Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:22][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([NH:34][CH3:35])=[O:33])[CH:27]=2)[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.16 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbonitrile (Example 10A), 38.9 mg (0.18 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride (Example 41A) and 53.8 mg (0.64 mmol) of sodium bicarbonate were dissolved in 1 ml of DMF and the mixture was stirred at RT overnight. 30 ml of water were added to the reaction mixture, and the precipitate was filtered off. The precipitate was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 70.8 %

Procedure:
Using 4-bromobenzoic acid (1.01 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (1.03 g) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.38 g) was obtained.
Reaction SMILES: C(OC(C1(CCCBr)CCC1)=O)C.C([O:16][C:17]([C:19]1([CH2:23][CH2:24][CH2:25][S:26][CH3:27])[CH2:22][CH2:21][CH2:20]1)=[O:18])C>>[CH3:27][S:26][CH2:25][CH2:24][CH2:23][C:19]1([C:17]([OH:18])=[O:16])[CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)C1(CCCSC)CCC1
Agent: CCOC(=O)C1(CCCBr)CCC1
Product: CSCCCC1(C(=O)O)CCC1
Yield: 16 %

Procedure:
Using the general procedure described in example 41, starting with 1-(3-bromopropyl)cyclobutanecarboxylic acid ethyl ester, 1-[3-(methylthio)propyl]cyclobutanecarboxylic acid ethyl ester was prepared in 58% yield as a colorless oil. HR MS: Obs. mass, 216.1182. Calcd. mass, 216.1184 (M+). Also, 1-[3-(methylthio)propyl]cyclobutanecarboxylic acid was obtained in 16% yield as a colorless oil. HR MS: Obs. mass, 188.0872. Calcd. mass, 188.0871 (M+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([N:2]([CH2:3][CH2:4][CH2:5][OH:6])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCI
Reactant: CNCCCO
Product: CCCCCCCCCCCCN(C)CCCO
Yield: 96 %

Procedure:
A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C. J. Michejda, J. Org. Chem., 44, 2718, 1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96%) of the title material as an oil, b.p. 100-105° C./0.04 torr.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH3:29])[CH:5]([C:10]1([CH:16]([N:18]2C(=O)C3=CC=CC=C3C2=O)[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7].O.NN.[ClH:34]>C(O)C>[ClH:34].[NH2:18][CH:16]([C:10]1([CH:5]([C:6]([F:8])([F:9])[F:7])[CH:4]([CH3:29])[C:3]([OH:30])=[O:2])[S:11][CH2:12][CH2:13][CH2:14][S:15]1)[CH3:17]
Reactant: COC(=O)C(C)C(C(F)(F)F)C1(C(C)N2C(=O)c3ccccc3C2=O)SCCCS1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)C(C(F)(F)F)C1(C(C)N)SCCCS1

Procedure:
A solution of 1.1 g of the product of Example 5 in 20 ml of ethanol is treated with hydrazine hydrate (2 ml) for 2 hours at reflux. The ethanol is evaporated and the residue treated with 1 N NaOH then extracted with ether. The ether solution is dried and concentrated leaving a residue thatis taken up in 20 ml of ethanol and 10 ml of 6 N HCl and heated at reflux for 1 hour. The solvents are evaporated to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)O
Product: C[C@@H]1c2ccccc2C[C@@H]1C(=O)Cl

Procedure:
cis-2,3-Dihydro-1-methyl-1H-indene-2-carboxylic acid (52.6 g) is converted to its acid chloride by treatment with thionyl chloride (130 ml). Excess thionyl chloride is distilled off and the acid chloride is distilled, b.p. 86°-89° C./0.45 mmHg. The yield is 47.9 g, 83%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([N:21]([CH3:25])[CH:22]([CH3:24])[CH3:23])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([N:21]([CH3:25])[CH:22]([CH3:23])[CH3:24])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=3)[N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(NC(C)=O)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of methyl 2-(4-acetamidophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (45 mg, 1.12 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, dissolved in water (50 ml), adjusted to pH 6 with HCl (1N), and collected by filtration to give 2-(4-acetamidophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p. 131° C. and MS: m/e=383 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromo-benzenesulfonyl chloride.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]2[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH:17]=2)=[C:13]([OH:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=3[OH:15])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: Oc1cc(OCc2ccccc2)ccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Reaction time: 64 h
Yield: 99.9 %

