Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH3:14].[OH:10][CH2:9][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.[NH:11]1[C:3]2[CH:2]=[CH:8][CH:7]=[CH:6][C:4]=2[N:5]=[N:12]1
Reactant: C=O
Reactant: Nc1cccc(F)c1
Agent: c1ccc2[nH]nnc2c1
Product: CNc1cccc(F)c1
Product: OCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Fluoro-N-methylaniline was prepared from 3-fluoroaniline using a modified reductive amination. First, 1-hydroxymethylbenzotriazole was prepared by adding 37% aqueous formaldehyde to benzotriazole at 40° C. in a 1:1 ratio, then cooling to room temperature to precipitate the product. After filtration the hydroxymethylbenzotriazole (125 g) was heated to reflux in toluene with 3-fluoroaniline (92.2 g). Water was removed azeotropically using a Dean-Stark trap. After three hours, the mixture was cooled to room temperature, then refrigerated for several hours to complete precipitation. The white crystalline solid was filtered off, yielding 174.2 g (86.6%) of 1-(3-fluoroanilino)methyl)-1H-benzotriazole.
Reaction SMILES: CC[O-].[Na+].[Na].[SH:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1.Cl[CH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[C:28]#[N:29]>C(O)C>[C:28]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[CH2:21][S:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)#[N:29]
Reactant: CCOC(=O)C(C)c1cccc(S)c1
Reactant: N#C[C@@H]1CCCC[C@H]1CCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)c1cccc(SCC2CCCCC2C#N)c1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
Sodium ethylate prepared from sodium (0.23 g) and ethanol (10 ml) was added to ethyl 2-(3-mercaptophenyl)propionate (2.10 g) and the mixture was stirred for a while. Thereto was added trans-2-(chloromethyl)cyclohexanenitrile (1.58 g) and the resulting mixture was refluxed for 5 hours in an oil bath maintained at 100° C. The reaction mixture was evaporated to dryness under reduced pressure and to the residue was added toluene. After removal of the insoluble material by filtration, the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, using chloroform as an eluent, to give ethyl 2-[3-(2-cyanocyclohexylmethylthio)phenyl]propionate (2.6 g) as an oil. IRνmaxfilm cm-1 : 2230 (C≡N), 1720 (C=O). MS m/e: 331 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18][CH3:19].ClN1C(=O)CCC1=O.C[O-].[Na+].CO>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([N:15]=[S:18]([CH3:19])[CH3:17])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(C)=Nc1nc(OCc2ccccc2)ncc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
A 10 mL oven-dried Schlenk flask was charged with 2-(benzyloxy)-5-fluoropyrimidin-4-amine (101 mg, 0.462 mmol), CH2Cl2 (2 mL), and dimethylsulfide (75.0 μL, 1.02 mmol) and was cooled to 0° C. in an ice bath. N-Chlorosuccinimide (122 mg, 0.914 mmol) was added and the resulting mixture was allowed to stir at 0° C. for 45 minutes, and then at room temperature for 30 minutes. A solution of NaOMe in MeOH (25%, 360 μL, 1.35 mmol) was added. After 20 minutes, the reaction was quenched with water (3 mL) and allowed to stir for 1 hour. The crude reaction mixture was then diluted with CH2Cl2 and washed with water (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation and then on high vacuum to give the title compound (120 mg, 93%) as an off white solid: mp 125-129° C.; 1H NMR (300 MHz, DMSO-d6): δ 7.70 (d, J=3.9 Hz, 1H), 7.25-7.44 (m, 5H), 5.21 (s, 2H), 2.75 (s, 6H); MS (ESI) m/z 281.1 (M+H)+. *Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128-4129.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([Cl:16])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OC

Procedure:
A mixture of veratric acid (1.0 g), toluene (10 ml) and thionyl chloride (2 ml) is heated under reflux for one hour, and the reaction mixture is concentrated under reduced pressure. Veratryl chloride thus obtained was dissolved in N,N-dimethylformamide (5 ml). The solution is added dropwise, while stirring under ice-cooling, to a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.96 g), triethylamine (2.2 g) and N,N-dimethylformamide (8 ml) in the course of 3 minutes, followed by stirring for two hours at room temperature. After addition of water (50 ml), the reaction mixture is extracted twice with ethyl acetate (40 ml each portion). The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate:acetone=2:3:1). The oily product thus obtained is dissolved in ethyl acetate (10 ml). To the solution is added a hydrogen chloride-ethanol solution (5N) (1 ml). Resultant precipitates are recrystallized from acetone to afford 1-(3,4-dimethoxybenzoyl)-4 -(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.6 g) as colorless powdery crystals, m.p. 212°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:17]1[O:18][CH:5]([C:4]2[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=2[O:2][CH3:1])[O:6][CH2:16]1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1OC

