Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.[F-].[Cs+].CO[Si](OC)(OC)OC.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>O1CCCC1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: C=CC(=O)OC
Agent: CO[Si](OC)(OC)OC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CCn1ccc(OCc2ccccc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (5.00 g, 17.85 mmol) and cesium fluoride (0.27 g, 1.78 mmol) were suspended in tetrahydrofuran (50 mL) followed by dropwise addition of tetramethylortho silicate (2.70 g, 17.85 mmol) at room temperature. After stirring for 10 minutes at room temperature, methyl acrylate (2.00 g, 23.20 mmol) was added dropwise and the reaction stirred at room temperature for 48 hours. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the resulting residue subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a white solid (6.10 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.65 Hz, 1H), 7.41-7.29 (m, 5H), 6.04 (d, J=7.65 Hz, 1H), 5.20 (s, 2H), 4.17 (t, J=5.91 Hz, 2H), 3.63 (s, 3H), 2.85 (t, J=5.91 Hz, 2H). ES-HRMS m/z 366.0350 (M+H C16H16BrNO4 requires 366.0335).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[CH:3][C:2]=1[NH2:8].O[CH2:10][CH:11]([CH2:13]O)O.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O>[N:1]1[C:6]2[C:5](=[N:7][CH:10]=[CH:11][CH:13]=2)[CH:4]=[CH:3][C:2]=1[NH2:8]
Reactant: OCC(O)CO
Reactant: Nc1ccc(N)nc1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Nc1ccc2ncccc2n1
Temperature: 135 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A mixture of pyridine-2,5-diamine (5.2 g, 71% pure, 33.9 mmol), glycerol (15.6 g, 169.5 mmol), sodium 3-nitrobenzenesulphonate (15.2 g, 67.8 mmol), sulfuric acid (20 mL), and water (30 mL) was heated to 135° C. and stirred at this temperature for 16 h. The mixture was cooled to room temperature and then poured into ice water (150 g). The pH of the reaction mixture was adjusted to 9 with saturated sodium hydroxide aqueous solution. Then the mixture was extracted with EtOAc (3×100 mL). The extracts were dried over sodium sulfate, concentrated under reduce pressure to give the crude product. The crude product was purified by column chromatography to give 2.0 g of 1,5-naphthyridin-2-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[N:1]/[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11]
Reactant: O=Cc1ccccn1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccn3)cccc21
Yield: 49.9 %

Procedure:
4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), picolinaldehyde (856 mg, 8 mmol) and 1 g of MgSO4 were added into 40 mL of dichloromethane and the mixture was stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 476 mg of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one was obtained. A mixture of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), sodium methanolate (432 mg, 8 mmol) and ethyl propionate (40 mL) was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate 20:1 to 5:1) to give 30 mg of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate; yield 5%. LC-MS (ESI) m/z: 459 (M+1)+.
