Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.C([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH:37]([CH2:40][OH:41])[CH2:38][OH:39])=[O:35])[CH:28]=2)(O)=O>CCOC(C)=O>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH:37]([CH2:38][OH:39])[CH2:40][OH:41])=[O:35])[CH:28]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Reactant: O=C(NC(CO)CO)c1ccc2cc(C(=O)O)[nH]c2c1
Solvent: CCOC(C)=O
Product: O=C(NC(CO)CO)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 29 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with 2-carboxy-N-(1,3-dihydroxy-2-propyl)indole-6-carboxamide by the method described above, the EtOAc layer dried (Na2SO4), evaporated, and the residue recrystallised from EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-(1,3-dihydroxy-2-propyl)indole-6-carboxamide as a cream powder (29%), mp 230-231° C. (dec.). 1H NMR [(CD3)2SO] δ12.13 (s, 1H, indole NH), 8.98 (d, J=2.1 Hz, 1H, H-7), 8.05 (dd, J=8.3, 2.2 Hz, 1H, H-5), 8.04 (s, 1H, H-3' or H-7'), 7.95 (d, J=8.0 Hz, 1H, amide NH), 7.76 (d, J=8.5 Hz, 1H, H-4'), 7.75 (d, J=8.3 Hz, 1H, H-4), 7.61 (dd, J=8.5, 1.4 Hz, 1H, H-5'), 7.29 (d, J=1.6 Hz, 1H, H-3' or H-7'), 4.87 (t, J=10.1 Hz, 1H, H-2), 4.70 (t, J=5.7 Hz, 2H, OH), 4.51 (dd, J=10.7, 5.1 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 4.04-3.97 (m, 1H, CONHCH), 3.55 (t, J=5.7 Hz, 4H, CH2OH); 13C NMR δ166.8 (CONH), 160.4 (CON), 147.6, 144.6, 139.9, 135.7, 131.8, 131.0, 128.9 (C-6,8,9,2',6',8',9'), 125.5, 121.4, 119.4, 119.1, 112.2, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 60.4 (CH2OH), 54.0 (C-2), 53.8 (CONHCH), 47.0 (CH2Cl), 42.0 (C-3). Anal. (C22H21,ClN4O6).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:11](O)[C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2c(-c3ccc(Br)cc3)nc(-c3c(F)cccc3Cl)n2O)cc[nH]1
Solvent: CO
Product: O=c1cc(-c2[nH]c(-c3c(F)cccc3Cl)nc2-c2ccc(Br)cc2)cc[nH]1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from Example 1 Step C (11 g, 0.024 mol) in methanol (0.5 L) at 0° C. under nitrogen was added TiCl3 (15˜20%, 120 mL) over 45 minutes while maintaining the reaction temperature under 10° C. The solution was warmed to RT and stirred overnight. The volatiles were removed under reduced pressure, and the solution was made basic with saturated NaHCO3 and 5 N NaOH. Ethyl acetate was added and the mixture was stirred overnight. The solution was filtered through a Solka floe pad to remove the solids. The filtrate was extracted with EtOAc and the organic layer was then washed twice with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the crude residue which was purified by on silica gel (gradient elution with 2%-10% DCM-methanol as an eluant) to yield the title compound. 1H NMR (300 MHz, DMSO-d6): δ13.12 (m, 1H), 11.45 (br, 1H), 7.22˜7.70 (m, 9H), 6.10˜6.32 (m, 2H).
Reaction SMILES: N.[Na].C([O:10][CH:11]1[CH2:16][CH2:15][C:14]([CH:19]([NH2:22])[CH2:20][CH3:21])([O:17][CH3:18])[CH2:13][CH2:12]1)C1C=CC=CC=1>O1CCCC1>[NH2:22][CH:19]([C:14]1([O:17][CH3:18])[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]1)[CH2:20][CH3:21]
Reactant: CCC(N)C1(OC)CCC(OCc2ccccc2)CC1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CCC(N)C1(OC)CCC(O)CC1
Temperature: 25 °C
Yield: 160.2 %