Procedure:
A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16.0 g, 75 mM), ethylene glycol (64 g, 103 mM), and p-toluenesulfonic acid monohydrate (0.2 g) in benzene (750 ml) is refluxed in a Dean-Stark apparatus for 48 hours. The solution is then poured into water (1 l.). The organic phase is washed with saturated aqueous NaHCO3 (2×20 ml), dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane (2 l.); yield 15.2 g (78.2%); m.p. 74°-76° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([SH:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28]I.[OH-].[K+].CO>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(S)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-2-sulfanyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.6 g), methyl iodide (0.83 mL), potassium hydroxide (0.68 g) and methanol (30 mL) was stirred at room temperature for 3 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 a colorless solid (3.5 g, 95%).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>O1CCCC1>[C:1]([NH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of benzoic acid hydrazide (5.70 g, 0.042 mol) in tetrahydrofuran (75 mL) was added acetophenone (5.5 g, 0.046 mol) followed by concentrated. HCl (3 drops). The reaction was allowed to stir for 12 h at 25° C. during which time the product precipitated as a colorless crystalline solid. The product was filtered, washed with tetrahydrofuran (1×30 mL), diethyl ether (3×60 mL) and pentane (2×60 mL), and the crystalline solids were dried in vacuo (6.65 g, 64%). 1H NMR (CD2Cl2): δ2.35 (s, 3H, CH3), 7.30-8.0 (m, 10H, Ph), 9.0 (br, 1H, NH). All other substrates were prepared in a similar fashion.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CO[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[CH3:26].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=2[CH3:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
A mixture of (3,4-dichlorophenyl)acetonitrile (0.149 mol) in DMF (100 ml) was stirred at 0° C. under N2 flow. Sodium hydride (0.223 mol) was added portionwise. The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of, 2-methoxy-1,3-dimethyl-5-nitrobenzene (0.149 mol) in DMF (100 ml) was added dropwise at 0° C. under N2 flow. The mixture was stirred at RT for 6 hours, then cooled, hydrolized with H2O and with HCl 3N and extracted with EtOAc. The organic layer was separated, washed several times with H2O, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 43.4 g (87%) of (±)-α-(3,4-dichlorophenyl)-2,6-dimethyl-4-nitrobenzeneacetonitrile (interm. 48).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])=[CH:24][C:23]=1[C:22]([F:21])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Yield: 88 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-trifluoromethyl-4-chloro-phenylisocyanate to afford the title compound, yield: 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=O)=[N:10][N:11]=2)[CH:8]=1.Cl.Cl.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][N:34]([C:12]([C:9]3[N:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]4=[N:11][N:10]=3)=[O:14])[CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1nnc2ccc(OC)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nnc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)n2c1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (66 mg, 0.30 mmol) in THF (2.5 mL) was added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (1.6 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.3 mL) under an atmosphere of N2. To this mixture was added 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (266 mg, 0.60 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with a saturated brine solution (3×30 ml) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 2% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2). The obtained residue was dissolved in CH2Cl2 (10 mL) and hexanes (100 mL). The solution was partially concentrated and the resulting solids were collected by filtration to provide (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl) methanone as an off-white solid (80 mg, 56%): mp 146-149° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.0 Hz, 1H), 8.03 (s, 2H), 7.95-7.89 (m, 2H), 7.38 (dd, J=10, 2.5 Hz, 1H), 5.40-5.33 (m, 1H), 4.81-4.73 (m, 1H), 3.85 (s, 3H), 3.39-3.31 (m, 1H, overlaps with H2O), 3.26-3.16 (m, 1H), 3.02-2.93 (m, 1H), 2.03-1.77 (m, 4H); ESI MS m/z 473 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[F:8].CN>>[NH2:19][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(c1ccc(F)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CC(C)(C)OC(=O)NCC(N)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
6.13 g of rac-tert-butyl [2-(3,4-difluorophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-carbamate (Example 53A, purity about 60%, about 9.14 mmol) were initially charged in 13.1 ml of 40% strength aqueous methylamine solution and stirred in a closed vessel at 60° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane:methanol:diethylamine 30:1:0.1; 20:1:0.1). This gave 1.83 g of the title compound (74% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11](C(OC(C)(C)C)=O)[CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][N:10]=1)=[O:4]
Reactant: COC(=O)c1ncc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 50.7 %

