Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19].N1C=CC=CC=1>C(O)C>[CH3:16][NH:17][C:18](=[O:19])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CN=C=O
Solvent: CCO
Solvent: c1ccncc1
Product: CNC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.5 g), methyl isocyanate (0.48 ml) and pyridine (40 ml) was stirred at room temperature for 4.5 hours, and ethanol (5 ml) was added. The solvent was then distilled off under reduced pressure. To the oily residue was added 10% HCl, and the thus-produced crystals were collected by filtration, washed with water, dried and recrystallized from aqueous dimethylformamide to give 6-[4-(3-methylureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH2:7][NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1cc(Cl)ccc1-c1cnsn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc(Cl)ccc2-c2cnsn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzaldehyde (0.155 g, 0.69 mmol), 4-methoxybenzylamine (0.09 mL, 0.69 mmol) and acetic acid (0.05 mL, 0.83 mmol) in 1,2-dichloroethane (5.2 mL) was added sodium triacetoxyborohydride (0.731 g, 3.45 mmol). The solution was stirred at ambient temperature for 16 h then partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4) and reduced in vacuo. The residue was purified by automated preparative chromatography on silica (eluting with 5% CH2Cl2/EtOAc/hexanes gradient, 5–50% EtOAc). N-[5-Chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-N-(4-methoxybenzyl)amine was isolated as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 2H), 3.81 (s, 3H), 3.82 (s, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 8.84 (s,1H); MS m/z=346.5.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10]([CH3:14])=[CH:11]CO.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH:9]=[C:10]([CH3:14])[CH3:11])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C/C=C(/C)C(=O)OC
Reactant: CC(C)=CCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC=C(C)C

Procedure:
A mixture of 19.6 g. of methyl angelate, 22.2 g. of 3-methyl-2-butenyl alcohol, 100 ml. of toluene and 1.6 g. of dioctyltin laurate was placed in a glass flask which was equipped with a Soxhlet extractor filled with molecular sieve 4A on the top and a reflux cooler. The mixture was heated under reflux while returning the refluxed liquid through the molecular sieve 4A to the flask. The mixture obtained from the heating for a total of 26 hours was subjected to single distillation to give 24.24 g. of a distillate boiling at 102°-105° C. (25 mmHg).
Reaction SMILES: C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.[CH3:16][C:17]([CH3:30])([CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][OH:19].O.C(=O)(O)[O-].[Na+]>ClCCl>[OH:29][CH:20]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]([CH3:16])([CH3:30])[CH:18]=[O:19]
Reactant: CC(C)(CO)C(O)CCc1ccccc1
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C=O)C(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
DMN-AZADO (2.00 mg, 0.012 mmol) and diacetoxyiodobenzene (117 mg, 0.362 mmol) were added to a dichloromethane solution (0.24 ml) of 2,2-dimethyl-5-phenylpentane-1,3-diol (50.2 mg, 0.241 mmol), and the mixture was stirred at room temperature for 15 min. This was followed by addition of saturated sodium bicarbonate water (1 ml) and a sodium thiosulfate solution (1 ml), and extraction with diethyl ether. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 3-hydroxy-2,2-dimethyl-5-phenylpentanal (49.2 mg, 92%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1ccoc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccoc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-furaldehyde (0.5 g, 5.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.103 g, 87%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.[SH:21][CH2:22][CH2:23]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7]2([CH2:8][N:9]3[CH:13]=[N:12][CH:11]=[N:10]3)[S:21][CH2:22][CH2:23][O:14]2)=[CH:5][CH:6]=1
Reactant: OCCS
Reactant: O=C(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(C3(Cn4cncn4)OCCS3)cc2)cc1
Yield: 41.6 %

Procedure:
To a slurry of 13.1 g of 1-[1,1'biphenyl]-4-yl-2-(1H-1,2,4-triazol-1-yl)ethanone in 175 ml dry toluene and 70 ml 1-butanol was added, with stirring, 7.8 g 2-mercaptoethanol and 12.3 g p-toluenesulfonic acid. The resultant thickened slurry was refluxed under a Dean-Stark [trademark] trap for 72 hours. At this point, no further water was collected. After the reaction was allowed to cool, the solid was filtered out, slurried in dichloromethane and shaken with 10% aqueous sodium hydroxide and once with water. The organic layer was dried and evaporated to leave an oil which solidified on high-vacuum pumping. This solid was triturated with petroleum ether to give 6.7 g of 1-[(2-[1,1'-biphenyl]-4-yl-1,3-oxathiolan-2-yl)methyl]-1H-1,2,4-triazole, the product of this reaction. The melting point of this compound was 85°-90° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[O:23][CH3:24])(=O)=O)=CC=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>O1CCOCC1>[CH:26]([NH:29][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: COc1cc([N+](=O)[O-])ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1OCCNC(C)C
Temperature: 73 °C
Reaction time: 9 h
Yield: 68.8 %

