Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[N:13][CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:28].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:28])=[N:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CNc1cnc(-c2cccc(C#N)c2)nn1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CNc1cnc(-c2cccc(C(N)=O)c2)nn1)c1ccc(F)cc1
Reaction time: 24 h
Yield: 7.8 %

Procedure:
To a solution of 3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile (220 mg, 0.60 mmol) in DMSO (3.0 mL) was added K2CO3 (300 mg, 2.2 mmol) and 30% hydrogen peroxide (0.60 mL, 7.5 mmol). The mixture was stirred 24 h and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and evaporated to dryness in vacuo. Purification using silica gel chromatography (0-100% EtOAc/hexanes) gave the desired product (17 mg), m/z=366.1 [M+H].
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[CH:20]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1>CCO>[CH:20]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=4[N:6]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1
Reactant: C1CN(C2CC2)CCN1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Yield: 52.6 %

Procedure:
To a solution of 2-chlorobenzooxazole-5-carbonitrile (1.69 g, 9.5 mmol) in EtOH (34 mL) was added Et3N (4.8 g, 47.5 mmol), followed by 1-cyclopropylpiperazine (1.44 g, 11.4 mmol) and the mixture was heated at reflux for 12 h. Then the volatiles were evaporated to remove EtOH and water (120 mL) was added. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 10% ethyl acetate in petroleum ether, 0.1% NH4OH added) to give 1.34 g (53%) of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1.C([Li])CCC.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[S:35][C:34]1=[O:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[S:35][C:34]1([C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[CH:18]=1)[OH:64])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 6-(5-bromo-2-chlorobenzyl)-2,3-dihydrobenzo[b][1,4]dioxine (124, 384 mg, 1.1 mmol) in tetrahydrofuran (5 mL) at −78° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (2.5 M in hexane, 0.45 mL, 1.1 mmol), and the mixture was stirred for 0.5 h at the same temperature. Then a solution of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (123, 300 mg, 0.54 mmol, This compound was synthesized by reference to H. Driguez and B. Henrissat, Tetrahedron Lett. 1981, 22, 5061-5062, Kakinuma, H., et al., J. Med. Chem. 2010, 53, 3247-3261) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred for 15 min at the same temperature. The reaction mixture was quenched by addition of saturated ammonium chloride solution. After complete addition, the solution was gradually raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (silica gel, 3 to 30% tetrahydrofuran in hexane) to yield (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)phenyl)tetrahydro-2H-thiopyran-2-ol (125, 416 mg, 0.51 mmol, 95%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 3.63 g (20 mmol) sample of 3-chloro-5-trifluoromethylpyridine dissolved in 15 mL of DMF and cooled to 0° C. was added 960 mg of NaH (60%), 2.07 mL of benzyl alcohol was added slowly. The reaction mixture was stirred for 2 hours at 40° C. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and a brine solution. The organic layer was then dried over MgSO4. The resulting crude material was purified by flash chromatography on silica gel to give the title product. MS (DCI/NH3) m/e 154 (M+H)+. 1H NMR (CDCl3, 300 MHz) d: 8.56 (d, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 7.51 (dd, J=1, 0.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[C:20]([Cl:27])=[CH:19][N:18]=1>C(O)(C)C>[Cl:27][C:20]1[C:21]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:2]=3[Cl:1])[CH2:10][CH2:9]2)=[C:22]([N+:23]([O-:25])=[O:24])[C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3c(F)cccc3Cl)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min—400, 402, 404 [(M+H)+, Cl2 isotopic pattern].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:17]3=[C:18]4[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][CH:10]=[C:9]4[CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30].ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-]>CO>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29]([C:4]1[CH:5]=[C:6]2[C:17]3=[C:18]4[C:13]([CH:12]=[CH:11][CH:10]=[C:9]4[CH:8]=[CH:7]2)=[CH:14][CH:15]=[C:16]3[C:3]=1[O:2][CH3:1])=[O:30]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc2ccc3cccc4ccc1c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COc1c(C(=O)c2ccc3ccccc3c2)cc2ccc3cccc4ccc1c2c34
Reaction time: 2 h

