Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=O.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=[CH:31][C:32]#[N:33]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)ccc2OC)c1
Yield: 89 %

Procedure:
(2,5-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.92 g, 3.04 mmol), cyanomethylphosphonic acid diethyl ester (0.96 ml, 6.09 mmol) in anhydrous THF (15 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 6.09 ml, 6.09 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane in about 20 min.) to give a brown oil, which was lyophilized to give 3-(2,5-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a light yellow solid (0.88 g, 89%): δ 1HNMR (CDCl3) δ 6.94-6.43 (m, 12H, Ar), 5.89 (s, 0.65H, double proton of one isomer), 5.87 (s, 0.84H, double proton of the other isomer), 3.83-3.67 (multiple singlets, 24H, 8OCH3). The product was a mixture of two isomers with the ratio of 43.6%:56.4%; 13C NMR (CDCl3) δ 161.0, 160.7, 159.9, 159.8, 153.6, 153.5, 151.9, 151.2, 140.3, 140.0, 128.9, 126.9, 117.9, 117.5, 117.3, 116.3, 116.2, 115.8, 113.2, 107.0, 105.8, 102.0, 102.0, 98.3, 97.4, 56.5, 56.0, 56.0, 55.6, 55.6; Anal. Calcd. For C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.78; H, 5.77; N, 4.20.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:25]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:26](=[O:35])[CH2:27][CH2:28][C:29]([CH3:34])([S:31][S:32][CH3:33])[CH3:30])[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:25]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:26](=[O:35])[CH2:27][CH2:28][C:29]([CH3:34])([S:31][S:32][CH3:33])[CH3:30])[CH:13]=[C:14]([CH2:16][OH:17])[CH:15]=1
Reactant: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred solution of N-(3,5-bis((tert-butyldimethylsilyloxy)methyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267b)(315 mg, 0.447 mmol) in anhydrous acetonitrile (7.0 mL) at 0° C. was added anhydrous pyridine (7.00 mL) followed by dropwise addition of HF.Pyridine (3.1 mL, 1 mL/100 mg). The reaction stirred at 0° C. for two hours. It was diluted with ethyl acetate and slowly quenched with saturated sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography, eluting with 5% MeOH/CH2Cl2, yielded N-(3,5-bis(hydroxymethyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267c)(190 mg, 89%). 1H NMR (400 Hz, CDCl3): δ 7.21 (s, 1H), 7.16 (s, 2H), 4.63 (s, 4H), 3.79 (t, J=5.2, 5.6 Hz, 2H), 3.53 (m, 6H), 3.48 (m, 4H), 3.29 (s, 3H), 2.53 (s, 2H), 2.27 (s, 3H), 2.07 (m, 2H), 1.84 (m, 2H), 1.08 (s, 6H); MS (m/z): found 498.2 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:7])([O-])=O.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([N:15]([CH3:16])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:14])=[CH:11][CH:10]=1)=[O:7]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution of 4-(2-nitrobenzoyl)amino-N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-N-methylbenzamide (800 mg), 20% palladium hydroxide (200 mg) in ethanol (20 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 2 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by rotary evaporation and the crude product was purified by silica gel column chromatography (SiO2 30 g, ethyl acetate/hexane=3/1) to give 4-(2-aminobenzoyl)amino-N-methyl-N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]benzamide (700 mg).
Reaction SMILES: C(N=[CH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[CH:21]1[CH2:23][CH2:22]1)CCC.Cl.[OH2:25]>>[CH:21]1([C:8]2[CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:6]=[O:25])[CH2:23][CH2:22]1
Reactant: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: O
Agent: Cl
Product: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Crude butyl-[1-(2-cyclopropyl-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate M, 3.54 g, 10.5 mmol) was dissolved in 8 mL water. Hydrochloric acid (25%, 0.49 mL) was added and the mixture was refluxed for 2 h. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (1.01 g, 34%) was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1.O.O1[CH2:35][CH2:34]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:35]2[CH:34]=[N:4][CH:3]=[CH:2][N:1]=2)[CH:22]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(Br)c2)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(-c3cnccn3)c2)c1N
Yield: 63 %

