Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:34]([C:30]4[C:29]([CH3:36])=[CH:28][C:27](/[CH:26]=[CH:25]/[C:24]([O:23][CH3:22])=[O:37])=[CH:32][C:31]=4[CH3:33])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (1.83 g, 6.46 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (1.55 g, 7.10 mmol) (from Example 6-17) in DMF (25 mL) and water (2.5 mL) was added oxone (2.66 g, 4.33 mmols) and the mixture was stirred at ambient temperature for 1 h. The mixture was poured into ethyl acetate, extracted once with water and five times with brine, and the organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using a 50-90% gradient of heptane/ethyl acetate to give methyl (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]2)[C:19](=[O:34])[C:18]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:31][CH2:30][O:29][C:28]([CH3:32])([CH3:33])[CH2:27]2)[C:19](=[O:34])[C:18]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)=[CH:38][CH:37]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(C)(C)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 42%).
Reaction SMILES: N1C=C[CH:3]=N1.C[N:7]([C@@H:26]([C:28]1C=CC=CC=1)C)[C:8]([C:10]1[C:14]([Br:15])=[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[NH:12][N:11]=1)=[O:9].ClC1C=CC=CC=1C(Cl)=O.[N:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][N:53](CCN)[CH2:52][CH2:51]2)=[CH:46][CH:45]=1>>[N:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:51][CH2:52][N:53]([CH2:28][CH2:26][NH:7][C:8]([C:10]3[C:14]([Br:15])=[C:13]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[N:12]([CH3:3])[N:11]=3)=[O:9])[CH2:54][CH2:55]2)=[CH:46][CH:45]=1
Reactant: c1cn[nH]c1
Reactant: C[C@H](c1ccccc1)N(C)C(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br
Reactant: NCCN1CCN(c2ccncc2)CC1
Agent: O=C(Cl)c1ccccc1Cl
Product: Cn1nc(C(=O)NCCN2CCN(c3ccncc3)CC2)c(Br)c1NC(=O)c1ccccc1Cl

Procedure:
The pyrazole acid, prepared by coupling methyl ester 85 (Gen. Proc. 26) with 2-chlorobenzoyl chloride (21) followed by hydrolysis and bromination as shown in Gen. Proc. 8. was coupled to 2-(4-pyridin-4-yl-piperazin-1-yl)ethylamine (CA 985683) using the method of Procedure 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Te:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([Te:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:14]1([O:17][CH3:18])[CH:15]=[CH:16][C:11]([Te:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:25])[CH2:4][CH:5]=2)=[CH:12][CH2:13]1
Reactant: Cc1ccccc1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Product: COC1(c2ccccc2C)C=CC([Te]C2=CCC(OC)(c3ccccc3C)C=C2)=CC1
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Yield: 26 %
Yield: 59 %

Procedure:
p-Tolylydrazine (61 mg, 0.50 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.2 h. to yield toluene (30%); p.l.c. (benzene-petroleum ether 1:1) afforded bis-(p-methoxyphenyl)-telluride (102 mg, 59%) and p-tolyl-p-methoxyphenyltelluride (28) (43 mg, 26%). The latter, on recrystallisation from methanol gave white needles, m.p. 65.5°-67° (lit., 64°-64.5°), δ(CDCl3) 7.67 and 7.47 (both d, J 9 Hz, combined integral 4H), 6.93 and 6.70 (both d, J 9 Hz, combined integral 4H), 3.77 (3H,S), and 2.30 (3H, S), m/e 328 (M+), 210, 198 (100%), 183, 145, 91, 77 and 65 (Found: C, 51.62; H, 4.31 Calc. for C14H14O Te: C, 51.60; H 4.33%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CC[N:17](CC)CC.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:17])=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cnco2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0° C. and ClCOOi-Bu (745 mg, 5.46 mmol) was added dropwise. After the addition was over, the reaction mixture was stirred for additional 5 min and then aq NH4OH (0.63 mL of 28% solution, 10.46 mmol) was added. After overnight stirring, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to provide 500 mg (48%) of the 4-(5-oxazolyl)-benzamide: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.20-7.80 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1(C)[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:3]1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][CH:7]=1)=[O:5].F[C:22](F)(F)S(O)(=O)=O.[CH3:29][C:30]([CH3:32])=[CH2:31].[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][C:30]([CH3:32])([CH3:29])[CH3:31])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:22])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccc(C(=O)C2C(Cl)=CC=CC2(C)Cl)cc1O
Reactant: C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(C)(C)C