Procedure:
35 mL of ammonia were condensed into a Schlenk flask, cooled in a dryice-isopropanol bath. 170 mg of sodium were dissolved and 1.1 g of 40, dissolved in 3 mL of dry tetrahydrofurane, were added. After complete conversion, the reaction was quenched by addition of methanol and the mixture was warmed to room temperature. The solvents were evaporated and the crude material was taken up in methanol and dilute hydrochloric acid and evaporated several times to give 1.19 g of crude product as a cis/trans mixture, which was used directly in the next step, Rt=0.10 min (Method P). Detected mass: 188.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:8](I)[CH3:9]>C(O)C>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCI
Reactant: C1CNCCNC1
Solvent: CCO
Product: CCN1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Homopiperazine (100 g) is dissolved in ethanol (500 ml), and thereto is added dropwise gradually ethyl iodide (19.8 ml). The mixture is stirred at room temperature overnight, and the insoluble materials are removed by filtration. The filtrate is evaporated to remove the solvent. Purification is perfomed by distillation to give 1-ethylhomopiperazine (50 g) as colorless oil.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][NH:6][C:7](=[O:28])[C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:11]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:30][OH:31]>CO>[CH:1]1(/[C:4](=[N:30]\[OH:31])/[CH2:5][NH:6][C:7](=[O:28])[C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:11]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[N:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC(=O)C1CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reactant: NO
Solvent: CO
Product: O=C(NC/C(=N/O)C1CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 0.100 g N-(2-cyclopropyl-2-oxo-ethyl)-5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide in 1.0 ml methanol was added 0.052 g of 50% aqueous hydroxylamine and the mixture was kept at ambient temperature for 18 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 0.093 g of the title compound as white crystals. MS (EI): 462.0599 (M+H).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[C:4]([CH3:20])[CH:3]=1.[Li]CCCC.[CH3:26][S:27]SC>C1COCC1>[CH3:19][C:17]1[CH:18]=[C:2]([S:27][CH3:26])[CH:3]=[C:4]([CH3:20])[C:5]=1[O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9]
Reactant: CSSC
Reactant: Cc1cc(Br)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a stirring solution of (4-bromo-2,6-dimethylphenoxy)triisopropylsilane (0.5 g, 1.4 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.56 mL), the reaction mixture was stirred at −78° C. for 1 hr, then dimethyldisulfide (0.16 mL, 1.82 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (2,6-dimethyl-4-methylsulfanylphenoxy)triisopropyl-silane as an oil (0.46 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 6.92 (s, 2 H), 2.41 (s, 3 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase ethyl acetate-hexanes (2:98); Rf=0.57.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=1.[OH-].[K+].CO>O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:25])=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Yield: 93.1 %

Procedure:
The title compound is prepared by the procedure of Example 2 using 234 g of 3-(tetradecyloxy)benzoic acid methyl ester, 113.0 g of potassium hydroxide, 1 L of methyl alcohol and 120 ml of water. The solid residue is recrystallized from methyl alcohol/ethyl alcohol to give 209 g of the desired product.
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)(=[O:10])[NH2:9]>>[ClH:1].[NH2:23][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]([NH2:9])=[O:10])=[CH:16][N:15]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(N)=O)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred solution of HCl/EtOAc (9 ml, 3N) was added tert-butyl 1-(5-carbamoylpyridin-2-yl)piperidin-4-ylcarbamate (400 mg) and the mixture was stirred at room temperature for 4 h. The solid was collected by filtration and washed with EtOAc to give a white solid (300 mg, 94%). [LCMS RtA=0.85 min, [M+H]+=221.1].
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)c(C#N)cnc2c(OC)c1OC
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC

Procedure:
A stirred mixture of 1.30 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorous oxychloride, and 1 drop of N,N-dimethylformamide was refluxed for 10 minutes and evaporated free of volatile matter. The residue was stirred with 20 ml of 5% methyl alcohol in ethyl acetate. The product was collected and dried to give 1.12 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 161-163° C.; mass spectrum (EI, m/e): M 278.0452.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2cccnc2)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1c(-c2cccnc2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as an off-white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.62 (2H, dd, J 7 and 7), 7.85-7.96 (3H, m), 8.36 (1H, s), 8.58 (1H, d, J 8), 8.86 (1H, dd, J 5 and 1), 9.14 (1H, s), 9.33 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@H:27]([CH3:45])[O:28][C:29]1[CH:30]=[C:31]([OH:44])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:44][C:31]1[CH:32]=[C:33]([C:2]2[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:4][CH:3]=2)[CH:34]=[C:29]([O:28][C@@H:27]([CH3:45])[CH2:26][O:25][CH3:24])[CH:30]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)n2C(=O)OC(C)(C)C)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.75 g, 23.0 mmol) synthesized in Example (66b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.11 g, 23.1 mmol) synthesized in Example (38c) were dissolved in a mixed solvent of 1,4-dioxane (92 mL) and water (23 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (570 mg, 0.698 mmol) and potassium carbonate (7.95 g, 57.5 mmol) were added, followed by stirring at 55° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-35%) to afford the desired compound (8.32 g, yield 75%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:23])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[CH3:23][C:16]1([CH2:15][CH2:14][CH2:13][O:12][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]
Reactant: CC1(CCCO)NC(=O)NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC2(C)NC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
P-toluenesulfonyl chloride (22.5 g., 0.118 mol) was added to a stirred solution of 5-(3-hydroxypropyl)-5-methyl-2,4-imidazolidine-dione (20.0 g, 0.116 mol) in pyridine (250 ml.) at 5° C. The mixture was stirred for one hour, refrigerated overnight and diluted with water (275 ml.) The resulting solution was extracted three times with chloroform (375, 190 and 190 ml.), the combined extracts were washed with 5 N aqueous sulfuric acid (4 × 125 ml.), water (2 × 150 ml.) and saturated aqueous sodium bicarbonate solution (2 × 125 ml). Concentration of the dried chloroform phase yielded 5-methyl-5- {3-[(4-methylphenyl)sulfonyloxy]-propyl}-2,4-imidazolinedione (22.2 g., 0.068 mol, 58%) upon addition of ether and petroleum ether, m.p. 126-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[H-].[Na+].O1CCC[CH2:17]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=Cc1ccc(OC)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-methoxy-3-nitrobenzaldehyde (0.6 g) in tetrahydrofuran (10 mL) was added sodium hydride (50% suspension in mineral oil, 0.5 g) followed by methyltriphenylphosphonium bromide (1.8 g) and the resulting mixture was heated at reflux for 1 hour. The reaction mixture was cooled, diluted with water, extracted with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 150 mg of 1-methoxy-2-nitro-4-vinyl-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[S:10])[NH:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: S=c1[nH]c2cc(Br)ccc2o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSc1nc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
5-Bromo-3H-benzooxazole-2-thione (530 mg, 2.30 mmol) was dissolved in DMF (5.75 mL). Potassium carbonate (318 mg, 2.30 mmol) and iodomethane (172 μL, 2.76 mmol) were added and the reaction mixture was allowed to stir at RT for 3.5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (4×10 mL): The combined organic extracts were washed with water (3×10 mL), brine (10 mL) and dried (Na2SO4), filtered and concentrated to afford 538 mg (96%) of the title compound as a dark brown solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C#CC(=O)OC
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Product: COC(=O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 46.6 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (2.00 g) and methyl propiolate (2.55 g) by the process as described for the preparation of Intermediate (7 a) to afford an orange solid which was purified by FCC eluting with System A (3:17) to afford the title compound (1.194 g) as a white solid. λmax (MeOH) 248.4 (22,180) and 300 (inf) nm (ε9410).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:4].C(OCC)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1CC(=O)O
Reaction time: 18 h

