Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]#[N:21])[N:11]=2)=[CH:5][CH:4]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[NH:25][N:24]=[N:23][N:21]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(N(C)c2nc(C#N)nc3ccccc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(-c3nnn[nH]3)nc3ccccc23)cc1
Temperature: 130 °C
Yield: 13.2 %

Procedure:
To 4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-carbonitrile (100 mg, 0.34 mmol) in DMF (3.4 mL) was added sodium azide (269 mg, 4.1 mmol) and ammonium chloride (220 mg, 4.1 mmol). The reaction was heated to 130° C. for 15 min in a microwave. The reaction was quenched with aqueous NaHCO3 and diluted with EtOAc. The aqueous phase was acidified with HCl (12 M) to pH 1 and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated. Purification via gradient MPLC gave 15 mg (13%) of the title compound as a solid. 1H NMR (MeOH-d4) δ 7.91 (d, 1H), 7.74-7.70 (t, 1H), 7.30 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 7.0 (d, 1H), 3.86 (s, 3H), 3.82 (s, 3H); LC-MS (ESI+; 334 ([M+H]+)).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([O:17][Si](C)(C)C)([CH3:16])[C:12]([F:15])([F:14])[F:13])[S:7]/[C:6]/1=[CH:22]\[C:23]([C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])=[O:24])[CH2:2][CH2:3][CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13])[S:7]/[C:6]/1=[CH:22]\[C:23]([C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(C)=C(C(C)(O[Si](C)(C)C)C(F)(F)F)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCN1C(C)=C(C(C)(O)C(F)(F)F)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h
Yield: 889.1 %

Procedure:
The product from Example 123A (80 mg, 0.015 mmol) in THF at 0° C. was treated with TBAF (0.015 mmol) and stirred for 1 hr. The reaction mixture was partitioned between EtOAc and brine, dried (MgSO4), concentrated and the residue was purified by flash chromatography eluting with 0-100% EtoAc in hexane to give 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.33-1.49 (m, 2 H), 1.66 (d, J=7.1 Hz, 2 H), 1.74 (s, 3 H), 2.41 (s, 3 H), 3.86 (s, 3 H), 3.90-4.01 (m, 2 H), 6.57 (s, 1 H), 7.05 (s, 1 H), 7.12 (d, J=8.8 Hz, 1 H), 7.42 (dd, J=8.8, 2.7 Hz, 1 H), 7.64 (d, J=3.1 Hz, 1 H). MS (DCI), m/z 450 (M+H)+. Anal calcd for C20H23ClF3NO3S: C, 53.39; H, 5.15; N, 3.11. Found: C, 53.20; H, 5.01; N, 2.89.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].[NH2:13][CH2:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:16]>O>[N+:23]([C:20]1[N:19]=[CH:18][C:17]([C:15](=[O:16])[CH2:14][NH:13][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)c1ccc([N+](=O)[O-])nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NCC(=O)c1ccc([N+](=O)[O-])nc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
1.575 cm3 (16.66 mmol) of acetic anhydride and then 1.367 g (16.66 mmol) of sodium acetate in solution in 3 cm3 of water are added at a temperature in the region of 5° C. to 1.05 g (4.166 mmol) of 2-amino-1-(6-nitropyridin-3-yl)-ethanone in solution in 25 cm3 of water. After stirring for 3 hours at 5° C., the reaction mixture is extracted with three times 10 cm3 of ethyl acetate. All the organic phases are combined, washed with 30 cm3 of a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.618 g of N-[2-(6-nitropyridin-3-yl)-2-oxoethyl]acetamide, in the form of a yellow solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.90 (s, 3H); 4.66 (d, J=4.5 Hz, 2H); 8.37 (broad t, J=4.5 Hz, 1H); 8.43 (d, J=8.5 Hz, 1H); 8.68 (dd, J=2.0 and 8.5 Hz, 1H); 9.16 (d, J=2.0 Hz, 1H). 2-Amino-1-(6-nitropyridin-3-yl)ethanone may be prepared in the following manner:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:17][C:16]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([O:20]C)=[O:19])[CH2:15]1.Cl>O1CCOCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:17][C:16]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([OH:20])=[O:19])[CH2:15]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CN(C/C=C/c2cc(F)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CN(C/C=C/c4cc(F)ccc4F)C3)c2c1
Yield: 74.7 %