Procedure:
A solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2-methyl-benzophenone (3.0 g; 9.6 mmol) in 50 ml of methylenechloride is cooled down to -70° C., trifluoromethanesulfonic acid (0.3 ml) is added, then a stream of 2-methylpropene (5.5 g; 100 mmol) is introduced within 4 hours. Triethylamine (1.2 ml) is added, the temperature goes up to 20° C. The solution is shaken twice with diluted sodium hydroxide and the solvent is evaporated. The residue is purified chromatographically (flash column with 30 g of silicagel, elution with toluene/acetone 20:1 (v/v)). The residue is treated with petrolether to give 0.7 g of white crystalls (20% y); mp. 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[N:19]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[N:17]=[N:19][NH:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Oc2cc3nn[nH]c3cc2Br)c(F)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.071 g, 0.22 mmol) in acetic acid (0.4 mL) was treated with water (1.1 mL) followed by sodium nitrite (0.078 g, 1.1 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give a crude brown oil. Purification by flash column chromatography (100% hexanes to 60% EtOAc/hexanes) gave the desired product (57 mg, 78%) as a yellow solid. LCMS calculated for C12H7BrF2N3O (M+H)+: m/z=326.0, 328.0. found: 325.9, 327.9.
Reaction SMILES: C(C1C=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7]C=1)#N.FC1C=[C:41](C=CC=1F)[CH2:42][N:43]1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=O)C1=O.[B].N1C=CN=C2NC=CC=12>>[N:43]1[CH:42]=[CH:41][N:7]=[C:6]2[NH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])[C:5]=12
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Agent: c1cnc2[nH]ccc2n1
Product: O=C(NCc1cccc(-c2c[nH]c3nccnc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5H-Pyrrolo[2,3-b]pyrazine as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.287 (s, 1H) 10.040 (t, J=5.7 Hz, 1H) 8.448 (d, J=2.4 Hz, 1H) 8.410-8.374 (m, 1H) 8.386 (d, J=2.9 Hz, 1H) 8.286 (d, J=2.4 Hz, 1H) 8.224 (dd, J=7.0, 2.3 Hz, 1H) 8.182 (s, 1H) 8.104 (d, J=7.9 Hz, 1H) 7.462-7.337 (m, 3H) 7.170 (d, J=7.9 Hz, 1H) 7.190-7.125 (m, 1H) 6.592 (t, J=7.1 Hz, 1H) 5.192 (s, 2H) 4.556 (d, J=5.8 Hz, 2H); MS m/z=472.29 M+H.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.Cl[CH:12]([S:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([C:18]#[C:19][CH3:20])[CH3:17])=[O:14]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][CH:12]([S:22][CH3:23])[C:13]([NH:15][C:16]([CH3:17])([C:18]#[C:19][CH3:20])[CH3:21])=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Reactant: Oc1ccc2c(c1)OCO2
Product: CC#CC(C)(C)NC(=O)C(Oc1ccc2c(c1)OCO2)SC

Procedure:
In a similar procedure, 3,4-methylenedioxyphenol was reacted with 2-(chloro)-2-(methylthio)-N-(2-methylpent-3-yn-2-yl)acetamide to give 2-(3,4-methylenedioxy-phenoxy)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2.[N+:17]([O-])([OH:19])=[O:18].C(OCC)C>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2
Reactant: COC(=O)C1CCc2c(cccc2OC)C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)C1CCc2c(OC)ccc([N+](=O)[O-])c2C1
Temperature: 0 °C
Yield: 20 %

Procedure:
Methyl 5-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.1 g, 5 mmol; described in: Johnson, D. W.; Mander, L. N. Aust.J Chem. 1974, 8, 1277-1286) dissolved in acetic anhydride (20 mL), was treated with 70% nitric acid (0.4 mL) at 0° C. for 1 h and the mixture was poured into ice-water and diethyl ether. The organic phase was separated, evaporated in vacuo and the residue triturated with diisopropyl ether to yield 0.27 g (20%) of the title compound as crystals: mp 100-104° C.; EIMS (70 eV) m/z (relative intensity) 265 (35, M+).
Reaction SMILES: Br.NN=[CH:4][S:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21]CS(OC1C=CC(C)=CC=1)(=O)=O.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][CH2:4][S:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: NN=CSCc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(OS(=O)(=O)CCc2cccs2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CSCCc2cccs2)cc1
Temperature: 50 °C

Procedure:
A mixture containing 7.2 grams of 4-(((aminoiminomethyl)thio)methyl)benzoic acid monohydrobromide (0.025 mole), 7.1 grams of 4-methylphenyl 2-thiopheneethanesulfonate (0.025 mole), 50 ml of ethanol, 25 ml of 20% sodium hydroxide in water, and 25 ml of water were warmed to approximately 50° C. The orange solution obtained was mixed with 1 liter of ice-water and acidified with glacial acetic acid giving a pink solid. The pink solid was collected and recrystallized from acetonitrile to give the final product 4-(((2-(2-thienyl)ethyl)thio)methyl)benzoic acid as a pale pink solid having a melting point of 136°-137° C.
Reaction SMILES: [CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([O:7]CC)=[O:6])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C=Cc1ccc(OC)cc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC(C(=O)O)C(C)C)cc1

