mmol, and DIPEA (0.19 mL, 1.1 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.06 g, 34%). 1H NMR (500 MHz, CDCl3) δ 8.02-7.94 (m, 1H), 7.80-7.58 (m, 1H), 7.51-7.39 (m, 1H), 6.60-6.50 (m, 1H), 4.42 (q, J=7.6 Hz, 1H), 2.95 (s, 4H). MS (ESI): mass calculated for C15H10ClF6N3O, 397.042. m/z found 398.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:11]=1.[CH3:37][OH:38]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22](=[NH:23])[O:38][CH3:37])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[CH:11]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C#N)c3)cc12
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1

Procedure:
HCl gas was bubbled through a suspension of 3-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzonitrile (287.8 mg, 0.60 mmol) in, 3.5 mL of anhydrous MeOH. The mixture was then stirred for 5 hours at room temperature before ether (20 mL) was added. The precipitate was then collected by filtration and dried to afford methyl 3-(3-(2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzimidate without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2S)=[CH:4][CH:3]=1.[Cl:22][O-].[Na+].[S:25](=[O:29])(=O)(O)[OH:26]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:25]([Cl:22])(=[O:29])=[O:26])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(S)n2Cc1ccc(Cl)cc1
Reactant: [O-]Cl
Agent: [Na+]
Product: Cn1c(=O)[nH]c(=O)c2c1nc(S(=O)(=O)Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione (400 mg, 1.24 mmol) in concentrated sulfuric acid (5 mL) was added aqueous sodium hypochlorite solution (5 mL, 5% active chlorine) dropwise at 0° C. and the mixture was stirred at room temperature for 15 min. The mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl chloride (230 mg, 47.6% yield) as brown solid, which was directly used immediately without purification.
Reaction SMILES: Cl[CH:2](OCC)[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH2:13](N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C[N:28](C)C=O>>[CH2:13]([C:2](=[NH:28])[CH:3]([O:4][CH2:5][CH3:6])[O:7][CH2:8][CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCOC(Cl)C(OCC)OCC
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(OCC)C(=N)Cc1ccccc1
Reaction time: 0.75 h
Yield: 82 %

Procedure:
A mixture of 158 mg (0.80 mmole) of 1-chloro-1,2,2-triethoxyethane (produced in accordance with Example IV), 0.10 mL (0.92 mmole) of benzylamine, and 136 mg (0.985 mmole) of anhydrous potassium carbonate in 1.00 mL of dimethylform-amide, spectrophotometric-grade, commercially available from Aldrich Chemical Co., Milwaukee, Wis., was stirred, while being protected from atmospheric moisture, at 0° C. for 45 minutes. Isolation of the product as described in the procedure of Example XVII afforded 146 mg (82% yield) of the title compound, whose IR and proton NMR spectral properties were consistent with the assigned structure. This transformation should prove to be quite useful for an industrial-scale synthesis of isoquinoline, previously prepared in high yield by treatment of the named imine with aqueous acid. Unfortunately, the reported preparation of this imine required using glyoxal monoacetal derivatives which are susceptible to polymerization and therefore not easily purified. See: E. Schlittler and J. Muller, Helv. Chim. Acta, 31:914 (1948).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)/[CH:5]=[N:6]\[OH:7].[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:7]/[N:6]=[C:5](\[Cl:11])/[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: O/N=C\c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of (E)- and/or (Z)-3-fluoro-benzaldehyde oxime (6.9 g, 50 mmol) in DMF (50 mL) was added N-chlorosuccinimide (6.6 g, 50 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (6.3 g, 73%) which was obtained as an off white solid. MS m/e (EI): 173.1 [M].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(O[CH:8](OCC)[CH2:9][NH:10][CH2:11][C:12]#[CH:13])C.[CH3:17]COCC>>[CH3:1][N:2]1[CH:8]=[CH:9][N:10]([CH:11]([CH3:17])[C:12]#[CH:13])[C:3]1=[O:4]
Reactant: C#CCNCC(OCC)OCC
Reactant: CCOCC
Reactant: CN=C=O
Product: C#CC(C)n1ccn(C)c1=O
Temperature: 50 °C