Procedure:
Next, to the solution of (S)-1-benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester (2.50 g, 9.01 mmol) in methanol (30 mL)/ethyl acetate (30 mL) is added Pd/C (300 mg) and the mixture is stirred under an atmosphere of hydrogen (H2 balloon) for 18 hours. The catalyst is filtered through a Celite pad and the filtrate is evaporated under reduced pressure to give the title compound; HPLC Retention time 0.94 minutes (condition C): MS188.4 (M+1).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)c1ncccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.30 g of 3-ethylsulfanyl-N-(6-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 7).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)[CH3:2].C[CH:12]([C:20]1C=C(O)C=C([CH:26]=1)O)[CH:13](C)[CH2:14]CCCC.Cl>C(O)(=O)C>[CH2:9]1[C:4]2[CH2:1][C:2]3[C:14](=[CH:13][CH:12]=[CH:20][CH:26]=3)[O:10][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)C1CCCCC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC1=C(CCCC1)O2
Reaction time: 23 h

Procedure:
A solution of 2.48 g. of 2-acetylcyclohexanone and 4.17 g. of 5-(1,2-dimethylheptyl)resorcinol in 100 ml. of acetic acid is cooled to 15° and saturated with hydrogen chloride gas. The reaction mixture is allowed to warm to 25° and stirred for 23 hours. The solvent is removed in vacuo, the residue is distilled twice and the fraction boiling at 170°-190° (0.02 mm.) is collected and chromatographed on silica gel with benzene as eluant. The nonpolar fractions are rechromatographed on a silver nitrate impregnated silica gel "dry-column" with 18:1:1 cyclohexaneacetic acid-ether to give a mixture which is separated by distillation to give the title compounds, b.p. 180° (0.005 mm.), tetrahydro xanthene; b.p. 190° (0.003 mm.), aromatic xanthene.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[K+].C1(C=CC(O)=CC=1)O.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[CH2:2]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1

Procedure:
4-(2-Bromoethyl)-N-(3-methyl-2-pyridinyl)benzenesulfonamide (183 g, 0.5 mol) and potassium hydroxide (120 g, 1.83 mol) and hydroquinone (1 g) in ethanol (21) was refluxed for 1 h. 51 water was added and the solution acidified with acetic acid. The precipitated product was collected by filtration, washed with water and dried. Yield 137 g (quantitative).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:5]2[CH2:4][NH:3]1.Cl.CO>C(OCC)C>[CH2:13]1[C@H:6]2[C@H:5]([CH2:4][NH:3][C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=32)[CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2c3ccccc3C(=O)NC[C@@H]2C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C1NC[C@@H]2CNCC[C@@H]2c2ccccc21
Reaction time: 8 h

Procedure:
To a suspension of Example 180G in 400 mL of diethyl ether was added 80 mL of HCl/methanol (5N) at 25° C. The mixture was stirred overnight. The solid formed was collected and dried to obtain the title compound as the hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].C([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)(=O)C(C)C>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)=[O:21])[CH2:15][CH2:14]1)=[O:4]
Reactant: CCC(C)C(=O)O
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CCC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 88 %

Procedure:
2-Methylbutyric acid (50 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.215 mmol, 88% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (d, J=8.4 Hz, 1H), 7.57 (s, 4H), 6.37 (s, 1H), 4.22 (m, 1H), 3.88 (d, J=13.2 Hz, 1H), 3.71 (m, 1H), 3.17 (t, J=12.8 Hz, 1H), 2.84 (m, 2H), 1.85 (m, 2H), 1.54 (m, 1H), 1.29 (m, 3H), 0.97 (s, 3H), 0.81 (d, J=6 Hz, 3H).