Procedure:
5 cm3 of a 5 N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 614 mg (1.267 mmol) of methyl 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylate in solution in 20 cm3 of dioxane. After stirring under reflux for 1.5 hours, 6 cm3 of a 5 N aqueous sodium hydroxide solution are again added, and the medium is kept under reflux for another 3 hours; the reaction medium is cooled and supplemented with 4.5 cm3 of hydrochloric acid at 37%, and then concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is flash-chromatographed on a 200 cm3 column of fine silica [eluent: solvent gradient (dichloromethane-methanol-aqueous ammonia at 28%) (from 100-0-0 to 72-24-4 by volume)]. The fractions containing the product are combined and evaporated to dryness (2.7 kPa). The residue (530 mg) is taken up in 10 cm3 of dichloromethane, diluted with 25 cm3 of diethyl ether to give 445 mg of 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylic acid in the form of a slightly pink solid melting at 211° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C28H30N4O5S
Reaction SMILES: [C:1](O)(=[O:3])C.CS[CH:7]([OH:19])[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[CH:13]=1.II.[CH3:22]O>>[CH3:1][O:3][CH:7]([O:19][CH3:22])[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[CH:13]=1
Reactant: CO
Reactant: CSC(O)c1cc(=O)c2ccccc2o1
Reactant: CC(=O)O
Agent: II
Product: COC(OC)c1cc(=O)c2ccccc2o1
Yield: 86 %

Procedure:
A stirred solution of 2-[(methylthio)hydroxymethyl)-4H-1-benzopyran-4-one acetate](2.64 g, 0.01 m) and iodine (1.39 g, 0.01 m) in methanol (50 ml) was refluxed under nitrogen for 6 hours. After cooling, the solvents were removed under reduced pressure. The red-brown oil was dissolved in chloroform and washed three times (30 ml) with aqueous saturated sodium thiosulfate. The chloroform extract was dried over sodium sulfate. Removal of the solvent under reduced pressure gave crude solid product. Recrystallization from isopropyl ether gave yellow crystals (1.9 g, 86%), m.p. 64°-68°.
Reaction SMILES: [H-].[Na+].COC(=O)[CH2:6][CH2:7][C:8]1[N:13]=[CH:12][C:11]2[O:14][CH2:15][CH2:16][C:10]=2[C:9]=1[C:17]([O:19]C)=O.Cl>O1CCCC1.CO>[CH2:16]1[C:10]2=[C:9]3[C:17](=[O:19])[CH2:6][CH2:7][C:8]3=[N:13][CH:12]=[C:11]2[O:14][CH2:15]1
Reactant: COC(=O)CCc1ncc2c(c1C(=O)OC)CCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCc2ncc3c(c21)CCO3
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a suspension of 65% sodium hydride (1.38 g, 37.4 mmol) in tetrahydrofuran (10 mL) were added a solution of methyl 5-(3-methoxy-3-oxopropyl)-2,3-dihydrofuro[2,3-c]pyridine-4-carboxylate (1.98 g, 7.46 mmol) in tetrahydrofuran (80 mL) and methanol (0.2 mL), and the mixture was stirred at 80° C. for 10 min. 12M Hydrochloric acid (40 mL) was added thereto under ice-cooling, and the organic solvent was evaporated under reduced pressure. The residual aqueous solution was stirred at 150° C. for 20 min, the reaction mixture was basified with 8M aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (886 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2.C([SiH](CC)CC)C.[ClH:26]>FC(F)(F)C(O)=O.O>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC1(CCCCN1)C2=O
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)CCC1(CCCCN1)C2
Reaction time: 1 h

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 6.57 g of 3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one followed by addition of 8.5 ml of triethylsilane and the mixture was stirred for 1 hour. This reaction mixture was poured portionwise in water and after addition of 1N-hydrochloric acid, washed with hexane. The aqueous layer was made basic with 1N-aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was then distilled off. The residue was treated with 7.0 ml of 4N-methanolic HCl to give a solid. This solid was recrystallized from methanolether to provide 5.09 g of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(Cl)cc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1N
Temperature: 0 °C

