Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.C([O:14][C:15](=O)[C:16](=[N:20]O)[C:17](=O)[CH3:18])(C)(C)C.O>C(O)(=O)C.[Zn]>[CH:15]([C:16]1[NH:20][C:6]([CH3:7])=[C:5]([C:4]([OH:3])=[O:9])[C:17]=1[CH3:18])=[O:14]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 60 °C

Procedure:
Ethyl-3-oxobutyrate (130 g, 1 mol) was dissolved in 400 mL of acetic acid in a 2 L 3-neck round bottom flask equipped with a thermometer, an addition funnel, mechanical stirring and placed in an oil bath. Zinc dust (50 g, 0.76 mol) was added and the mixture heated to 60° C. with stirring. The crude t-butyl-2-hydroximino-3-oxobutyrate solution prepared above was cautiously added keeping the temperature at about 65° C. by slowing the addition and cooling the flask. More zinc dust (4×50 g, 3.06 mol) was added in portions during the addition with the last portion added after all the t-butyl ester had been added. The temperature of the mixture reached a maximum of 80° C. At the end of the additions the temperature was 64° C. The temperature was increased by heating to 70-75° C. for one hour and then poured into 5 L of water. The gray floating precipitate was collected by vacuum filtration and washed with 2 L of water to give 354 g of wet crude product. The crude product was dissolved in 1 L of hot methanol and hot filtered to remove zinc. The filtrate was cooled to give a precipitate that was collected by vacuum filtration to give 118 g of product. The filtrate was put in the refrigerator overnight to give a total of 173.2 g of
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008 mol), 4fluorophenyl isothiocyanate (1.45g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.31 g (71%), m.p. 146°-148 ° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[C@H:41]([NH2:44])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])=[O:34]>CC(N(C)C)=O>[C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[CH:41]([NH:44][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH2:8])[S:10][CH:11]=3)=[N:18][O:19][CH3:20])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
The process of Example 8 was repeated except that after addition of triethylamine to the syn isomer of 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid, the mixture was cooled at 0° C. and the tosyl chloride in dimethylacetamide was added over 15 to 20 minutes. The reaction with 7-amino-cephalosporanic acid took place over 30 minutes.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[C:8]1([CH2:14][CH2:15][CH2:16][SH:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.C(N(CC)CC)C>[C:8]1([CH2:14][CH2:15][CH2:16][S:17][C:2]2[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC2OC12
Reactant: SCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1CCC=C1SCCCc1ccccc1
Yield: 63.7 %

Procedure:
2,3-Epoxycyclopentanone (1.0 g) and 1.06 g of 3-phenylpropyl mercaptan were dissolved in 20 ml of diethyl ether, and 20 drops of triethylamine were added. They were reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. The residue (1.50 g) was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 1.03 g of 2-(3-phenylpropylthio)cyclopent-2-en-1-one in a yield of 64%. The product had the following characteristics.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][Cl:27])=[CH:24][CH:23]=1>CCO>[ClH:27].[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: FC(F)(F)Oc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-trifluoromethoxybenzyl chloride (0.331 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 229 mg of the product 216. 1H NMR (DMSO-d6) δ 11.30 (s, 2H), 7.75 (d, 2H), 7.45 (d, 2H), 7.20-6.90 (m, 6H), 6.90-6.60 (m, 4H), 5.79 (s, 2H), 4.85 (s, 2H); MS: m/z 429 (M++1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[C:1]1([S:7]([N:10]2[CH:11]=[CH:12][CH:13]=[C:14]2[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
To a solution of 1-benzenesulfonyl-1H-pyrrole (284 g, 1.37 mol) in dichloromethane (1.0 L) were added p-toluoyl chloride (318 g, 2.06 mol) and boron trifluoride-diethyl ether (350 g, 2.47 mol) under an atmosphere of nitrogen. The mixture was allowed to stand at room temperature for 7 days. The reaction solution was washed with 1N hydrochloric acid (750 ml) twice, an aqueous 1N sodium hydroxide solution (750 ml) and a saturated aqueous sodium chloride solution (100 ml) in the order, dried and filtered. The filtrate was further concentrated to about 500 ml at atmospheric pressure, followed by addition of hexane (500 ml). Further the solution was concentrated to about 500 ml and cooled to 10° C. The precipitate was filtered, washed with hexane and toluene in the order, and dried to give the subject compound (315 g, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17]CC3C=CC=CC=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2o1
Yield: 97.3 %