Procedure:
A round bottomed flask was charged with 5-benzyloxy-2-(1,4-dioxaspiro[4.5]dec-7-en8-yl)phenol (6.90 g), ethanol (300 ml) and palladium (2.00 g, 10% on activated carbon). The reaction vessel was then evacuated and placed under a hydrogen atmosphere. This process was repeated 15 times before stirring vigorously for 64 hr under a hydrogen atmosphere. The reaction mixture was filtered through a celite plug, washing with ethyl acetate. The filtrate was concentrated in vacuo, furnishing the title compound (5.10 g, 100%) as a solid. δH (CD3OD) 1.65-1.87 (8H, m), 2.86-2.90 (1H, m), 3.90-4.06 (4H, m ), 6.27 (1H, dd), 6.29 (1H, d), 6.92 (1H, d); m/z(ES+) 251 (M+H+).
Reaction SMILES: [CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[N:34]=[CH:33][O:32][N:31]=2)[S:8](=[O:10])(=[O:9])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].CCCCCC>C1C(O)=CC=CC=1C>[CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[N:34]=[CH:33][O:32][N:31]=2)[S:8](=[O:9])(=[O:10])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: C[C@]1(/C=C/c2ncon2)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Solvent: Cc1cccc(O)c1
Solvent: CCCCCC
Product: C[C@]1(/C=C/c2ncon2)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
355 mg (0.74 mmol) of benzhydryl (E)-(2S,3S,5R)-3-methyl-3-[2-(1,2,4-oxadiazol-3-yl)-vinyl]-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 3 ml of m-cresol and stirred at 50° C. for 4 hours. 20 ml of n-hexane are added to the pale brown solution, the separated crystals were filtered off under suction and rinsed with n-hexane. The crude crystallizate was recrystallized from ethyl acetate/n-hexane. Yield: 170 mg (73%) of colorless crystals MS: (M--H)- 312.2 IR (KBr): 2900(br), 1811, 1714, 1660, 1331, 1194, 980 cm-1M.p.: 161° C. (dec.) Elementary analysis: C11H11N3O6S (313.284) Calc. C 42.17 H 3.54 N 13.41 Found C 42.41 H 3.64 N 13.18
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:10]
Reactant: CCOC(=O)CN
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)COC
Temperature: -78 °C
Yield: 75 %

Procedure:
1.5 ml of triethylamine was added to 500 mg of amino-acetic acid ethylester hydrochloride dissolved in 5 ml of chloroform, and the solution was cooled to −78° C. 0.34 ml of methoxyacetylchloride diluted with 3 ml of chloroform was slowly added thereto, and the resulting solution was heated slowly to room temperature and reacted for 6 hours. The reacted solution was washed with distilled water, adjusted to pH 8 to 9 by adding saturated sodium bicarbonate solution, extracted with organic solvent, dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (595 mg, 75%).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]1([S:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[O:20])[CH2:14][CH2:13]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)C2CC2)CC1
Yield: 54.1 %

Procedure:
Cyclopropylsulfonyl chloride (75 mg, 0.536 mmol) was reacted with ITU (70 mg, 0.268 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (53 mg, 0.145 mmol, 54.1% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.20 (s, 1H), 7.26 (d, J=6.9 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 6.14 (d, J=7.8 Hz, 1H), 3.59 (m, 1H), 3.52 (d, J=12.8 Hz, 2H), 2.98 (t, J=11.4 Hz, 2H), 2.79 (m, 1H), 2.57 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.42 (m, 2H), 1.15 (d, J=6.6 Hz, 6H), 0.95 (m, 4H).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C(=O)(SC)OC(OC(=O)C(C)C)C.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50]O)=[O:49])[CH:43]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:41][C:42]1[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=1)[C:48]([OH:50])=[O:49]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: CSC(=O)OC(C)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an alternative synthesis of (10), N-hydroxysuccinimide (558 mg, 4.8 mmol) was added to a solution of compound (6) (500 mg, 2.4 mmol) in CH2Cl2 (10 mL) and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (1.62 g, 7.2 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane, resulting in analytically pure product (66 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[Na].Br[CH2:15][CH2:16][CH3:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:15][CH2:16][CH3:17])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9]
Reactant: CCCBr
Reactant: COc1ccc(O)c(C(N)=O)c1
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
5-Methoxysalicylamide (56.0 g., 0.335 mole) was added to a cooled, stirred solution of sodium (8.55 g., 0.372 g-atom) in ethanol (335 ml.). To the resulting suspension was added 1-bromopropane (41.3 g., 0.335 mole) dropwise over 20 minutes. The mixture was stirred at room temperature for one hour, then was heated under reflux for 19 hours. The solvent was removed under reduced pressure. The residue was treated with cold water (500 ml.). The solid was collected by filtration and recrystallized from acetonitrile to give 5-methoxy-2-n-propoxybenzamide (29.0 g., 41.4%), m.p. 83°-87°.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.O>CC(C)=O>[Cl:1][C:2]1[C:3]([O:15][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(O)c(Cl)c([N+](=O)[O-])c1
Reactant: ICCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCCOC2CCCCO2)c(Cl)c([N+](=O)[O-])c1

