Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].OS(O)(=O)=O.[CH3:42][CH2:43]O>O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:22][C:23]=2[NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:42][CH3:43])=[O:28])=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)O)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2nc(-c3ccccc3)sc2NCCC(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 61 (6 mg) in EtOH (0.2 mL) was added concentrated H2SO4 (20 μL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined org. layers were dried over Na2SO4 and concentrated to dryness. Purification by CC(CH2Cl2/MeOH 97:3) gave 3 mg of the desired product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[C:3]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.B([O-])[O-].[Cl-].[NH4+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:7]([C:5]1[S:6][CH:2]=[C:3]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:4]=1[CH3:9])=[O:8]
Reactant: Cc1c(C=O)sc(Br)c1C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: Cc1c(C2CCCCC2)csc1C=O

Procedure:
5-bromo-3-methyl-4-cyclohexyl-2-formylthiophene (1.5 g, 5.2 mmol), 3-methyl-4-cyclohexylthiophene-2-boryl pinacolate (1.9 g, 6.24 mmol) and Bu4NBr (33 mg, 0.1 mmol) were added to a 100 ml flask. The mixture of solids was evacuated for 2 hours, then dissolved in dry toluene (30 ml) under argon with stirring. Tetrakis(triphenylphosphine)palladium (100 mg, 0.09 mmol) was added and the solution was heated to 95° for 16 hours. Afterwards, an additional aliquot of boronate (0.5 g) and tetrakis(triphenylphosphine)palladium (50 mg) were added. The reaction was checked, after stirring an additional 20 hours, and found to be complete. The mixture was poured into a saturated solution of ammonium chloride, and extracted with toluene (3×20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After the solvent was removed by rotary evaporation. The remaining oil was purified by column chromatography (CH2Cl2:petroleum ether, 2:3) to afford the product 2-formyl-3-methyl-4-cyclohexylthiophene dimer as a yellow solid (1.5 g, 75%). 1H NMR (CDCl3) δ 10.08 (s, 1, CHO), 7.01 (s, 1,thienyl-H), 2.67 (m,1,cyclohexyl methane), 2.65 (s, 3,CH3), 2.52 (m,1,cyclohexyl methane), 2.07 (s, 3,CH3), 1.78 and 1.31 (m, 20, cyclohexyl). 13C NMR (CDCl3) δ 182.5, 148.3, 147.9, 146.5, 140.4, 138.2, 136.7, 128.6, 119.4, 39.7, 38.8, 33.8, 31.3, 27.1, 26.9, 26.3, 25.9, 14.01, 13.3.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([Cl:10])[N:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1([C:19]2[S:20][CH:21]=[C:22]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[N:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CC(C)([O-])C.[K+].O>O1CCCC1>[Cl:1][C:2]1[C:6]([C:7](=[O:8])[CH:24]([C:22]2[N:23]=[C:19]([C:13]3([CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[S:20][CH:21]=2)[P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])=[C:5]([Cl:10])[N:4]([CH3:11])[N:3]=1
Reactant: CCOP(=O)(Cc1csc(C2(C)CCCCC2)n1)OCC
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C(C(=O)c1c(Cl)nn(C)c1Cl)c1csc(C2(C)CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
0.85 g (4 mmols) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride and 1.32 g (4 mmols) of diethyl {2-(1-methylcyclohexan-1-yl)-thiazol-4-yl}methylphosphonate were dissolved in 15 ml of dry tetrahydrofuran, and 1.12 g (10 mmols) of potassium t-butoxide was added thereto at room temperature. The reaction mixture was stirred for 1 hour at room temperature, and 20 ml of water was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified through silica gel column chromatography to obtain 0.4 g of the intended 1-(3,5-dichloro-1-methylpyrazol-4-yl)-2-{2-(1-methylcyclohexan-1-yl)-thiazol-4-yl}-2-diethylphosphonoethanone.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:7]1[CH:8]=[C:9]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(-c2cncs2)cc(-c2ccc(C)cc2F)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cncs3)c2)c(F)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 2′-fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid methyl ester (0.327 g, 1 mmol) in THF (10 mL) was added a solution of LiOH—H2O (1.2 mmol) in H2O (15 mL) at 0° C. The reaction was allowed to warm to room temperature and THF was removed under reduced pressure. The aqueous solution was acidified to pH=2, and the solid was collected by filtration and dried to yield 2′-Fluoro-4′-methyl-5-thiazol-5-yl-biphenyl-3-carboxylic acid as a white solid (75%), MS (M+H)=314.