Reaction SMILES: [C:1]12[CH2:8][CH:7]([C:9]([OH:11])=O)[C:6]1=[CH:5][CH:4]=[CH:3][CH:2]=2.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[C:1]12[CH2:8][CH:7]([C:9]([N:13]([CH3:12])[C@H:14]3[CH2:33][N:18]4[C:19]5[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]4[CH2:16][CH2:15]3)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:11])[C:6]1=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: O=C(O)C1Cc2ccccc21
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1Cc2ccccc21)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 389.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)=[O:19])[C:10](OC(C)(C)C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[BH4-].[Li+].[Cl-].[NH4+]>CO>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:17][C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)=[O:19]
Reactant: Cn1ccc(NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccc(NC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-((1-methyl-1H-pyrazol-3-yl)amino)-4-oxobutanoate (1.17 g) in a mixed solvent of THF (10.6 mL)/methanol (5.29 mL) was added lithium borohydride (0.484 g), and the mixture was stirred at room temperature for 2 hr, and then at 60° C. for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.553 g).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]=[N:7]1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]=[N:7]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cn(C[Si](C)(C)C)nn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)Cn1cc(CO)nn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole-4-carboxylate (1.00 g, 4.40 mmol) and THF (14.6 mL) was cooled to 0° C. and a solution of LAH (4.40 mL, 1M in THF) was added dropwise. The mixture was stirred for 1 h, and the cold bath was removed and stirred for an additional hour. The reaction was cooled to 0° C. and a solution of saturated sodium sulfate (4.4 mL) was added. The mixture was warmed to room temperature, stirred 30 min, and filtered. The filtrate was concentrated and the residue azeotroped with ethanol to afford a colorless oil purified via MPLC, 40M column, 1-8% MeOH in DCM afforded the title material as a clear, colorless oil. MS: cal'd 186 (MH+), exp 186 (MH+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:19]1[C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:10]([CH2:9][CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCSc3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(SCCn2c3c(c4ccccc42)CCNCC3)cc1
Reaction time: 0.08 h

Procedure:
tert-Butyl 6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0532 g, 0126 mmol) was dissolved in trifluoroacetic acid (2 mL), and the solution was stirred for 5 min. The reaction mixture was concentrated to dryness to give phenyl 2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl sulfide trifluoroacetate (0.70 g) as a tan solid. 1H NMR (300 MHz, CD3OD) δ 3.12, 3.18, 3.30, 3.34-3.41, 4.41, 7.08, 7.15, 7.17-7.26, 7.45; MS (ESI+) for C20H22N2S m/z 323.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH:24]([CH3:26])[CH3:25])[N:7]=3)=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)n1
Temperature: 34 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (200 mg, 0.54 mmol) and isopropylamine (5.0 mL) was stirred at 34° C. for 18 h. The reaction mixture was diluted with dichloromethane (50 mL) and treated with silica gel (20.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (1:9 to 1:0) as eluant to give 115 mg of the title product, a compound of the present invention, as an off-white solid.
Reaction SMILES: [Na+].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([N:17]3[CH2:22][CH2:21][N:20](N=CSCC4CSC5N(C(=O)C5NC(=O)CC5SC=CC=5)C=4C([O-])=O)[CH2:19][CH2:18]3)=[C:11]([F:16])[CH:12]=2)[N:7]([CH:48]2[CH2:50][CH2:49]2)[CH:6]=1)([OH:4])=[O:3].C([N:59]=[C:60]=[S:61])(=O)C1C=CC=CC=1.C1C2C(=O)C(C(O)=O)=CN(C3CC3)C=2C=C(N2CCNCC2)C=1F.[Na]>C1COCC1>[NH2:59][C:60](=[S:61])[N:20]1[CH2:19][CH2:18][N:17]([C:10]2[CH:9]=[C:8]3[C:13]([C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[CH:6][N:7]3[CH:48]3[CH2:49][CH2:50]3)=[CH:12][C:11]=2[F:16])[CH2:22][CH2:21]1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CSC=NN3CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)CSC12