Procedure:
A solution of 6-benzyloxy-benzofuran-2-carboxylic acid tert-butyl ester (5.68 g, 17.5 mmol) in THF (50 mL) and MeOH (20 mL) is added to Pd/C (5%, 200 mg). The mixture is stirred under a balloon of hydrogen for 16 hours at room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (3.99 g, 97%). LC-ES/MS m/e 233.0 (M−1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:30]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccccc1Cl
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:35])([F:36])[F:34])[N:21]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a cooled and stirred solution of 5-{3-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide (example 169) (0.175 g, 0.32 mmol) in dichloromethane (4 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.12 g, 75%). MS (ISN) 494.1 [(M−H)−]; mp 226° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].[F:30][C:31]([F:41])([F:40])[CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[F:30][C:31]([F:40])([F:41])[CH2:32][C:33]1[CH:39]=[CH:38][C:36]([N:37]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:29])([F:28])[F:16])(=[O:26])=[O:25])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:35][CH:34]=1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 521.13 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride and 4-(2,2,2-trifluoroethyl)-aniline.
Reaction SMILES: [C:1]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:17][CH3:18])[N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:13][CH:12]=[N:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)nccc2c1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reaction time: 1 h
Yield: 71 %

Procedure:
4.93 g of 3-butyryl 8-methoxy-1,7-naphthyridin-4(1H)-one and 4.2 ml of triethylamine were dissolved into 70 ml of dichloromethane, and a solution of methanesulfonyl chloride (1.85 ml) in dichloromethane (10 ml) was added dropwise at a temperature of 0° C. to 5° C. The resulting mixture was stirred for 1 hour at the same temperature. Water was added, and the resulting mixture was extracted with dichloromethan three times, and the organic phase was washed with water and then brine, dried over magnesium sulfate and distilled under reduced pressure. Ether was added to the residue to give 4.61 g (71%) of the titled compound as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[Br:10][CH2:11][CH2:12][CH2:13][Cl:14]>CO>[Br-:10].[Cl:14][CH2:13][CH2:12][CH2:11][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH3:3])[CH3:1]
Reactant: ClCCCBr
Reactant: CCCCCCN(C)C
Solvent: CO
Product: CCCCCC[N+](C)(C)CCCCl
Product: [Br-]
Temperature: 65 °C

Procedure:
A 500 mL, 3-necked, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged with N,N-dimethylhexylamine (199.46 grams, 1.54 moles), 1-bromo-3-chloropropane (243.00 grams, 1.54 moles) and 250 mL of methanol The reaction was maintained at 65° C. for 24 hours. Solvent was removed by rotary evaporation under reduced pressure to yield a brown, viscous oil. Yield 445.8 grams (1.55 moles, 100%).
Reaction SMILES: C(O)=O.[CH2:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[S:18][C:19]([CH2:23][N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[C:20]([CH3:22])[CH:21]=3)[O:14][N:13]=2)[CH:9]=[C:8]([CH3:29])[C:7]=1[CH2:30][CH2:31][C:32](O)=[O:33])[CH3:5].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:67]([O:69][C:70](=[O:73])[CH2:71][NH2:72])[CH3:68]>CN(C=O)C>[CH2:67]([O:69][C:70](=[O:73])[CH2:71][NH:72][C:32](=[O:33])[CH2:31][CH2:30][C:7]1[C:8]([CH3:29])=[CH:9][C:10]([C:12]2[N:16]=[C:15]([C:17]3[S:18][C:19]([CH2:23][N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[C:20]([CH3:22])[CH:21]=3)[O:14][N:13]=2)=[CH:11][C:6]=1[CH2:4][CH3:5])[CH3:68]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc(C)c1CCC(=O)O
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-[2-ethyl-4-(5-{5-[(isopropyl-methyl-amino)-methyl]-4-methyl-thiophen-2-yl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenyl]-propionic acid formate salt (9 mg, 18 μmol) in DMF (1 mL), DIPEA (14.3 mg, 0.111 mmol) and TBTU (7 mg, 20 μmol) is added. The mixture is stirred for 5 min before glycine ethyl ester hydrochloride (3.9 mg, 28 μmol) is added. The mixture is stirred at rt for 1 h before it is separated by prep. HPLC to give the title compound (8 mg) as a pale yellow resin; LC-MS: tR=0.61 min; [M−1]−=527.19.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12](O)=[O:13])[N:3]=1.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([Cl:23])=[O:13])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)O
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Cl