Procedure:
85.3 g of 2-amino-4-chlorobenzamide obtained in Step (1) was dissolved in 350 ml of pyridine, and to the resulting solution, while maintaining it at 10° to 20° C., there was added dropwise 92 g of phosphorus oxychloride. After being reacted at room temperature for 1 hour, the reaction mixture was poured into ice water. The crystals thus-deposited were collected by filtration, washed with water and dried. Yield: 39 g (51.1%).
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:3][CH3:4])=[CH:7][C:8]=1[CH3:12]
Reactant: CCSc1cccc(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCSc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (2.2 ml) was added to a solution of 1-(ethylthio)-3-methylbenzene (6.6 g) in acetic acid (20 ml) at 0° C. The mixture was stirred at RT for 2 h then the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with DCM. Yield 6.6 g
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:29](=[O:30])[C:23]2[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=2)[C:32]1=[O:31]
Reactant: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-6-methylbenzoxazole (58 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 54 mg (55%). 1H NMR (DMSO) δ 8.31(dd, 1H) 8.16(m, 3H), 7.97(d, 1H), 7.50(d, 1H), 7.43(s, 1H), 7.32(d, 1H), 7.08(d, 1H), 3.73(s, 3H), 2.33(s, 3H). MS 427 m/z (M−H)−.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:20][C:21]=2[F:22])=[NH:15])[CH:10]=[CH:11][CH:12]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[F:22][C:21]1[CH:20]=[CH:19][C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:17][C:16]=1[C:14]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:2]=[O:1])[CH:8]=1)=[NH:15]
Reactant: N=C(Nc1cccc(C2OCCCO2)c1)c1cc(-c2ccccc2)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(Nc1cccc(C=O)c1)c1cc(-c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To acetal (56) (378 mg) in THF (2 mL) was added 1N hydrochloric acid (2 mL) and the reaction mixture stirred at ambient temperature overnight followed by heating to 50° C. for a further 3 hours. The reaction mixture was cooled to 0° C. and neutralised with saturated NaHCO3 solution. The organics were extracted with EtOAc, dried (MgSO4) and the solvent concentrated in vacuo to give the title compound. Yield: 307 mg, 96%; LC-MS tr 1.26 min; HPLC Purity: 71%; MS (ES+) m/z 319 (M+H)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])[CH3:2]
Reactant: CCNc1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(C(=O)C(C)(C)C)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
15.7 g of N-ethyl-2,4-difluoroaniline and 11.0 g of triethylamine are dissolved in 40 ml of toluene. 12.1 g of pivaloyl chloride are added dropwise with cooling, and the mixture is then heated at the boiling point for 1 hour. The mixture is discharged into 100 ml of ice water, and the toluene phase is separated off, washed with 1 N HCl and then with H2O and evaporated in vacuo. 23.7 g of a yellowish oil which crystallizes on standing are obtained. Melting point: 69°-71° (recrystallized from dilute ethanol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 68.7 %

Procedure:
2-Propoxy-4-trifluoromethyl-benzaldehyde (232 mg, 1 mmol) in toluene was reacted with methyl (triphenylphosphoranylidene)acetate (382 mg, 1.14 mmol) at 110° C. overnight. The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography to yield title compound (198 mg, 69%).
Reaction SMILES: [CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([S:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 75 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
Thiophenol (80 mg) was stirred for 45 min with potassium hydride (40 mg) in N,N-dimethylformamide (1 ml) to produce a homogeneous solution of potassium thiophenolate. To this mixture was added 3-benzyl-3-(4-bromophenylsulfonyl)-propionic acid (100 mg) dissolved in N,N-dimethylformamide (1 ml) at room temperature. After stirring for 16 hours at 75° C. the mixture was partitioned between aqueous citric acid and water, giving a product which was purified by preparative TLC to afford 3-benzyl-3-(4-phenylthiophenylsulfonyl)-propionic acid (30 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:10][N:11]([CH2:29][C@@H:30]([NH:38]C(OC(C)(C)C)=O)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=O)(C)(C)C.FC(F)(F)[C:55]([OH:57])=[O:56].[C:60](=[O:78])([O:71][CH2:72][C:73]1[S:77][CH:76]=[N:75][CH:74]=1)OC1C=CC([N+]([O-])=O)=CC=1>ClCCl.C(OCC)(=O)C>[S:77]1[C:73]([CH2:72][O:57][C:55]([NH:38][C@H:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][NH:11][CH2:10][C@@H:9]([NH:8][C:60]([O:71][CH2:72][C:73]2[S:77][CH:76]=[N:75][CH:74]=2)=[O:78])[CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:56])=[CH:74][N:75]=[CH:76]1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reaction time: 1 h
Yield: 30 %