Procedure:
2-(2-Methoxy-4-nitrophenoxy)ethyl p-toluenesulfonate (19.5 g) and 70% aqueous isopropylamine solution (15.7 g) were dissolved into dioxane (100 ml) and the mixture was stirred for 9 hours at 73° C. After being concentrated under vacuum, the reaction mixture was dissolved into 2N HCl (50 ml) and washed with ethyl acetate (50 ml) two times. Resulting aqueous layer was neutralized with 2N sodium hydroxide (50 ml) and then extracted with ethyl acetate (100 ml). The organic layer was dehydrated with anhydrous sodium sulfate and then concentrated under vacuum to almost dryness to obtain N-isopropyl-2-(2-methoxy-4-nitrophenoxy)ethylamine (9.29 g) as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2c(-c3ccccc3)csc2n1
Temperature: 50 °C

Procedure:
2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (2 g, 7.112 mmol), morpholine (0.9294 g, 10.67 mmol) and triethylamine (1.454 g, 2.00 mL, 14.22 mmol) were combined in ethanol (23.7 g, 30 mL, 493 mmol) and heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. The solvent volume was reduced by half and the resulting precipitate filtered off and washed with water and dried in vacuo overnight at 40° C. to afford 4-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)morpholine as a white solid.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[Y:6].[O-2:7].[Y+3].[O-2].[O-2].[Y+3]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Y+3:6].[O-2:7].[Y+3:6].[O-2:2].[O-2:2].[Y+3:6]
Reactant: [Y]
Reactant: O=P(O)(O)O
Agent: [O-2]
Agent: [Y+3]
Product: O=P([O-])([O-])[O-]

Procedure:
Generally, a 75 to 85 weight percent solution of phosphoric acid is added to the slurry over a period of about 15 minutes to about 90 minutes as the slurry is continuously agitated and maintained at a temperature that typically ranges between about 20° C. and about 70° C. The amount of the phosphoric acid added to the slurry is usually about 1.5 molar percent less than the amount of the yttrium compound present in the slurry. When the yttrium compound used is yttrium oxide, the reaction takes place to form yttrium phosphate, minor amounts of yttrium oxide, minor amounts of surface adsorbed phosphoric acid and water. The yttrium phosphate formed comprises approximately 95.5 percent of the solids portion in the slurry.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]=NO.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)cc1Cl
Product: O=C1Nc2c(Cl)cc(F)cc2C1=O
Reaction time: 1 h

Procedure:
N-(2-Chloro-4-fluorophenyl)-2-(hydroxyimino)-acetamide (5.4 g, 24.9 mmol) was added portionwise to conc. sulfuric acid (70 mL) at 70° C. The mixture was stirred for 1 h, poured onto ice-water (200 mL) and filtered. The filter-cake was dried in vacuo to give crude 7-chloro-5-fluoroindole-2,3-dione which was used immediately without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([OH:28])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20]CCCCCC.ON1C(=O)CCC1=O.CCN(C(C)C)C(C)C.C(Cl)(=O)CCCCCCCCCCC>C1COCC1>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([OH:28])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)O
Temperature: 0 °C

