Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:21]=1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Reactant: FC(F)Oc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(OC(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (2.5 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 100 mg (2.5 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.50 g (2.5 m mol) of 2,3-dichloro-5-difluoromethoxypyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reaction mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 1-(3-chloro-5-difluoromethoxypyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:12])=[O:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 20 %

Procedure:
To a mixture of 4-iodo-2-nitrotoluene (9.0 g, 34 mmol) in H2O (340 mL) was added KMnO4 (22.0 g, 139 mmol). The mixture was heated at reflux for 5 h and then cooled to rt and filtered through Celite®. The filtrate was acidified to pH=2 with conc. HCl. The precipitate that formed and was filtered and dried to give 4-iodo-2-nitrobenzoic acid (2.0 g, 20%). The filtrate was extracted with DCM (3×200 mL). The organic solutions were combined, dried over Na2SO4, filtered, and concentrated to provide a second lot of 4-iodo-2-nitrobenzoic acid (0.18 g, 2%).
Reaction SMILES: [OH:1][C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:7][CH2:6][CH:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:10]2)[CH2:4][CH2:3]1.[CH2:36]=[O:37].[BH-](OC(C)=O)(OC(C)=O)[O:39][C:40](C)=O.[Na+]>C1COCC1>[OH:1][C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:3][CH2:4][CH:5]([N:8]([CH3:40])[C@H:9]2[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:10]2)[CH2:6][CH2:7]1.[C:36]([OH:39])([C:24]([F:27])([F:26])[F:25])=[O:37]
Reactant: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccccn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reactant: C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCC(O)(c2ccccn2)CC1)[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-{(3S)-3-[(4-hydroxy-4-pyridin-2-ylcyclohexyl)amino]pyrrolidin-1-yl}-2-oxoethyl)-3-(trifluoromethyl)benzamide (49 mg, 0.1 mmol) and formaldehyde (0.3 mL, 37% water solution) in THF (2 mL) was added Na(OAc)3BH (64 mg, 0.3 mmol). After being stirred at room temperature overnight, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with EtOAc and the EtOAc layer was dried (MgSO4) and concentrated. Purification by prep HPLC provided the title compound as a TFA salt. MS (M+H)+ 505.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].Br[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41].CS(C)=O.[I-].[K+]>[Cu].ClCCl>[F:2][C:1]([F:3])([C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:18])([F:17])[C:19]([F:21])([F:20])[C:22]([F:24])([F:23])[C:25]([F:27])([F:26])[C:28]([F:31])([F:30])[F:29]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(C)c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
A solution of C10F21I (4.2 g, 6.5 mmol) was added dropwise over 10 min to a stirred mixture of 2-bromo-p-xylene (1 g, 5.4 mmol), copper powder (1.9 g, 29.7 mmol), and DMSO (80 mL) at 130° C. The reaction mixture was subsequently stirred for a further 2 d at this temperature. After cooling to room temperature, it was poured into a beaker containing dichloromethane (50 mL) and saturated potassium iodide solution (50 mL). After filtering, the organic layer was separated, washed with water (3×30 mL), and dried over MgSO4. Recrystallization from hexane gave the product 215 as a white solid (2.7 g, 82%): 1H NMR (300 MHz, CDCl3): 7.31 (1H, s), 7.24 (1H, d, J=8.1 Hz)), 7.17 (1H, d, J=8.1 Hz)), 2.46 (3H, t, J=3.0 Hz)), 2.39 (3H, s); 19F NMR (282 MHz, CDCl3): −81.4, −106.7, −121.1, −121.8, −122.0, −122.9, −126.3; HR-MS (EI) calcd. for C18H9F21 (M+): 624.0363, found: 624.0353.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:12])[CH:3]=1.O[C:14]1C=CN(CCC(C)C)C(=O)C=1.C1(CN2C=CC(O)=CC2=O)CC1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCCC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:11]([CH3:10])[CH3:14])[C:4](=[O:12])[CH:3]=1
Reactant: O=c1cc(Br)ccn1CC1CC1
Reactant: CC(C)CCn1ccc(O)cc1=O
Agent: O=c1cc(O)ccn1CC1CC1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CC(C)CCBr
Product: CC(C)CCn1ccc(Br)cc1=O

Procedure:
Intermediate D7 was prepared following the same procedure implemented for the synthesis of D3, using 4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material, which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with 1-bromo-3-methylbutane.
Reaction SMILES: C1C=C[C:4]2N(O)N=N[C:5]=2[CH:6]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][C@@H](C(O)=O)C1C=CC=CC=1)=[O:17])(C)[CH3:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:15]([CH:5]([CH3:4])[CH3:6])[CH:12]([CH3:13])[CH3:11].[C:16](=[O:15])([O-:17])[NH2:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: NC(=O)[O-]
Temperature: 23 °C
Reaction time: 18 h
Yield: 494.7 %