Procedure:
The product from Example 26C (952 mg, 1.35 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (10 mL) at ambient temperature. After stirring for one hour, the mixture was concentrated. The residue was immersed in an aqueous solution of 10% K2CO3 (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and treated with a solution of 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (857 mg, 2.71 mmol, 2.0 eq) by extraction with aqueous NaHCO3] in ethyl acetate (5 mL) at ambient temperature. After stirring for 1 hour, the mixture was washed with aqueous 10% K2CO3 (5×25 mL), brine (25 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with (chloroform:methanol, 98:2) to provide the title compound (0.39, 30%). 1H NMR (CDCl3) δ 8.78 (s, 2H), 7.84 (s, 2H), 7.33-7.04 (m, 10H), 5.00-4.86 (m, 4H), 3.98-3.83 (m, 4H), 2.90-2.50 (m, 9H); MS (ESI+) m/z 566 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]1([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]1([C:13]([F:14])([F:16])[F:15])[CH2:12][O:11]1
Reactant: Cc1ccccc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1CBr
Temperature: 70 °C

Procedure:
To a stirred solution of (R)-2-[2-(2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (37 g, 0.143 mmol) in 500 mL of anhydrous CCl4 at room temperature was added N-bromosuccinimide (26 g, 0.146 mmol). The reaction mixture was heated to 70° C. and the reaction flask was irradiated with a UV light (500 W) for 1 hour. The reaction mixture, after cooling to normal room temperature, was washed with saturated aqueous sodium bicarbonate solution followed by water, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo to give (R)-2-[2-(2-bromomethylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane as a light yellow oil (46.6 g, 81%; ˜85% pure) which was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:42])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[NH:26][C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClC1C=CC=C(C(OO)=[O:51])C=1.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:42])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24]([C:25]1[NH:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1)=[O:51])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCN(CCCCCS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea (0.59 g, 0.001 mol) in methylene chloride (50 mL) cooled to -78° was added, dropwise, a solution of metachloroperbenzoic acid (0.286 g, 0.0017 mol) in methylene chloride (10 mL). The reaction mixture was stirred at -78° for 1 hour and then allowed to warm to ambient temperature. The reaction mixture was then cooled to 0° and then added, dropwise, was a solution of saturated sodium bisulfite. The layers were separated and the organic layer was washed with saturated sodium bisulfite. The layers were separated and the sodium chloride solution dried over magnesium sulfate and concentrated under vacuum. The residue (0.76 g) was chromatographed with 1: 1 hexane-ethyl acetate to give the title compound (0.43 g, 0.00071 mol) as a yellow solid, mp 77°-79°.1H NMR (CDCl3) δ 8.1-7.9(m,1H), 7.6-7.2 (m,10H), 6.9-6.7(m,2H), 6.4(d,1H,J=3.3 Hz), 3.4-3.1(m,6H), 2.0-1.1(m,18H), 0.9 (t,3H,J=6.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])SC1C=CC=CN=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23].C(Br)C(C)C.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[Mg]Br
Reactant: CN(CCC(=O)Sc1ccccn1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CC(C)CBr
Solvent: C1CCOC1
Product: CC(C)CC(=O)CCN(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of S-2-pyridyl 3-(N-t-butoxycarbonyl-N-methylamino)propanethioate (490 mg) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added dropwise a solution of isobutylmagnesium bromide prepared from isobutyl bromide (1.13 g) and magnesium (200 mg) in dry tetrahydrofuran (30 ml), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride (50 ml). The resulting slurry was extracted with diethyl ether (50 ml×2), and the combined extract was dried over magnesium sulfate and concentrated to give 1-(N-t-butoxycarbonyl-N-methylamino)-3-oxo-5-methyl hexane (400 mg) as an oil.