Procedure:
It was prepared exactly in a similar way as in the preparation of oleic acid N-hydroxy succinimide. In brief, 1.33 gr. of N-hydroxy succinimide (11.56 mmole, 1.5 eq.) and DIEA (1.35 ml) were dissolved in 50.0 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. Then, Lauroyl chloride (1.8 ml, 99% Sigma, 7.8 mmole, 1.0 eq.) dissolved in 50 ml of anhydrous THF was added dropwise during 1 h. The mixture was gently stirred for 2 h at 0° C. and over-night at room temperature. The resulting precipitate were discarded by filtration and the filtrate was evaporated under reduced pressure, redissolved in small amount of DCM and purified over silica-gel column using DCM as eluent. Fractions containing the product were combined and solvent was removed under reduced pressure. The resulting white solid was dried in vacuum over NaOH-pellets.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.S(Cl)([Cl:18])=O>>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:18])=[O:8])[O:2]1
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
5 g (0.23 mole) of 4,5-methylenedioxy-2-nitrobenzoic acid are suspended in 50 ml of thionyl chloride and refluxed for 2 hours. The solution obtained is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of 50 ml of petroleum ether. The crystals are spun and recrystallized in ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][N:22]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Product: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
A mixture of 1.0 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene and 4.0 g of 2-amino-5-(trifluoromethyl)pyridine was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and subjected to silica gel chromatography, which afforded 0.14 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)-2-pyridylamino)propyloxy)benzene (12% yield), nD25.0 1.5525.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[F:27][C:24]([F:25])([F:26])[CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=3[CH:11]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water affored as residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1[C:24]([O:25][C:26](Cl)=[O:27])=[CH:23][CH:22]=[C:21]([Cl:29])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:29][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]([N:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:18])[NH:9]2)=[O:27])=[CH:19][CH:20]=1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C1NN(C(=O)Oc2ccc(Cl)cc2)C(c2ccccc2)C1c1ccccc1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A solution of 4,5-diphenyl-3-pyrazolidinone (1.25 g, 5.26 mmol) in 50 mL CHCl3 was treated with a solution of 4-chlorophenylchloroformate (1.0 g, 5.26 mmol) in 10 mL CHCl3 and stirred overnight. The solvent was removed in vacuo and the residue recrystallized from EtOAc:hexane to give 1.6 g (58%) white solid: mp 175°-7° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:26]=[CH:25][C:24]=1[C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[N:40][CH:39]=1
Reactant: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H21F4N5O2S, 495.14; m/z found, 496.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.63-8.61 (d, J=1.4, 2H), 8.40-8.37 (d, J=1.4, 1H), 8.10-8.05 (m, 1H), 7.70-7.67 (d, J=8.0, 1H), 7.67-7.63 (m, 1H), 7.46-7.30 (m, 2H), 2.86 (s, 3H), 3.83-2.53 (br m, 8H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH:3]([NH:10]S(C(C)(C)C)=O)[C:4]1[O:5][C:6]([CH3:9])=[N:7][N:8]=1.Cl.O1CCOCC1>CO>[CH3:1][C:2]([CH3:18])([CH3:17])[CH:3]([C:4]1[O:5][C:6]([CH3:9])=[N:7][N:8]=1)[NH2:10]
Reactant: Cc1nnc(C(NS(=O)C(C)(C)C)C(C)(C)C)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nnc(C(N)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of N-[2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-2-methyl-propane-2-sulfinamide (example 174a, 462 mg, 1.69 mmol) in methanol (10 ml) was added a 4M solution of hydrochloric acid in dioxane (845 μl, 3.38 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was then concentrated in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (165 mg, 58%). MS (ESI, m/z): 170.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C:14]=3[C@@H:13]1[CH2:12][CH2:11][C:10]2=[O:28].[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C:14]=3[C@@H:13]1[CH2:12][CH2:11][CH:10]2[OH:28]
Reactant: COCCOCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2O
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
To the ketone 50 (58.0 g, 0.145 mol) in methyl alcohol (1 L) was added by portion NaBH4 (5.5 g, 0.145 mol) at 0° C. The solution was stirred for 20 min then quenched with saturated aqueous NH4Cl solution (500 mL); and methanol was evaporated. The residue was diluted with ethyl acetate (1 L) and washed with brine, dried over magnesium sulfate and rotary evaporated to give 55.6 g (95%) of crude product 51.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:10][CH:9]=1)[CH3:2].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([CH3:48])[CH:47]=1)[C:42](Cl)=[O:43]>O>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[C:42](=[O:43])[C:41]2[CH:45]=[C:46]([CH3:48])[CH:47]=[C:39]([CH3:38])[CH:40]=2)=[CH:12][CH:13]=1)[CH3:24]
Reactant: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 2.0 g. (6.2 mmol.) of the hydrochloride salt of 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran in 10 ml. of nitrobenzene was added a solution of 1.84 g. (13.9 mmol.) of aluminum chloride in 20 ml. of nitrobenzene. The solution was cooled to 0° and 1.24 g. (7.4 mmol.) of 3,5-dimethylbenzoyl chloride was added. The reaction mixture was stirred at 0° for 30 minutes then at 25° for 1.5 hours, after which time it was poured into water and the nitrobenzene was removed by steam distillation. The aqueous solution was extracted with ether, made alkaline with aqueous sodium carbonate solution and again extracted with ether. The etheral solution was dried (MgSO4) and concentrated to give the title compound.