Procedure:
Dissolve the product of Step 2 (134 g) in CH2Cl2 (1.5 L). Treat sequentially with HOBT (44.6 g), BOC-D-phenylglycine (86.3 g) and DEC (65.9 g). Stir the mixture at 23° C. for 18 h, heat at reflux temperature for 2 h, recool to 23° C., treat with saturated NaHCO3 solution (500 mL), separate the organic portion, dry (MgSO4), filter and concentrate. Recrystallize the crude material, once from Et2O and twice from iPr2O to give 1,1-dimethylethyl-[[[1-[[(3,5-dichlorobenzoyl)methylamine]methyl]-2-(3,4-dichlorophenyl)-5-methyl-hexen-1-ylidene]amino]oxy]-2-oxo-1-phenylethyl]carbamate (51 g). MS(FAB): m/e 722; [α]D 23 =-96.9° (c 0.4 CH2Cl2); m.p. 98-102° C. (dec).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:43]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:47])=[O:45])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.15 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.78 g of 3-ethylsulfanyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (Compound of Present Invention 10) and 10 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with MTBE and dried to obtain 0.78 g of 3-ethylsulfonyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 14).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].P(Cl)(Cl)(Cl)(Cl)[Cl:14].[ClH:19]>C1(C)C(C)=CC=CC=1>[Cl:19][C:3]1([Cl:14])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: Cl
Reactant: O=C1CCCc2ccccc2N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2CCC1(Cl)Cl
Reaction time: 0.5 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (48.3 g, see Briggs et al., J. Chem. Soc. 1937, 456), phosphorus pentachloride (188 g), and xylene (1300 ml) was heated with stirring under an atmosphere of nitrogen to 90° (oil bath temperature) during 30 min with pauses at 30° (to allow the phosphorus pentachloride to dissolve) and at 50°. There was a copious evolution of hydrogen chloride. The temperature was maintained at 90° for 30 minutes. The reaction mixture was filtered while hot to remove a small amount of suspended solid, and the filtrate was evaporated under reduced pressure until all the solvent was removed. The residue was added with stirring to saturated aqueous sodium carbonate (100 ml). The product was filtered after the solidification process was complete, then slurried in ethanol (150 ml), filtered, washed with ethanol (50 ml) and ether (50 ml) and dried to give 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 185°-187°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=O.[C:14]([OH:20])(=[O:19])[CH2:15]C(O)=O.C([O-])(=O)C.[NH4+:25]>C(O)(C)C>[NH2:25][CH:5]([C:4]1[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=[C:2]([Br:1])[CH:3]=1)[CH2:15][C:14]([OH:20])=[O:19]
Reactant: [NH4+]
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Br)cc(C(N)CC(=O)O)c1
Yield: 51.6 %

Procedure:
A suspension of 3-bromo-5-tert-butylbenzaldehyde (4.17 g, 17.30 mmol), malonic acid (2.15 g, 20.72 mmol) and ammonium acetate (2.66 g, 34.59 mmol) in isopropanol (35 mL) was heated at reflux under nitrogen for 3 h to afford a thick colorless solid. The solid was filtered hot, washed with hot isopropanol (2×25 mL) and dried in vacuo to give the desired racemic product as a colorless solid (2.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH3:42])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.296 mmol, 0.16 g; Example 43) in DMF (2 mL) at 0° C. was added sodium hydride (80 mg) followed by methyl iodide (0.2 mL) and continued stirring at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and quenched excess NaH by drop-wise addition of methanol. This was washed with brine (10 mL), organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.145 g) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19][CH2:20][C:21]#[N:22]>C1COCC1>[C:21]([CH2:20][S:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:22]
Reactant: CC(=O)Cl
Reactant: N#CCSc1ccc(F)cc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
Acetyl chloride (1.5 ml) in THF (10 ml) and subsequently pyridine (1.7 ml) in THF (10 ml) was added to a stirred solution of (2-amino-4-fluoro-phenylsulfanyl)acetonitrile (3.5 g) in THF (30 ml) at 0° C. The mixture was stirred at 0° C. for 50 min. Then the solvent was removed in vacuo and the residue was triturated with water (80 ml). The precipitate was filtered off and dried yielding 3.7 g (86%) of the title compound as yellow crystals; mp 113-115° C.; 1H-NMR (DMSO-d6), δ (ppm): 9.59 (s, 1H, NH), 7.73-7.57 (m, 2H, Ar—H), 7.19-7.05 (m, 1H, Ar—H), 4.05 (s, 2H, CH2), 2.12 (s, 3H, CH3). The title compound was used for the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
0.34 mL of triethylamine and 0.15 mL of benzoyl chloride were added to 4 mL of methylene chloride solution containing 0.40 g tert-butyl 2-amino-4-(4-phenylbutyl)benzoate while ice-cooled sequentially and stirred at room temperature for 19 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1]to obtain 0.50 g of tert-butyl 2-(benzamido)-4-(4-phenylbutyl)benzoate as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:7]2[CH:8]=[N:9][N:10]([CH3:22])[C:11]=2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]1[NH:18][CH:19]([CH3:21])[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cnn(C)c1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(NC(C)C)=NS(=O)(=O)c2c1cnn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of N-(4-ethoxycarbonylamino-1-methyl-5-pyrazolesulfonyl)-N'-isopropylthiourea (0.37 g) and triethylamine (0.45 ml) in 5 ml of dry THF at 0° C. was added 1.0 ml of a 20% solution of phosgene in toluene. The mixture was stirred at 0° C. for 30 min. and then evaporated to dryness. The residue was triturated with 10 ml of water, filtered off, rinsed on the filter with water and dried to give 0.27 g (82%) of the title compound; m.p. 141°-145° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>C1COCC1.CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[N:23]2[CH3:31])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1C(=O)OC[C@@]1(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of (R)-4-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (73 mg, 0.19 mmol) in THF (1 mL) and DMF (1 mL) was added sodium hydride (60% in mineral oil, 12 mg, 0.29 mmol). After the mixture was stirred at room temperature for 2 hrs, methyl iodide (60 μL, 0.96 mmol) was added. The mixture was stirred at room temperature for 3 hrs. LCMS showed about 30% of conversion. Additional sodium hydride (60% in mineral oil, 50 mg) was added. After the mixture was stirred at room temperature overnight, the mixture was partitioned between NH4Cl aq and EtOAc. The organic phase was washed with water, dried over anhydrous MgSO4, filtered, and concentrated to give 80 mg of crude product, 106%. ESI-MS (M+H)+: 396.20, room temperature 2.53 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8]1.CN(C=O)C.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1>O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:23]([C:25](=[O:27])[CH3:26])[CH:24]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)ccc1OC1CCCC1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 101 %