Procedure:
Methoxy pyrene (23.20 g, 0.1 mol), 2-naphthoyl chloride (56.8 g, 0.333 mol), and 1,2-dichloroethane (325 g) were put in a flask. Then, aluminum chloride (29.4 g, 0.12 mol) was slowly added to the solution at ambient temperature, and the mixture was agitated for 2 hours. When the reaction was terminated, a precipitate obtained by adding methanol thereto was filtered, obtaining 2-naphthoyl methoxy pyrene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[CH2:6][NH2:7].[C:15](Cl)(Cl)=[S:16].C(N(CC)CC)C>C(OCC)(=O)C>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: COCOc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1ccc(CN=C=S)cc1OC

Procedure:
A solution of 3-methoxy-4-methoxymethoxybenzylamine (5.3 g, 26.9 mmol) in ethyl acetate (50 mL) was added, via an addition funnel) to a solution of thiophosgene (2.15 mL, 28.2 mmol) and triethylamine (7.87 mL, 56.5 mmol) in ethyl acetate (30 mL) at 0° C. The resultant solution was stirred at ambient temperature overnight. The solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexanes (1/9 to 3/7) to give the product, 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene, as a waxy tan solid, 4.9 g (76%). 1H NMR (CDCl3): δ 3.51 (s, 3H), 3.91 (s, 3H), 4.64 (s, 2H), 5.23 (s, 2H), 6.83 (m, 2H) and 7.14 (d, J=8 Hz).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.038 g, 16%). MS (ISN) 480.1 [(M−H)−]; mp 289.5° C.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19]([CH3:21])=[O:20])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:34])(=O)=O>C(#N)C>[CH3:21][S:19]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[NH:8][C:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7])(=[NH:34])=[O:20]
Reactant: COc1cc(NC(=O)N2CCCC2)c(S(C)=O)cc1OC
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: CC#N
Product: COc1cc(NC(=O)N2CCCC2)c(S(C)(=N)=O)cc1OC

Procedure:
A reaction mixture containing 51.7 g. of N-pyrrolidinylcarbonyl-2-methylsulfinyl-4,5-dimethoxyaniline and 0.48 mole of O-mesitylenesulfonylhydroxylamine (prepared by the procedure of Tamura et al., J. Org. Chem. 38, 1239, 1973) and 1 l. of acetonitrile was stirred for 48 hours at ambient temperature. The reaction was then concentrated at reduced pressure and the resulting residue dissolved in 2 l. of methylene chloride. The methylene chloride solution was shaken with 1500 ml. of cold water containing 200 ml. of 14 N aqueous ammonium hydroxide. The organic layer was separated, washed with water, and dried. Evaporation of the methylene chloride solvent in vacuo yielded a residue comprising S-methyl-S-[2-(pyrrolidinylcarbonylamino)-4,5-dimethoxyphenyl]sulfoximine. Crystallization of the residue from a chloroform-cyclo hexane solvent mixture yielded 38 g. of crystalline material (70 percent yield) melting at 312°-314° C.
Reaction SMILES: O.S(O)(O)(=O)=O.[CH3:7][S:8][C:9](=[NH:11])[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:7][S:8][C:9](=[NH:10])[NH:11][S:20]([CH2:19][Cl:18])(=[O:22])=[O:21]
Reactant: CSC(=N)N
Reactant: O=S(=O)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSC(=N)NS(=O)(=O)CCl
Yield: 90.6 %

Procedure:
Water (250 ml) is added with stirring to a slurry of S-methylisothiourea sulfate (77.3 g, 0.556 mol) and sodium carbonate (273 g, 2.58 mol) in methylene chloride (1100 ml). Chloromethanesulfonyl chloride (85% pure, 94.8 g, 0.542 mol) is then added slowly with stirring at such a rate as to maintain gentle reflux of the solvent. The mixture is then stirred at room temperature for 16 hr, and the organic solution is decanted from the inorganic residue. The residue is washed with additional methylene chloride (500 ml), and the combined organic solutions are dried with magnesium sulfate, filtered, and concentrated to leave crude II as a yellow oil (99.5 g, 90%). This crude material is adequate for preparing the thiadiazole compounds of the invention (e.g., see Example 4, below). Purification by chromatography on silica gel (2.5% ethyl ether in methylene chloride as eluant) provides the title compound as a colorless solid, mp 60°-62° C. (72 g, 65%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.O>CS(C)=O>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12]
Reactant: C=C(c1cc(F)ccc1O)n1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(c1cc(F)ccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 55 °C
Reaction time: 0.83 h
Yield: 68 %