Reaction SMILES: ClC1C=CC=CC=1N1C(=O)C2C3C=CC=CC=3NC(=O)C=2N1.ClC1C=C(N2C(=O)C3C4C=CC=CC=4NC(=O)C=3N2)C=CC=1.ClC1C=CC(N2C(=O)C3C4C=CC=CC=4NC(=O)C=3N2)=CC=1.COC1C=CC(N2C(=O)C3C4C=CC=CC=4NC(=O)C=3N2)=CC=1.[Cl:90][C:91]1[CH:92]=[CH:93][C:94]2[C:95]3[C:104](=[O:105])[N:103]([C:106]4[CH:111]=[CH:110][C:109](OC)=[CH:108][CH:107]=4)[NH:102][C:96]=3[C:97](=[O:101])[NH:98][C:99]=2[CH:100]=1>>[Cl:90][C:91]1[CH:92]=[CH:93][C:94]2[C:95]3[C:104](=[O:105])[N:103]([C:106]4[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=4)[NH:102][C:96]=3[C:97](=[O:101])[NH:98][C:99]=2[CH:100]=1
Reactant: COc1ccc(-n2[nH]c3c(=O)[nH]c4cc(Cl)ccc4c3c2=O)cc1
Agent: COc1ccc(-n2[nH]c3c(=O)[nH]c4ccccc4c3c2=O)cc1
Agent: O=c1[nH]c2ccccc2c2c(=O)n(-c3ccc(Cl)cc3)[nH]c12
Agent: O=c1[nH]c2ccccc2c2c(=O)n(-c3cccc(Cl)c3)[nH]c12
Product: O=c1[nH]c2cc(Cl)ccc2c2c(=O)n(-c3ccccc3)[nH]c12

Procedure:
2-(2-chlorophenyl)-3,5-dihydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione; 2-(3-chlorophenyl)-3,5-dihydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione; 2-(4-chlorophenyl)-3,5-dihydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione; 3,5-dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)dione; 7-chloro-3,5-dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione; and salts and prodrugs thereof.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[OH-].[NH4+]>[NH2:11][C:3]1[C:4](=[O:10])[N:5]([CH3:9])[C:6](=[O:8])[NH:7][C:2]=1[NH2:1]
Reactant: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Cn1c(=O)[nH]c(N)c(N)c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione in ammonium hydroxide (100 mL) was added sodium hydrosulfite (6.8 g, 39.1 mmol) in small portions at 70° C., the mixture was stirred at 70° C. for 1 h. The mixture was concentrated and ice-water was added. The slurry was filtered and the filter cake was washed with water and ethanol and dried under vacuum to give 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione (2.0 g, 30.1% yield over two steps) as yellow solid. LCMS MH+ 157.