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR332## according to this invention, is made as follows. A solution of benzoyl isothiocyanate (0.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 g) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-dihydroxybenzaldehyde (21.6 g), potassium carbonate (21.56 g) and N,N-dimethylformamide (200 mL) was added dropwise benzyl bromide (18.5 mL) under ice-cooling, and the resulting mixture was stirred at room temperature for 16 hours. Two mol/L hydrochloric acid (40 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (19.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.C(OCC)C.O>[CH2:24]([O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1C(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxy-2′-methoxybenzophenone (12) (8.08 g, 0.0354 mol), potassium carbonate (24.5 g, 0.177 mol) and benzyl bromide (4.4 mL, 0.037 mol) in 90 mL of dimethylsulfoxide was stirred overnight at room temperature. The resulting reaction mixture was diluted with diethyl ether and water and the aqueous layer was extracted with fresh diethyl ether. The combined organic layers were washed with water, followed by saturated NaCI and dried over sodium sulfate. After purification by flash column chromatography (silica gel, dichloromethane/hexanes eluent), 2-benzyloxy-2′-methoxybenzophenone (13) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[C:38]([F:39])=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([F:40])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[C:38]([F:39])=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([F:40])[CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(N)cc1F
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1cc(F)c(C(=O)OC(C)(C)C)cc1F)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (0.43 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 154 mg (0.61 mmol, 1.4 eq.) of tert-butyl 4-amino-2,5-difluorobenzoate were reacted according to General Method 5B. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 20-40% mixtures). Yield: 180 mg (71% of theory)
Reaction SMILES: [Na+:1].[Na+].C([O:7][C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])=[O:9])(C)(C)C.C([O:47][C:48]([CH:50]([C:78]1[S:79][CH:80]=[CH:81][CH:82]=1)[C:51]([NH:53][CH:54]1[C:76](=[O:77])[N:56]2[C:57]([C:73]([O-:75])=[O:74])=[C:58]([CH:61]([S:67][C:68]3[NH:72][N:71]=[N:70][N:69]=3)[CH2:62][S:63]([OH:66])(=[O:65])=[O:64])[CH2:59][S:60][C@H:55]12)=[O:52])=[O:49])(C)(C)C.FC(F)(F)C(O)=O.COC1C=CC=C(OC)C=1>>[Na+:1].[Na+:1].[Na+:1].[C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:29][N:30]=[N:31][N:32]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])([OH:9])=[O:7].[C:48]([CH:50]([C:78]1[S:79][CH:80]=[CH:81][CH:82]=1)[C:51]([NH:53][CH:54]1[C:76](=[O:77])[N:56]2[C:57]([C:73]([O-:75])=[O:74])=[C:58]([CH:61]([S:67][C:68]3[NH:69][N:70]=[N:71][N:72]=3)[CH2:62][S:63]([OH:66])(=[O:65])=[O:64])[CH2:59][S:60][C@H:55]12)=[O:52])([OH:49])=[O:47].[C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:29][N:30]=[N:31][N:32]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])([OH:9])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C(CS(=O)(=O)O)Sc3nnn[nH]3)CS[C@H]12)c1cccs1
Agent: COc1cccc(OC)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C([O-])C1=C(C(CS(=O)(=O)O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)C(C(=O)O)c3cccs3)C(=O)N12

Procedure:
7-(α-t-Butoxycarbonyl-2-thienylacetamido)-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid disodium salt (1.0 g.) is stirred in a mixture of 10 ml. of trifluoroacetic acid and 10 ml. of m-dimethoxybenzene at 25° for 1 hour. The mixture is evaporated to dryness and the residue is triturated with ether. The precipitated product is collected by filtration and dissolved in methanol. A sodium methoxide solution is added until pH 7.0, the mixture is diluted with ether and the product is dissolved in water and lyophilized to give 7-(α-carboxy-2-thienylacetamido)-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid trisodium salt.