Procedure:
3.50 g (12.7 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoic acid are dissolved in 10 ml of thionyl chloride, and the mixture is heated at the boil for 2 hours. The reaction mixture is evaporated, the residue is taken up in toluene, and the solution is reevaporated, giving 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-pentanoyl chloride as a yellowish solid.
Reaction SMILES: [S-]C#N.[NH4+].C(Cl)(=O)C1C=CC=CC=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:25]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[O:25]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:23]([NH:22][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[S:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: O=C(NC(=S)Nc1ccccc1Oc1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of ammonium thiocyanate (30.2 g) in anhydrous acetone (660 ml) was added dropwise benzoyl chloride (47.6 g) with stirring at 50° C. After refluxing for 1.5 hours, the mixture was cooled to ambient temperature. To the mixture containing benzoyl isothiocyanate was added dropwise a solution of 2-phenoxyaniline (47.6 g) in anhydrous acetone (300 ml). The reaction mixture was refluxed with stirring for 1.5 hours and then concentrated under reduced pressure to give crystals, which were washed twice with water and dried to give crystalline 1-(2-phenoxyphenyl)-3-benzoylthiourea.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:9]=[CH:8][C:6](N)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N([O-])=O.[Na+].[S:17](=[O:19])=[O:18]>O.C(O)(=O)C.[Cu]Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:8][C:9]=1[S:17]([Cl:1])(=[O:19])=[O:18]
Reactant: Cl
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
In a beaker charged with 15 mL of concentrated hydrochloric acid was added 1 g (5.8 mmol) of 4-chloro-2-nitroaniline. The mixture stirred for 30 minutes at room temperature. The mixture was then chilled (−5° C.) and 400 mg (5.8 mmol) of sodium nitrite in 10 mL of water was added in several portions while maintaining the temperature between −5° C. and 10° C. After 30 minutes, the diazonium salt mixture was added in several portions to a chilled (ice-water bath) solution of 115 mg (1.16 mmol) of copper (I) chloride in 25 mL of acetic acid saturated with sulfur dioxide gas. The mixture was allowed to warm to room temperature. After 40 minutes, the mix was poured on to ice and stirred until the ice was melted. The bright yellow solid was collected by filtration, washed with several portions of water, and dried to afford 1.03 g (69%) of 2-chloro-4-nitrobenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.30 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 56(f)] was N-alkylated using 0.60 g of benzyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH:17][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC(C)(C)C)c1
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (5.0 g, 20 mmol, 1 equiv), DMAP (0.3 g, 2.46 mmol, 0.12 equiv) and pyridine (1.64 g, 20 mmol, 1 equiv) in CH2Cl2 (80 ml) was added 3-chloropropanesulfonyl chloride (2.4 ml, 20 mmol, 1 equiv) dropwise. The resulting mixture was stirred for 16 h then diluted with AcOEt (150 ml). The organic phase was washed with 2N aqueous HCl solution and saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 5-(3-chloro-propane-1-sulfonylamino)-isophthalic acid 1-tert-butyl ester 3-methyl ester (D81) (7.8 g, 99%) as a pale orange solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([CH:23]=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:23][C:22]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:14][C:15]2[C:20]([C:21]=1[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(C)c1c(C=O)c(-c2ccc(F)cc2)nc2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH2 Cl2 (10 ml) was added over a 15 minute period to a cold (-10° C.) solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-carboxaldehyde (1.744 gm, 5.95 mmol) (the preparation of which is described in Example 2) and triphenylphosphine (4,680 gm, 17.84 mmol) in CH2Cl2 (34 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow-orange oil. The oil was chromatographed (flash, Merck SiO2, 30% CH2 Cl2 in hexane followed by 1:1 CH2Cl2 in hexane followed by straight CH2Cl2) to give 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as a colorless foam (2.572 gm, 96%)