Procedure:
6.84 g of methyl 4-chloro-3-hydroxy-5-nitro-benzoate were dissolved in acetone (150 ml), treated at RT in succession with 10.19 g of potassium carbonate and 11.19 g of 2-(2-iodo-ethoxy)-tetrahydro-pyran and the mixture was heated at reflux for 16 hours. Subsequently, the mixture was poured into water, extracted with ethyl acetate, the organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was flash chromatographed on silica gel with hexane/ether (2/1) as the eluent. There was thus obtained the desired methyl 4-chloro-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:49])([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([C:40](=[O:41])[C:39]([CH3:49])([CH3:48])[CH3:38])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2,2-dimethyl-1-piperazin-1-yl-propan-1-one (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O3 [(M+H)+] 692.3129, observed 692.3129.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[NH:16][CH2:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[C:7]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1NCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNc1cc(C(C)(C)C)ccc1C=CC(=O)O
Reaction time: 12 h
Yield: 100 %

Procedure:
3-(4-tert-butyl-2-isobutylaminophenyl)acrylic acid methyl ester (0.08 mmol, 22.8 mg) and NaOH (0.39 mmol, 15.76 mg) were added in methanol and water. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl solution. The reaction mixture was concentrated in vacuo to give a solid (22.02 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].C[O-].[Na+].Cl[C:12]([CH3:19])([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:13].Cl>CO.O>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[S:7][C:12]([CH3:19])([CH3:13])[C:14]([CH:15]([CH3:17])[CH3:16])=[O:18]
Reactant: CC(C)C(=O)C(C)(C)Cl
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1occc1SC(C)(C)C(=O)C(C)C
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, reflux condenser, thermometer and heating mantle, is added 0.57 g (0.005 moles) 2-methyl-3-furan thiol in 3 ml absolute methanol and a solution of 0.27 g (0.005 moles) sodium methoxide in 3 ml of absolute methanol. After 10 minutes stirring, 0.74 g (0.005 moles) 2-chloro-2,4-dimethyl-3-pentanone in 1 ml absolute methanol is added slowly. The reaction mass is then warmed to 35° C using a hot water bath and while maintaining the temperature of the reaction mass at 35° C it is placed under a nitrogen blanket. The reaction mass is then heated to reflux (65°-66° C) and refluxed for a period of 1 hour. At the end of the 1 hour reflux period, the reaction mass is allowed to cool and is worked up by adding thereto 10 ml of water. The reaction mass, being at a basic pH (9-10), is acidified with dilute HCl bringing the pH down to 6. N-Hexane is added to the reaction mass giving rise to two phases; an aqueous phase and an organic phase. The aqueous phase is extracted with 2 × 10 ml of hexane. The hexane extracts are separated, combined, washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting solution is then concentrated to a weight of 1.02 g and the desired compound is isolated using GLC apparatus (conditions: SE-30 Column, 8 foot × 1/4 inch). NMR, IR and Mass Spectral analyses confirm that the structure of the resulting material is: ##SPC20##
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH2:35][O:36][CH2:37][C:38]([CH3:40])=[CH2:39]>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CN(C)C=O>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH2:35][O:36][CH2:37][C:38]1([CH3:40])[O:7][N:6]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[CH2:39]1
Reactant: C=C(C)COCc1c(F)cccc1F
Reactant: ON=Cc1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(COCc2c(F)cccc2F)CC(c2ccccc2C(F)(F)F)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
223 mg of 2-trifluoromethylbenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane, and then, washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 410 mg of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-(2-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].CS([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=O)=O>>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)CC(F)(F)F)CC1
Yield: 46 %

Procedure:
2,2,2-trifluoroethylsulfonyl chloride (89 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (48 mg, 0.111 mmol, 46% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.81 (s, 1H), 7.56 (s, 4H), 6.41 (d, J=6.9 Hz, 1H), 4.51 (q, J=9.9 Hz, 2H), 3.58 (d, J=12 Hz, 1H), 3.58 (m, 1H), 3.02 (t, J=11.4 Hz, 2H), 1.92 (d, J=12.4 Hz, 2H), 1.45 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34](=[O:38])[N:35]([CH3:36])[CH3:37])[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CN(C)C(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(N,N-dimethylcarbamoyl)phenyl]piperidin-3-ol (1.8 g) obtained in Step 2 in 10 ml of dimethylsulfoxide (DMSO), was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added slowly to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.2 g of the titled compound.