Procedure:
(+/−)-5-{tert-Butoxycarbonyl-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butyl]-amino}-pyrimidine-2-carboxylic acid methyl ester (1.498 g impure) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added. This was stirred at room temperature. At 70 min, another 3 mL of trifluoroacetic acid was added. At 90 min, the reaction was concentrated and the material was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (0.620 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.16 (s, 2H) 7.67-7.73 (m, 2H) 7.61-7.66 (m, 2H) 7.56 (d, J=8.2 Hz, 2H) 7.39 (d, J=8.2 Hz, 2H) 4.68 (d, J=5.7 Hz, 1H) 4.46-4.57 (m, 1H) 3.98 (s, 3H) 1.79-1.92 (m, 1H) 1.64-1.79 (m, 2H) 1.05 (d, J=6.2 Hz, 3H) 0.99 (d, J=6.2 Hz, 3H); MS (M+1): 444.3.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3[C:24]([Cl:28])=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 82.2 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (25 mg, 0.0466 mmol) in methanol (1 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo then 5% citric acid solution added. The precipitate was filtered off, washed with water and dried in vacuo to give the titled compound (20 mg).
Reaction SMILES: [CH:1]1C=C(Cl)C=[C:3]([C:8](OO)=O)[CH:2]=1.C(S[C:17]1[N:22]=[C:21]([N:23]2[C:31]3[C:26](=[C:27]([O:32][CH2:33][CH2:34][CH2:35][S:36]([NH2:39])(=[O:38])=[O:37])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH:20]=[CH:19][N:18]=1)CCC.[S:40](=O)(O)[O-:41].[Na+]>C(Cl)Cl>[CH2:1]([C:17]1[N:18]=[CH:19][C:20](=[S:40]=[O:41])[CH:21]([N:23]2[C:31]3[C:26](=[C:27]([O:32][CH2:33][CH2:34][CH2:35][S:36]([NH2:39])(=[O:37])=[O:38])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[N:22]=1)[CH2:2][CH2:3][CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCSc1nccc(-n2ccc3c(OCCCS(N)(=O)=O)cccc32)n1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC1=NC(n2ccc3c(OCCCS(N)(=O)=O)cccc32)C(=S=O)C=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
MCPBA (77%) was added dropwise to 3-[1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid amide (1.317 g, 3.13 mmol) in DCM (20 mL) at 0° C. The reaction mixture was allowed to warm to RT, and stirred for 1 h. Sodium bisulfite (10%) was them added, the mixture extracted with DCM, washed with NaHCO3 solution, water, and brine, dried over sodium sulfate, filtered and the solvent removed in vacuo to yield 3-[1-(2-butyl-sulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid amide (77.5%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.C(#N)C.[CH2:10]([Br:13])[CH:11]=[CH2:12].C(OCC)C>C(O)C>[Br-:13].[CH2:12]([N+:5]1[N:4]=[CH:3][N:2]([NH2:1])[CH:6]=1)[CH:11]=[CH2:10]
Reactant: Nn1cnnc1
Reactant: C=CCBr
Solvent: CCO
Solvent: CC#N
Solvent: CCOCC
Product: C=CC[n+]1cn(N)cn1
Product: [Br-]
Reaction time: 24 h

Procedure:
4-amino-1,2,4-triazole, 10.000 g, 118 mmoles, was dissolved into 200 ml of fresh acetonitrile and stirred vigorously. Allyl bromide, 43.10 g, 356 mmoles, was added slowly to the solution at room temperature. The reaction mixture was protected from light and allowed to stir for five days at ambient temperature, whereupon it was filtered, and transferred to a large round bottomed flask. The solvent and excess allyl bromide were rotary evaporated away leaving a viscous yellow oil. The oil was dissolved in a minimum amount of ethyl alcohol and the resultant clear, yellow solution layered with diethyl ether, and stored at 4° C. for 24 hours, resulting in a large crop of fine needles. The needles were filtered away washed with cold isopropyl alcohol and then cold diethyl ether, transferred to a preweighed Schlenk flask and vacuum dried overnight to leave a fluffy crystalline product of 1-allyl-4-amino-1,2,4-triazolium bromide in decent yield 12.657 g, 62 mmoles. Melting point: 59-62° C.; DSC onset: 130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 67 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 4-fluorobenzonitrile instead of 4-fluoroacetophenone, was converted to the title compound (90 mg, 67%) which was obtained as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCSc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCSc1ncc(C(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]phenylmethyl-malonate (0.66 g, 1.28 mmol), sodium carbonate (1.36 g, 1.28 mmol), ethanol (15 mL) and water (10 mL) was refluxed on a steam bath for 18 hours. The mixture was concentrated to a small volume, some insolubles were filtered, the aqueous layer was washed with diethyl ether and then the aqueous phase was adjusted to pH 3.4 with aqueous hydrochloric acid. The product was extracted into methylene chloride, washed with water, dried and concentrated to give 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-3-phenyl-propionic acid; mp 60°-63° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>C(OCC)(=O)C.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Reaction time: 3 h

Procedure:
A mixture of methyl 2-(2-nitro-4-trifluoromethylphenoxy)benzoate (12.7 g, 0.0373 mol) was dissolved in ethyl acetate (200 ml) and 10% palladium on carbon was added under argon. The mixture was hydrogenated in a parr bottle at 55 psi for three hours. The mixture was diluted with chloroform, filtered through Celite® and the filtrate evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound.