Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35]OS(C(F)(F)F)(=O)=O)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:44][C:45]1[S:46][C:47]2[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=2[C:49](=[O:51])[CH:50]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C=O)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:44][C:45]1[S:46][C:47]2[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=2[C:49](=[O:51])[CH:50]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: O=c1cc(S)sc2ccccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccccc4s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
7β-Tert-butoxycarbonylamino-3-(2-trifluoromethanesulfonyloxyvinyl)-3-cephem-4-carboxylic acid benzhydryl ester (trans isomer) (3.9 g, 6.1 mmol) was dissolved in anhydrous DMF (80 ml), added with 2-mercapto-4-oxo-4H-1-benzothiopyran (3.5 g, 18.3 mmol) and N-ethyldiisopropylamine (0.63 g, 4.87 mmol), successively, and stirred at room temperature under argon gas atmosphere for 24 hours. The reaction product was added with ethyl acetate (350 ml), washed with an aqueous solution of saturated sodium hydrogencarbonate (150 ml×2 times) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (Wago Gel™ C-200, methylene chloride-ethyl acetate (8:1)) to obtain 3.56 g (yield: 85.4%) of 7β-tert-butoxycarbonylamino-3-[2-(4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester as yellow-red froth.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[N:20]=[C:19]([C:21]([O:23]CC)=O)[O:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[N:20]=[C:19]([C:21]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:39][CH2:38]3)=[O:23])[O:18][N:17]=2)(=[O:11])=[O:12])=[C:5]([CH3:26])[CH:4]=1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)N3CCN(CCN4CCCC4)CC3)n2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.08 mmol), 1-[2-(pyrrolidin-1-yl)ethyl]piperazine (29 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14].[Cl-].[OH:23][NH3+:24].Cl>CO>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:24]\[OH:23])/[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=O)c1ccccc1COc1ccccc1C
Reactant: [NH3+]O
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)/C(=N/O)c1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
56.8 g (0.2 mol) of methyl 2-(2-methylphenoxymethyl)phenylglyoxylate and 15.2 g (0.22 mol) of hydroxylammonium chloride in 67.5 ml of methanol are refluxed for 6.5 hours. The resulting mixture (of E- and Z-oximes) is cooled to 0° C. and 14.2 g (0.39 mol) of hydrogen chloride are passed in, and the mixture is then stirred at 25° C. for 5 hours. The solvent is removed by distillation under reduced pressure, the residue is taken up in diethyl ether, and the solution is washed with water, dried over sodium sulfate and evaporated to dryness. 55.3 g of solid E isomer (melting point 115° C.) are obtained.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCN2CCCC[C@@H]2CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 18 h

Procedure:
(R)-2-Hydroxymethyl-1-[3-(4-methoxyphenyl)propyl]piperidine (422 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (210 mg, 2.08 mmol) and methanesulfonyl chloride (238 mg, 2.08 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 18 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-[3-(4-methoxyphenyl) propyl]homopiperidine in the form of a light yellow oil (278 mg, 62%).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[CH2:6][CH2:7][C:8]2[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10][N:11]([CH2:15][CH2:16][OH:17])[C:12]=2[C:13]\1=O)[CH3:3].[C:23]([O-:26])(=O)C.[K+].S(O)(O)(=O)=O.C[NH:34]C(=N)O>CN(C=O)C.C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][N:11]1[C:12]2[C:13]3[N:34]=[C:3]([O:26][CH3:23])[N:2]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]1
Reactant: CNC(=N)O
Reactant: CCOC(=O)c1nn(CCO)c2c1CC/C(=C\N(C)C)C2=O
Reactant: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(OC)nc1-2
Temperature: 100 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
To a solution of ethyl (6E)-6-[(dimethylamino)methylidene]-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate 15 g (49 mmol) in 50 ml of anhydrous DMF, 14.4 g (147 mmol) of anhydrous potassium acetate and 12.60 g (73.0 mmol) of methylisourea sulfate were added. The reaction was stirred at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and evaporated. The crude was purified by column (ethyl acetate:hexane 1:3) to give the title compound 1.2 g (10%). HRMS (ESI) calcd for C15H18N4O4 [M+H]+ 319.3278 found 319.3256.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.I[CH2:9][C:10]([O-:12])=[O:11].[Na+].[H-].[Na+].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: O=C([O-])CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of tetrahydro-2H-pyran-4-ol (286 μl, Acros) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624 mg), and successively added with sodium hydride (198 mg) as several portions at 0° C., and the mixture was stirred at the same temperature for 45 minutes, and then further stirred at room temperature for 23 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (43.4 mg).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](=[C:11]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[C:12]([NH2:14])=[O:13])[S:10][C:6]=2[CH:5]=1)(O)=[O:2].C(N(CC)CC)C.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[N:54]1([CH2:60][CH2:61][CH2:62][NH2:63])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.[ClH:64]>C(#N)C.O1CCOCC1>[ClH:64].[N:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:1]([C:4]2[CH:26]=[CH:25][C:7]3[NH:8][C:9](=[C:11]([C:15]4[N:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][N:16]=4)[C:12]([NH2:14])=[O:13])[S:10][C:6]=3[CH:5]=2)=[O:2])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1
Reactant: NCCCN1CCOCC1
Reactant: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: NC(=O)C(=C1Nc2ccc(C(=O)NCCCN3CCOCC3)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a room temperature solution of 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (350 mg, 0.92 mmol) in acetonitrile (5 mL) was added triethylamine (250 μL, 1.79 mmol, 2 eq.), DEPBT (299 mg, 1.0 mmol, 1.1 eq.), and 3-(4-morpholinyl)-propan-1-amine (134 μL, 0.92 mmol, 1.0 eq.), and the mixture was stirred at room temperature until a yellow-brown precipitate formed. The precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to give a yellow solid. About 2 mL of 4.0 M hydrogen chloride in dioxane was added, and the mixture was stirred for 15 min and then concentrated under reduced pressure to give 2-(6-{[3-(morpholin-4-yl)propyl]aminocarbonyl}-benzothiazol-2(3H)-ylidene)-2-(4-trifluoromethyl-pyrimidin-2-yl)acetamide hydrochloride (340 mg, 73% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(F)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C#N)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.18 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][C:14]([CH3:16])=[CH2:15]>>[CH3:15][C:14](=[CH2:13])[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1cccc(O)c1
Product: C=C(C)COc1cccc(C(=O)OC)c1

Procedure:
Using procedures analogous to those of D. W. Robertson, et. al., J. Med. Chem., 35, 310 (1992) and V. Peesapati, and N. Lingaiah, Org. Prep. Proc. Int., 24(1), 27 (1992), the hydroxy group of methyl 3-hydroxybenzoate was alkylated with 3-chloro-2-methyl-1-propene to give methyl 3-(2-methyl-2-propenyloxy)benzoate. This material then underwent a 3,3 sigmatrophic shift to give methyl 3-hydroxy-4-(2-methyl-2-propenyl)benzoate. Formic acid catalyzed ring closure resulted in 2,2-dimethyl-6-carboxymethyl-dihydrobenzofuran.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]([OH:20])([CH3:19])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:4]=1[C:24]([F:27])([F:26])[F:25])#[N:2].C1C=C(C(O)=[O:35])C(C(OO)=O)=CC=1.[OH-:41].[K+]>C(OCC)(=O)C>[CH3:19][C:9]([OH:20])([C:8]([NH:7][C:6]1[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:5]=1)=[O:21])[CH2:10][S:11]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)(=[O:35])=[O:41]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 4.5 °C
Yield: 92.9 %

Procedure:
In a four neck flask having a capacity of 200 ml, 4′-cyano-3-(4-fluorophenylthio)2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide (12.2 g, 30.6 mmol) produced by a method described in EP1462442-A and ethyl acetate (20 ml) were sequentially added, and then agitated under an ice cooling (2 to 7° C.). Ethyl acetate solution of monoperphthalic acid (166.58 g, net amount 22.31 g, 122.5 mmol) was added dropwise at a temperature of 10° C. or less, and then agitated for 1 hour. 20% Potassium hydroxide solution (117.5 g) was added dropwise and then subjected to a phase separation. The water layer was extracted with ethyl acetate (30 ml), and the organic layers were combined, and the combined organic layer was washed with an aqueous solution dissolving 3.0 g of sodium pyrosulfite in de-ionized water (30 ml), dried with magnesium sulfate, and then concentrated under a reduced pressure. The residue was added with 66 ml of ethyl acetate and then heated up to at 60° C. 40 ml of n-Heptane was added dropwise at a temperature of 60 to 65° C. for 40 minutes. After finishing the dropwise addition, the solution was gradually cooled down to a room temperature (about 20 to about 25° C.), followed by filtration to collect bicalutamide (12.24 g, yield 91.2%) as crystals. Purity 99.97%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([CH:23]=[O:24])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
4-Bromo-2-fluoro-biphenyl (2 gm, 8 mmole) was dissolved in 20 ml of anhydrous tetrahydrofuran, THF, cooled to −78° C. under argon (Ar), n-Butyl lithium 2.5 M (3.5 ml, 8.8 mmole) was added drop wise over 10 min, and was stirred for additional 1 hr, DMF anhydrous (0.68 ml, 8.8 mmole) was then added, stirred for additional 1 hr, then warmed to room temperature over 4 hr, It was then quenched with water, extracted with ether, ether was dried, evaporated, the produced compound was purified using 9:1 hexane/ethyl acetate, to produce white solid (1 gm, 62.5%); H1-NMR INOVA-500 (CDCl3) δ 7.416-7.495 (m, 3H), 7.581-7.661 (m, 4H), 7.723 (d, J=8.0 Hz, 1H), 9.991 (s, 1H).
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15](=[O:20])[C:14]([C:21](N(OC)C)=[O:22])=[N:13]1>C1COCC1>[C:21]([C:14]1[C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][N:12]([C:6]2[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=2[F:4])[N:13]=1)(=[O:22])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(I)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 23 %

Procedure:
MeMgBr (1 M solution in THF, 70 mL, 70 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (9.96 g, 23 mmol) in THF (250 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (2.05 g, 23% yield) as pale yellow crystals: mp 196-198° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.90 (3H, s), 7.36-7.41 (1H, m), 7.66-7.71 (2H, m), 7.73 (1H, d, J=2.6 Hz). Anal. Calcd for C13H10FIN2O3: C, 40.23; H, 2.60; N, 7.22. Found: C, 40.25; H, 2.87; N, 7.28.
Reaction SMILES: [CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[Cl-].[Li+].[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19]([CH:35]=[CH2:36])=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C=CCCCC(=O)CCC(C)OC(=O)c1c(OC)cc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCC(=O)CCC(C)OC(=O)c1c(C=C)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
A mixture of 2,4-dimethoxy-6-trifluoromethanesulfonyloxy-benzoic acid 1-methyl-4-oxo-non-8-enyl ester (0.041 g, 0.085 mmol), PdCl2(PPh3)2 (0.007 g, 0.01 mmol), lithium chloride (0.052 g, 1.2 mmol), and vinyltributyltin (50 μL, 0.17 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 24 hours. After addition of water (10 mL), extraction, and chromatography afforded 2,4-dimethoxy-6-vinyl-benzoic acid 1-methyl-4-oxo-non-8-enyl ester as a clear oil (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2Cl)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.24 g of (2-chlorophenyl)methanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.66 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.93 g) was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:24][CH2:25][CH3:26])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]1([O:11][CH2:12][CH2:13][NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: BrCCOc1cccc2ccccc12
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccccc1NCCOc1cccc2ccccc12