Procedure:
Methyl isocyanate (4.6 g, 0.081 mol) was added to a stirred solution of 2,2-diethoxy-N-(2-propynyl)ethylamine (13.7 g, 0.074 mol) in ether (150 mL). After 30 min the ether was evaporated and the residue was dissolved in water (150 mL), oxalic acid (6.7 g) was added, and the solution was heated at 50° C. for 30 min. The solution was then concentrated to 20 mL and neutralized with 4N NaOH solution, and extracted with ethyl acetate (4×150 mL). The ethyl acetate was evaporated and the residue was chromatographed on silica gel to give 9.6 g of product as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].CC(C)=O.[Cr](O)(O)(=O)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])[C:14]([C:17](=[O:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a stirred solution of 2.98 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate in 200 ml. of acetone was added dropwise 2.83 ml. of a 2.26 molar chromic acid solution. The reaction mixture was allowed to stir at room temperature for ten minutes, after which time approximately 10 ml. of isopropanol was added. The reaction mixture was stirred for 5 minutes and then evaporated in vacuo to dryness. The residue was taken up in a mixture of ethyl acetate and water and transferred to a separatory funnel with the aid of ethyl acetate. The organic layer was separated and washed successively with brine (4X), sodium bicarbonate solution, water, 1N.HCl, and brine (2X) and then dried over anhydrous sodium sulfate. The residue obtained upon evaporation in vacuo of the solution thereby obtained was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to provide 2.11 g. (71.2 percent) of the title product:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C:33]1[CH2:34][C@@H:35]2[C@H:38]([CH:39]=1)[C:37](=[CH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)(C(C)(C)C)(C)C>O>[OH:31][CH2:32][C:33]1[CH2:34][C@@H:35]2[C@H:38]([CH:39]=1)[C:37](=[CH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(CO[Si](C)(C)C(C)(C)C)=C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(CO)=C[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutyl ammonium fluoride (1.0 M tetrahydrofuran solution, 8.69 mL, 8.69 mmol) was added to a tetrahydrofuran solution (15 mL) of tert-butyl(±)-[(1R,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)bicyclo[3.2.0]hept-3-en-6-ylidene]acetate (2.03 g, 5.79 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (1.29 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([O:15][C:16]1[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C:18]2[CH:17]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[NH:20][N:19]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-isopropoxy-1H-pyrazol-3-amine (Intermediate 6, 1.5 g) in acetonitrile (50 mL) with triethylamine (5 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 1 g of the title compound. MS (electrospray): 299 (M+1) for C10H12ClN6O3.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24](O)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CCOC(C)=O>[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried, round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (1.1 eq), 3-nitrophenylacetic acid (7A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and N,N-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Tert-butyl 4-(2-(3-nitrophenyl)acetyl)piperazine-1-carboxylate (7B) was isolated as a solid (80%) and used without further purification.
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)(=O)C>C(O)C>[CH2:2]([S:9][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OC1CC(=O)N1
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(SCc2ccccc2)N1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Sodium (8.1 g, 0.35 mol) was dissolved in ethanol (250 ml) and benzyl mercaptan (45.2 g, 0.37 mol) added dropwise over 20 minutes keeping the temperature between 20° C.-25° C. whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5° C. and a solution of 4-acetoxyazetidin-2-one (45.0 g, 0.35 mol) in ethanol (50 ml) was added dropwise over 15 minutes whist maintaining the temperature at 5° C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (500 ml) was added, the mixture extracted with dichloromethane (2×300 ml), the extracts dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was cooled to -20° C. and titurated with ether (400 ml) to give a white solid which was isolated by filtration (50.2 g, 79%), mp 50-51.0° C.