Procedure:
A solution of 3-[5-amino-4-(3-bromobenzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide (60 mg), 2-tributyltinpyrazine (120 uL) and tetrakis(triphenylphosphine)palladium(0) (30 mg) in 1,4-dioxane (0.8 mL) was heated under microwave radiation at 160° C. for 25 min. Water (3 ml) was added and the mixture was extracted with ethyl acetate (4 mL×2). Evaporation of the solvent and purification by preparatory TLC (EtOAc: MeOH=10:1) gave the desired product (38 mg, 63%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 439.27 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:31][CH2:32]C)([O:28][CH2:29]C)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:32][O:31][C:24]1([O:28][CH3:29])[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Yield: 99.1 %

Procedure:
A mixture of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.5 g, 1.6 mmol), triethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (20 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled, was partitioned between aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.57 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
A solution of 2-bromo-1-fluoro-4-nitrobenzene (0.1 g, 0.45 mmol) and tert-butyl piperazine-1-carboxylate (85 mg, 0.45 mmol) in N,N-dimethylformamide (0.9 mL) was treated with potassium carbonate (94 mg, 0.68 mmol) and stirred at 20° C. for 23 h and at 60° C. for 3.5 h. The reaction mixture was diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellow oil. This material was purified by flash column chromatography to give the desired product (0.15 g, 87%) as a yellow solid. LCMS for C15H20BrN3O4Na (M+Na)+: m/z=407.9, 410.1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:50]([NH:57][C:47]([C:3]1[C:4]([CH3:46])=[CH:5][C:6]2[CH2:23][C@@H:22]([OH:24])[C@:21]3([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]4[C:19]([C:20]3=[O:27])=[C:18]([OH:28])[C:17]3[C:16](=[O:29])[CH:15]=[C:14]([NH:30][CH:31]5[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]5)[C:13](=[O:43])[C:12]=3[CH:11]=4)[C:7]=2[C:2]=1[OH:1])=[O:48])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)NCc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (50 mg, 0.073 mmol) in THF (5 mL) was added benzyl amine (15 μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) and lyophilized to afford (6R,6aS,14aR)—N-benzyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (19 mg, 33%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.32-7.21 (m, 5H), 6.61 (s, 1H), 5.99 (s, 1H), 4.96-4.87 (m, 2H), 4.53-4.33 (m, 2H), 3.75 (s, 3H), 3.75-3.72 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H), 3.47-3.38 (m, 4H), 3.25 (d, J=18.7 Hz, 1H), 3.06 (t, J=9.5 Hz, 1H), 2.19 (s, 3H), 1.27 (d, J=6.5 Hz, 3H); MS (ESI−) m/z 771 (M−H); HPLC >99% (AUC), tR 13.83 min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:23]Br>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:10]([Br:23])=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: COc1c(F)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1c(F)cnc2c1c(Br)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68b, (0.79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C.O>ClCCCl>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CCOC(=N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077) is reacted at about 0° C. in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is phenyl and R4 is ethyl) (about 8.3 g, 0.0448 moles) in 1,2-dichloroethane (about 650 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 500 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is phenyl).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18].ClCCCCN1C(=O)C2C(=CC=CC=2)N(C)C1=O.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18]
Reactant: [I-]
Reactant: Cn1c(=O)n(CCCCBr)c(=O)c2ccccc21
Agent: Cn1c(=O)n(CCCCCl)c(=O)c2ccccc21
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cn1c(=O)n(CCCCI)c(=O)c2ccccc21
Yield: 100 %

Procedure:
A solution of the title A compounds, 3-(4-bromobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline and 3-(4-chlorobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (1:1mixture; 2.35 g, 8.13 mmol) in 30 mL of methyl ethyl ketone is treated with sodium iodide (2.64 g, 17.62 mmol) at RT. The reaction is heated at reflux for 16 h, then cooled and the solvent is evaporated under reduced pressure. The residue is partitioned between 200 mL of ethyl acetate and 5 mL of water. The organic solution is washed with 10 mL of 1% aqueous sodium sulfite and 10 mL of brine, dried over anhydrous MgSO4, and concentrated to give 3.10 g (100%) of 3-(4-iodobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline as a white solid: m.p. 105-107° C.; NMR (CDCl3) 1.75-1.95 (m, 4H), 3.22 (t, 2H, J=6.8), 3.59 (s, 3H), 4.11 (t, 2H, J=7.1), 7.17-7.28 (m, 2H), 7.67 (dt, 1H, J=1.6, 7.9), 8.21 (dd, 1H, J=1.5, 7.9); IR 1702, 1658; ESI-MS 359 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:21])([F:20])C(OCC)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][Mg]I.C([O:27][CH2:28][CH3:29])C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:20])([F:21])[C:28]([CH3:29])([OH:27])[CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: C[Mg]I
Reactant: CCOCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 5 h
Yield: 62 %