Reaction SMILES: CN(C=O)C.[Na].[CH2:7]([SH:9])[CH3:8].[CH3:10][NH:11][C:12]1[C:17]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=2Cl)=[O:20])=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[CH:14][N:13]=1.C1COCC1>O>[CH3:10][NH:11][C:12]1[C:17]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=2[S:9][CH2:7][CH3:8])=[O:20])=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[CH:14][N:13]=1
Reactant: CCS
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cc(Cl)nnc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nnc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
6 ml of a DMF solution of 342 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 1.19 g of 3,6-dichloropyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 2 ml of DMF and 2 ml of THF under ice cooling, then the mixture was heated to room temperature, and stirred for 1 hour. The mixture was allowed to stand overnight, then water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.04 g of 6-chloro-3-ethylsulfanylpyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 6-chloro-3-ethylsulfanylpyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(Cc2ccc3ccccc3c2)CCO1)Nc1ccc(Cl)cc1
Yield: 34.2 %

Procedure:
Example 23 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 2-(bromomethyl)naphthalene (0.009 g) to give the title compound (0.0052 g). LC-MS (System A): Rt 2.81 mins, Mass Spectrum m/z 410 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C(=O)C2CC(C)CCC=2N(C2C(C)=C(C([O-])=O)C(C3C=CC=CC=3)=CC=2)C=1)CCC>>[CH2:1]([C:5]1[CH:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CNC2=C(CC(C)CC2)C1OCc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: CCCCc1cn(-c2ccc(-c3ccccc3)c(C(=O)[O-])c2C)c2c(c1=O)CC(C)CC2
Product: CCCCC1=CNC2=C(CC(C)CC2)C1OCc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Starting with product B of Example 32 and proceeding under the same conditions as in a), the product A of Example 32 was reacted to obtain the expected product.
Reaction SMILES: ClC(Cl)(Cl)F.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:12]F.[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[Na+]>C(#N)C>[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[F:12][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: FF
Reactant: c1ccncc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Solvent: CC#N
Product: F[n+]1ccccc1
Temperature: -40 °C

Procedure:
To a 50 ml trichlorofluoromethane solution containing 1.0 g (12.6 m moles) of pyridine a mixed gas of fluorine and nitrogen in a volumetric ratio of 1:9 was introduced at a rate of 30 ml/min. at -78° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 34.8 mmoles. Subsequent to the fluorine introduction, 20 ml of anhydrous acetonitrile and 2.2 g (12.8 mmoles) of sodium trifluoro-methanesulfonate as a XM reactant were added to the reaction solution after which the temperature of the solution was raised to -40° C., while removing the solvent with the aid of an aspirator. The solvent, after filtering sodium fluoride formed as a byproduct, was distilled off and the resultant residue was recrystallized from THF to give 1.75 g (yield: 67%) of N-fluoropyridinium trifluoromethanesulfonate, the physical properties of which are shown in Table 6.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:17][C:16]([C@@H:15]1[CH2:14][O:13][CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:18]
Reactant: CO
Reactant: O=C(O)[C@@H]1COCN1C(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1COCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic acid 9 (1.75 g, 6.96 mmol) in anhydrous methanol (15 mL) was added thionyl chloride (1.02 mL, 13.9 mmol) at 0° C. After 30 minutes, the ice/water bath was removed and the reaction mixture continued to be stirred at room temperature for 3.5 hours. The reaction was quenched by addition of saturated sodium bicarbonate and diluted with dichloromethane (100 mL) and water (50 mL). The mixture was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (Hexanes/AcOEt, 1.5:1) to give (s)-(−)-3-(Benzyloxycarbonyl)-4-oxazolidinecarboxylic methyl ester 10 as colorless oil (1.84 g, y=99%). 1H NMR (400 Hz, CDCl3): the compound appears as a pair of distinct rotomers. δ 7.35 (bs, 5H), 5.22-4.99 (m, 4H), 4.53-4.45 (m, 1H), 4.22-4.09 (m, 2H), 3.76 (s, 1.5H), 3.65 (s, 1.5H); MS (m/z). found 288.0 (M+Na)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:19]1([C:18]2[O:25][C:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][CH:10]=3)=[N:14][N:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4ccccc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 3.17 g of benzoyl chloride was added. Temperature was elevated to 100° C., and stirring was conducted for 2 hours under flux. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with adsorption purification (carrier: NH silica gel, eluting solution: chloroform) to obtain 6.11 g (yield 91%) of PhpyOXDPh. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.23-8.26 ppm (3H), 8.14-8.17 ppm (2H), 7.90-7.99 ppm (2H), 7.48-7.58 ppm (6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].N1C=CC=CC=1.[SH:15][CH2:16][C:17]#[N:18]>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:15][CH2:16][C:17]#[N:18])=[O:7]