Reaction SMILES: [C:1]([Si:5]([CH3:50])([CH3:49])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:14]2[CH2:15][O:16][C:17]3[C:22]([C:23]=2[C:24]([OH:40])([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=2)[CH3:25])=[CH:21][CH:20]=[C:19]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:18]=3)=[C:11](O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:45]([Si:42]([CH3:44])([CH3:43])[O:41][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)=[CH:30][CH:31]=4)([CH3:25])[O:40][C:9]4[CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:49])[CH3:50])[CH:12]=[CH:11][C:10]=4[C:14]=3[CH2:15][O:16][C:17]=2[CH:18]=1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2ccc(OCCN3CCCC3)cc2)Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-(Tert-butyl-dimethyl-silyloxy)-2-(7-(tert-butyl-dimethyl-silyloxy)-4-{1-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ethyl}-2H-chromen-3-yl)phenol, prepared as in STEP A above, was dissolved in toluene (8 mL) and treated with diluted HCl (0.4 mL of concentrated HCl:H2O=1:2 v/v). The reaction mixture was vigorously stirred at room temperature for 1.5 h. The mixture was then diluted with water and ethyl acetate. The layers were separated and the organic layer washed successively with saturated NaHCO3, brine and dried over MgSO4. The desiccant was filtered off, and the filtrate concentrated. Flash chromatography with ethyl acetate:hexane:CH3OH (containing 1% NH4OH)=49:49:2 as the eluent to yield the title compound as a light oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17](=[O:18])[CH2:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,3-Dichloroanisole (57.8 g., 0.327 mole) is dissolved in dichloromethane (300 ml.) and cyclopentylacetyl chloride (52.7 g., 0.367 mole) is added. The solution is cooled to +5° C. and aluminum chloride (48.0 g., 0.36 mole) is added gradually over a one-hour period at +5° C. The mixture is stirred for 2 hours at +5° C. and at 20°-25° C. for 16 hours and then poured into 1 liter of ice water containing 150 ml. of 12N hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with sodium chloride solution, 10% sodium hydroxide and again with sodium chloride solution and dried over magnesium sulfate. On evaporation of the solvent a brown solid is obtained which is crystallized from hexane to obtain 53.2 of 2',3'-dichloro-4'-methoxy-2-cyclopentylacetophenone, m.p. 60°-61.5° C.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@@:13]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][C:17]2([CH2:19][CH2:18]2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[NH2:12][C@@:13]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][C:17]2([CH2:19][CH2:18]2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OCc1ccccc1)(C(=O)OCC)CC21CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)CC21CC1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Charge absolute ethanol (100 mL, 10 volumes), concentrate. HCl (2.1 mL, 1.0 N) and diethyl (1S,2S,5R,6S)-2-benzyloxycarbonylaminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (9.7 g, 24.16 mmol) to a HEL reactor followed by Pd black (3.9 g, 40 wt %). Purge the reactor three times with nitrogen followed by three hydrogen purges and pressurization to 40 psi hydrogen. Allow the reaction to stir between 20-30° C. for at least two hours until the completion of the reaction monitored by HPLC. Filter the resulting slurry through a pad of Hyflo Super Cel® and wash the wet cake with absolute ethanol (2×30 mL, 3 volumes). Transfer the filtrate to a clean reactor and displace ethanol with isopropyl acetate to approximately 5 volumes based on in-situ product yield from calibration curve. Cool the resulting slurry to 0-5° C. over at least 3 hours. Filter the resulting slurry and wash the wet cake washed with cold isopropyl acetate (3×5 mL, 0.5 volumes). Dry under reduced pressure at 30° C. for at least 12 hours to provide the title compound (4.66 g, 15.34 mmol 63.5%) 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (s, 3H), 4.31-4.15 (m, 2H), 4.03 (q, J=7.0, 2H), 2.42 (dd, J=3.1, 2.6, 1H), 2.24 (dd, J=6.2, 2.6, 1H), 1.94 (d, J=14.1, 1H), 1.68 (d, J=14.1, 1H), 1.63 (dd, J=6.6, 3.1, 1H), 1.25 (t, J=7.0, 3H), 1.17 (t, J=7.0, 3H), 0.77-0.71 (m, 1H), 0.65-0.59 (m, 1H), 0.56-0.51 (m, 1H), 0.50-0.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:4]([CH2:33][CH:32]=[CH2:31])[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: C=CCBr
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1C(OC)=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (4.0 g, 12.0 mmol; see Example 1A) in dry dimethylformamide (10 ml) was treated with finely ground potassium carbonate (6.6 g, 48.0 mmoles) and allyl bromide (1.7 ml, 20.0 mmole). The resulting suspension was allowed to stir under argon at room temperature for 10 hours. The reaction was diluted with ethyl acetate, filtered and the filtrate was washed with water and brine. It was dried over anhydrous magnesium sulfate and evaporated to provide a yellow oil. Purification by flash chromatography (20% ethyl acetate in hexanes) yielded the title compound (2.64 g) as a yellow oil.