Procedure:
Ethyl (4′-bromobiphenyl-4-yl)(difluoro)acetate (0.10 g, 0.28 mmol) obtained in Example 30-(1) was dissolved in tetrahydrofuran (20 mL), and a solution of methylmagnesium iodide in diethyl ether (3.0 M, 1.0 mL, 3.0 mmol) was added under a nitrogen atmosphere at room temperature, followed by stirring at the same temperature for 5 hours. Hydrochloric acid (1 M) was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the extract was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.35 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.063 g, 0.18 mmol) as a yellow oil (yield 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](C(O)=O)=[CH:10][C:9]=2[S:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.O>C(CN)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[CH:10][C:9]=2[S:16][C:17]([F:19])([F:18])[F:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: NCCO
Solvent: O
Product: FC(F)(F)Sc1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
A mixture of 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylic acid (0.5 g, 0.00155 mol) in ethanolamine (1.5 mL) is stirred at 160° C. for five hours, cooled to room temperature overnight with stirring, poured into water and. extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.11 g, mp 59°-64° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([CH3:6])[C:8]=1[N+:15]([O-:17])=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
At 10-15° C., 27 g (0.23 mol) of methanesulfonyl chloride dissolved in 20 ml of CH2Cl2 is dripped into a mixture of 34 g (0.2 mol) of 3-methyl-2-nitrobenzyl alcohol and 27 g (0.27 mol) of triethylamine in 100 ml of CH2Cl2. The reaction mixture is stirred for 1 hour at room temperature and is then extracted with water. The organic phase is dried over MgSO4 and evaporated down. There is obtained as residue 48 g of the title compound as a yellow oil, containing about 10% of the corresponding benzyl chloride as impurity. The crude product is used for the next reaction without any further purification.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])(C)(C)[CH3:2].C(O)(=[O:16])C>>[C:1]([O:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])(=[O:16])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OCCC1CCOC1=O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
In a stirred vessel, a mixture of 10 g of 3-(2'-tert-butoxyethyl)-dihydro-2(3H)furanone, 50 g of glacial acetic acid, and 5 g of Nafion is heated to 120° C. Following a period of 19 h, the reaction is terminated (conversion: 100%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 98% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8](=O)[N:9]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[NH:11][C:12]=1[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:8]1[C:7]([Cl:6])=[C:12]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[N:11]=[C:10]([CH:20]2[CH2:22][CH2:21]2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(OCC)c1[nH]c(C2CC2)nc(=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (35.1 g, 0.229 mol) in toluene (93 mL) was added to 5-chloro-2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the product of Example 4) (51.75 g, 0.190 mol) and N,N-dimethylformamide (34.7 g, 0.475 mol) in toluene (186 mL) at −5 to 0° C. The mixture was allowed to warm to room temperature over about 2 h. Then the mixture was added to aqueous sodium carbonate solution (saturated, 600 mL). The aqueous phase was further extracted with ethyl acetate (4×50 mL), and the organic extracts were combined, dried and evaporated to leave the product as an oil (52.9 g, 95% yield).
Reaction SMILES: Cl.FC(F)(F)C(O)=O.C([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:40][O:41][CH:42]2[CH2:46][CH2:45][CH:44]=[CH:43]2)[C:18]([NH:20][C@@H:21]2[C:38](=[O:39])[N:23]3[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1)=O.C(=O)(O)[O-].[Na+]>CO.O>[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:40][O:41][CH:42]2[CH2:46][CH2:45][CH:44]=[CH:43]2)[C:18]([NH:20][C@@H:21]2[C:38](=[O:39])[N:23]3[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]4[N:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Conc. hydrochloric acid (4.1 g) was added to a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (A isomer) (syn isomer) (5.8 g) in methanol (60 ml), and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added water (60 ml) and adjusted to pH 2.0 with 5% aqueous solution of sodium bicarbonate. The separated aqueous solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (120 ml) and eluted with 30% aqueous solution of methanol. The fractions containing the object compound were collected and concentrated in vacuo, then lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)-acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (A isomer) (syn isomer) (1.1 g).