Reactant: N#CCS
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CCSC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To an ice cold solution of furoyl chloride (4.0 ml; 0.04 mol) in ether (100 ml) is added dropwise a freshly prepared solution of pyridine (3.24 ml; 0.04 mol) in 1 N mercaptoacetonitrile (40 ml; 0.04 mol). After the addition is completed, the mixture is allowed to stir at room temperature overnight. The reaction mixture is then washed with water, saturated sodium bicarbonate solution, saturated brine, dried over sodium sulfate, and is concentrated in vacuo. The residue (6.0 g) is filtered through a 25 g column of silica gel and eluted with methylene chloride. The methylene chloride eluent is diluted with hexane, cooled and filtered to yield 4.3 g (64%) of title product, an orange solid, melting point 76°-78° C. Recrystallization from methylene chloride-hexane affords 3.7 g product, as a pale orange solid, melting point 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:34])[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:30][CH2:29][C:24]4([NH:28][CH2:27][CH2:26][CH2:25]4)[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:33])[CH3:32])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43].C(O)(C(F)(F)F)=O>ClCCl.O.CO>[C:42]([N:28]1[C:24]2([CH2:29][CH2:30][C@@H:22]([C:20]([NH:19][C@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([N:11]3[CH2:12][CH2:13][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[C:9]([CH3:32])([CH3:33])[CH2:10]3)=[O:31])=[O:21])[CH2:23]2)[CH2:25][CH2:26][CH2:27]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC2(CCCN2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCC12CC[C@@H](C(=O)N[C@@H](C(=O)N1CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C1)C(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of (7R)-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1-azaspiro[4.4]nonane-7-carboxamide (from experiment 9, step C, peak 3, 13 mg, 0.027 mmol) in dichloromethane (0.5 mL) was added triethylamine (7.39 μL, 0.053 mmol) and acetic anhydride (4.06 mg, 0.040 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The peak corresponding to the desired product was collected, concentrated and freeze dried to give (7R)-1-acetyl-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1-azaspiro[4.4]nonane-7-carboxamide (6 mg, 0.011 mmol, 42.5% yield) as a solid. Anal. RP-HPLC: Retention time=3.44 min (YMC S5 ODS 4.6×50 mm; gradient solvent A: 10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B: 90% MeOH, 10% H2O, 0.2% H3PO4). Purity: >95%; MS (ESI) m/z 532 M+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](N(OC)C)=[O:38])[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:44]([Mg]Br)[CH3:45].Cl>O1CCCC1>[CH3:28][C:26]1[N:27]=[C:19]2[N:18]([C@H:29]3[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37](=[O:38])[CH2:44][CH3:45])[CH2:33][CH2:34]3)[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=1
Reactant: CC[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2nc(C)nn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)CC)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.3 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesium bromide (3.0 M diethyl ether solution, 0.52 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 100%).
Reaction SMILES: [Mg].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:17][C:18]([CH3:20])=[O:19].[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:18]([OH:19])([CH3:20])[CH3:17])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 99.2 %

Procedure:
16.10 g (0.659 mol) of magnesium turnings was treated under argon in 450 ml of diethyl ether with 150 g (0.507 mol) of 3,5-bis-trifluoromethylbromobenzene at 33° C. for 1.5 h. Then a solution of 56.0 ml (0.763 mol) of acetone in 100 ml of diethylether was added at 16-22° C. under stirring. 110 ml of 25% Ammonium chloride solution was added at ca. 20° C. after 1.5 h to the reaction mixture and the suspension stirred for 1 h. The organic phase was dried over sodium sulfate, rotary evaporated and finally dried at 35° C. and 10 mbar, affording 136.96 g of 2-(3,5-bis-trifluoromethyl-phenyl)-propan-2-ol, which had a 99.2% purity according to GC analysis. Light yellow crystals, m.p. 59-60° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCCCC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2551.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:32]
Reactant: O=C(Cl)Cc1ccccc1I
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Cc1ccccc1I)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 532 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and o-iodophenylacetyl chloride.