Procedure:
A solution of 12.54 g. of 2-(1-naphthyloxy)ethyl bromide and 16.5 g. of ethyl anthranilate in 50 ml. of hexamethylphosphoramide are heated at 110° for 18 hours. After cooling and diluting with water, the mixture is extracted twice with 200 ml. of ether. The combined ether extracts are washed with water, dried and evaporated to a brown oil. The oil is dissolved in 60 ml. of ethanol and chilled in an ice-bath yielding a beige solid which is recrystallized from 100 ml. of ethanol affording pale yellow crystals, m.p. 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12]([Mg]Br)[CH3:13].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:17])[O:11][C:9]([CH2:12][CH3:13])([CH3:10])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC1(C)OC(=O)Nc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred solution of 1-(2-amino-5-bromophenyl)-ethanone (10.00 g, 46.70 mmol) in THF (150 mL) was added 3.0M ethyl magnesium bromide (50 mL, 150 mmol) slowly at 0° C. over 20 minutes. The reaction was stirred 1 hr at 0° C., quenched with ammonium chloride solution (sat.) and extracted with ethyl acetate several times. The organic layer was washed with brine and dried over magnesium sulfate. The concentrated crude material was dissolved in THF (150 mL). 1,1′-Carbonyldiimidazole (9.00 g, 56.04 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was partitioned between ammonium chloride solution (sat.) and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 30% ethyl acetate/hexane followed by trituration with ether gave 6-bromo-4-ethyl-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (5.84 g, 46%). 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 7.43 (m, 2H), 6.783 (d, J=8.3 Hz, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.57 (s, 3H), 0.82 (t, J=7.3 Hz, 3H). MS (ESI) m/z 270/272 ([M+H]+); MS (ESI) m/z 268/270 ([M−H]−); HRMS: calcd for C11H12BrNO2, 269.0051; found (ESI_FT), 270.01259. Anal. Calcd for C11H12BrNO2: C, 48.91; H, 4.48; N, 5.19. Found: C, 48.94; H, 4.38; N, 5.00.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=O)[NH:7][C:6]=2[CH:14]=1.Cl.[CH3:20][CH:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]=[C:8]([NH:25][CH:21]([CH3:20])[CH:22]([CH3:24])[CH3:23])[NH:7][C:6]=2[CH:14]=1
Reactant: CC(C)C(C)N
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NC(=O)NS2(=O)=O
Agent: Cl
Product: CC(C)C(C)NC1=NS(=O)(=O)c2cc(S(N)(=O)=O)c(Cl)cc2N1

Procedure:
The title compound was prepared from 6-chloro-2,3-dihydro-3-oxo-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (4.94 g, 15.84 mmol) and 1,2-dimethylpropylamine hydrochloride (8.0 g, 65.0 mmol) by a method analogous to the method described in example 37, except that the product was purified by column chromatography affording 143 mg (2.4%) of pure product; m.p. (DSC) 244° C. (methanol); 1H-NMR (DMSO-d6): δ 0.90 (dd, 6H, CH(CH3)2), 1.11 (d, 3H, NCHCH3), 1.76 (m, 1H, CH(CH3)2), 3.71 (m, 1H, NHCH), 7.34 (br., 1H, NH), 7.41 (br.s, 1H, ArH), 7.80 (br.s, 2H, SO2NH2), 8.18 (s, 1H, ArH), 10.58 (br.s, 1H, NH); MS (FAB): m/e 381/383 (MH+); (C12H17N4Cl1O4S2) calc. C, 37.84; H, 4.50; N, 14.71; found C, 37.66; H, 4.65; N, 14.52.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:41](=[O:42])[N:11]2[C:12]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:13]([CH:16]=[CH:17][S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[I:44].[CH:45](OC(C)C)(C)C>CN(C)C=O>[I-:44].[C:1]([O:5][C:6]([NH:8][CH:9]1[C:41](=[O:42])[N:11]2[C:12]([C:25]([O:27][CH:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[C:13]([CH:16]=[CH:17][S:18][CH2+:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[CH3:45])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OC(C)C
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccccn3)CS[C@H]12
Reactant: CI
Solvent: CN(C)C=O
Product: CN1C=CC=C[CH2+]1SC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)[C@H]2SC1
Product: [I-]
Reaction time: 216 h

Procedure:
A mixture of benzhydryl 7-tert-butoxycarbonylamino-3-[2-(2-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (5.0 g) N,N-dimethylformamide (25 ml) and methyl iodide (5 ml) was allowed to stand for 9 days at ambient temperature. The reaction mixture was poured into diisopropyl ether and the resultant oily residue was triturated with ethyl acetate and collected by filtration to give benzhydryl 7-tert-butoxycarbonylamino-3-[2-(1-methyl-2-pyridinio)thiovinyl]-3-cephem-4-carboxylate iodide (trans isomer) (5.2 g).