Procedure:
The thus-prepared ester is hydrolyzed by treatment with potassium hydroxide in methanol/water to give 2-isopropyl-4-(4-methoxyphenyl)-3-butenoic acid, which is reacted with m-phenoxybenzyl bromide using the procedure of Example 1 to give m-phenoxybenzyl 2-isopropyl-4-(4-methoxyphenyl)-3-butenoate, MS m/e 416 (M+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]1[N:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:27][C:28]4[N:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][CH:29]=4)[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(CBr)n1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
The mixture of 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one (70 mg, 0.228 mmol, 1 eq) in DMF (1 ml) and sodium hydride (11.8 mg, 0.296 mmol, 1.3 eq) was stirred at room temperature for 60 min, followed by the addition of 6-Bromomethyl-pyridine-2-carbonitrile (74.1 mg, 0.296 mmol, 1.3 eq). The mixture was stirred for 60 min, quenched with water, taken up with ethyl acetate, dried over sodium sulfate and purified with flash chromatography to give the desired product (17 mg). LCMS observed for (M+H)+: 424.1.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:28])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:28])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Product: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Temperature: 25 °C
Yield: 73.9 %

Procedure:
8-Cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.51 g, 3.76 mmol) and 2-benzenesulfonyl-3-phenyloxaziridine (0.98 g, 3.76 mmol) were combined in dichloromethane (14 mL) and stirred at room temperature until no starting material remained. The solvent was removed in vacuo and the residue was purified by chromatography (gradient 50% ethyl acetate in heptane to 100% ethyl acetate) to provide 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.16 g, 74%) as a white solid. MS (ESI); M++1: Calc'd, 418. Found 418. 1H NMR δ (300 MHz, CDCl3) 9.13 (s, 1H), 6.14-6.02 (m, 1H), 2.98 (s, 3H), 2.80 (s, 3H), 2.27-2.06 (m, 4H), 2.00-1.87 (m, 2H), 1.72-1.63 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:24]1[NH:27][C:26](=[O:28])[CH2:25]1)(=O)C.[Cl:29][CH2:30][C:31](=[O:42])[C:32](=[N+:40]=[N-:41])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[C:36]([O:35][C:33]([C:32](=[N+:40]=[N-:41])[C:31](=[O:42])[CH:30]([CH:24]1[NH:27][C:26](=[O:28])[CH2:25]1)[Cl:29])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CCl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)C(Cl)C1CC(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
1.8 ml (13.0 mmol - 2.6 equivalents) of triethylamine and then 2.3 ml (12.0 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.42 g (6.5 mmol) of tert.-butyl 4-chloro-2-diazo-3-oxobutanoate in 45 ml of anhydrous dichloromethane. The cooling bath was removed and the mixture was stirred at room temperature for 5 h, then 0.3 ml (1.5 mmol - 0.3 equivalent) of trimethylsilyl trifluoromethanesulphonate was added and the mixture was stirred at room temperature for 1 h. To work up, it was poured into a mixture of cold saturated NaHCO3 solution and ethyl acetate, extraction with ethyl acetate was carried out, and the organic extracts were washed with saturated NaCl solution and dried over MgSO4. After evaporation of the solvent in vacuo and chromatography on 40 g of silica gel (toluene:ethyl acetate 1:1), 426 mg (30%) of the title compound were obtained as a mixture of diastereomers (10:1), Rf: 0.35 (toluene:ethyl acetate 1:1).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48][CH:49]=[O:50])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48][CH:49]=[O:50])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Yield: 68.4 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (24 ml) were added anisole (2.8 g) and trifluoroacetic acid (7.5 g) with stirring under ice-cooling and then the resulting mixture was stirred for one hour and 15 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated and washed with ethyl acetate (×2) and thereto were added ethyl acetate and tetrahydrofuran. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol- 4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10]2)[S:5][C:4]1=[S:19])[CH3:2].[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29]C)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10]2)[S:5][CH2+:4]1[S:19][CH3:20])[CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCN1C(=O)C(=C2Sc3ccccc3N2C)SC1=S
Product: CCN1C(=O)C(=C2Sc3ccccc3N2C)S[CH2+]1SC
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The title compound was prepared from 3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-one and methyl p-toluenesulfonate in a manner similar to that described in Example 1. 1H-NMR (CDCl3): δ 7.82 (1H, d), 7.77 (2H, d), 7.58-7.66 (2H, m), 7.49 (1H, m), 7.08 (2H, d), 4.52 (3H, s), 4.21 (2H, q), 3.29 (3H, s), 2.29 (3H, s), 1.45 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]\[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg, 2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the major isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.65-1.79 (m, 2H), 1.83-1.97 (m, 2H), 2.38 (s, 3H), 2.39 (s, 3H), 2.94-3.08 (m, 3H), 3.10-3.23 (m, 2H), 4.23 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.84-6.98 (m, 3H), 7.03-7.18 (m, 3H), 7.88 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 344 (M+H)+.