Procedure:
85% Potassium hydroxide powder (36.0 g, 0.545 mole) was suspended in dimethyl sulfoxide (500 g) and stirred at 55° C. for 50 minutes. After cooling to 25° C., 1-[1-(2-hydroxy-5-fluorophenyl)vinyl]-1H-imidazole (90.0 g, 0.441 mole) was added and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichlorobenzyl chloride (94.5 g, 0.483 mole) was added dropwise over 1 hour and the mixture was stirred for 2 hours. Water (680 ml) was added dropwise over 25 minutes to the reaction mixture with stirring and then stirring was continued for additional 1 hour. The precipitated crystals were filtered off and washed with water (135 ml×5) and n-hexane (135 ml×3). The resulting crude crystals were recrystallized from n-hexane/ethyl acetate to obtain the title compound (109 g, 68.1%), m.p. 118°-120° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: ClCCCCBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCl

Procedure:
Using 5 g of of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 120 ml of methylisobutylketone, 3.5 g of potassium carbonate, and 2.9 ml of 1-bromo-4-chlorobutane, a reaction similar to that conducted in Example 106 was carried out. As a result, 5.79 g of N-(trans-4-methylcyclohexyl)-4-(4-chlorobutoxy ) - 3 -methoxycinnamamide ( a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=2)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)c(F)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (4.08 g, 12.5 mmol) and phosphoryl chloride (40 mL) according to the general procedure I. Obtained as a yellow solid (4.26 g, 99%). MS (EI) 344.0 [(M)+]; mp 41° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 738.0 [(M+H)+]
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(NC(C)C)(C)C.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>ClCCl>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: OCCc1cccs1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COCCOCOCCc1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
15.0 g of 2-thiopheneethanol was dissolved in 350 mL of dichloromethane, and 30.2 g of diisopropylamine was added thereto. The resulting mixture was cooled to 0° C. and 17.5 g of 2-methoxyethoxymethyl chloride was added thereto. The resulting mixture was stirred for 2 hours and heated to reflux for 2 hours. The reaction product solution was cooled and concentrated by evaporation under reduced pressure. To the residue, 200 mL of water and 250 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.5 g (yield of 85%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.ClC1C=C(C=CC=1)C(OO)=[O:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:37])=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c(C)cc[n+]([O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 42.8 %

Procedure:
A solution of 7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (9 mg) and m-chloroperoxybenzoic acid (6 mg) CHCl3 (2 mL) was heated to reflux for 2 hours. Concentration and purification (SiO2, 80:20:1 CH2Cl2 /MeOH/NH4OH) gave 4 mg of the title compound as a solid. 1H NMR (300 MHz, CD3OD) δ 8.07 (d, 1H, J=6 Hz), 7.60-7.43 (m, 4H), 7.19, (d, 1 H, J=6 Hz), 7.09 (s, 4H), 6.14 (s, 2H), 2.82 (t, 2H, J=7.5 Hz), 2.63 (s, 3H), 1.81-1.67 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[F:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[C:28](/[N+]([O-])=O)\[CH3:29])=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([CH3:29])=[CH:2][NH:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C(=C\c1ccc(F)cc1)[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Ethyl isocyanoacetate (4.36 mL, 42.09 mmol) and DBU (6.28 mL, 42.09 mmol) was added to a solution of (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (6.0 g, 33.14 mmol) in THF (60 mL) at 0° C. The reaction mixture was stirred for 30 min at room temperature; quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (1×100 mL) and brine (75 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel; 60-120 mesh). The pure product was eluted with 10% EtOAc in petroleum ether to yield the desired compound (6.0 g, 73%) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[CH3:15][Mg]Cl>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[CH:4][C:3]=1[F:14]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (58.5 g, 0.223 mol) in tetrahydrofuran (500 mL) was added 3.00 M of methylmagnesium chloride in tetrahydrofuran (125 mL, 0.38 mol) at 0° C. The mixture was stirred for 1 h at 0° C., and was quenched with cold saturated NH4Cl solution (150 mL). The organic layer was separated and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The aqueous layer was diluted with water (100 mL) and was extract with ethyl acetate (3×50 mL). The organic solution and extracts were combined, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give product (48.4 g, 99%) which was directly used in next step without further purification.