Procedure:
Potassium carbonate (6.55 g, 47.4 mmol), cyclopentyl bromide (8.25 g, 55.3 mmol) and DMF (5 ml) were added to a DMF solution (10 ml) of 5′-bromo-2′-hydroxyacetophenone (8.5 g, 39.5 mmol), and the resulting mixture was stirred at 60° C. for 4.5 hours. Potassium carbonate (3.0 g, 21.7 mmol) and cyclopentyl bromide (2.0 g, 13.4 mmol) were added to the resultant mixture, and stirred at 60° C. for 9 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 11.3 g of oily pale yellow 1-(5-bromo-2-cyclopentyloxyphenyl)ethanone (yield: 100%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:6]([NH:8]C1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=[O:7])(=[O:3])[CH3:2].[OH:30][CH:31]([CH2:57][OH:58])[CH2:32][N:33](NC(=O)C)[C:34](=[O:52])[C:35]1[C:44]([I:45])=[C:43](OC(=O)C)[C:42]([I:50])=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=1[I:51].C(OCC(NC1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=O)(=O)C>>[OH:30][CH:31]([CH2:57][OH:58])[CH2:32][NH:33][C:34](=[O:52])[C:35]1[C:44]([I:45])=[C:43]([NH:8][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:42]([I:50])=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=1[I:51]
Reactant: CNC(=O)c1c(I)c(OC(C)=O)c(I)c(C(=O)N(CC(O)CO)NC(C)=O)c1I
Reactant: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: CNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Product: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
Compound (12) is prepared from compound (11) in the same manner according to the procedure described for the preparation of compound (4) from compound (3) in Example I, C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.Cl[CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1cc(SC[Si](C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), and dimethylacetamide (50 mL) and stir at room temperature under argon atmosphere. Add chloromethyltrimethylsilane (1.3 g, 10 mmol) and stir overnight. Warm on a steam bath for 2 hours, cool, and dilute with water. Extract with ethyl ether, dry, evaporate to a light yellow solid (2.8 g) and recrystallize (CH3CN) to give 1.1 g (34%) of the title compound; mp 100°-101° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16][CH2:15]1.[C:21]([O-])([O-])=O.[K+].[K+]>C(O)C>[OH:20][CH:17]1[CH2:18][CH2:19][CH2:14][CH2:15][CH:16]1[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH2:8][CH3:21])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: C1CCC2OC2C1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(OC)c(OC2CCCCC2O)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxybenzoate (210 mg, 1.15 mmol) and cyclohexane oxide (466 uL, 4.61 mmol) in ethanol (11 mL) was added K2CO3 (637 mg, 4.61 mmol) at room temperature. The reaction mixture was then refluxed overnight then cooled down to room temperature, and evaporated under reduced pressure until a small amount of ethanol remained. The solution was diluted with DCM and successively washed with 1N HCl and brine, dried over Na2SO4 filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (Eluent: 0-20% EtOAc/Hexanes) to afford (±)-ethyl 3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate as a colorless oil (307 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.34 (m, 7H), 1.61 (m, 2H), 1.84-1.94 (m, 2H), 3.55 (m, 1H), 3.83 (s, 3H), 4.03 (m, 1H), 4.28 (q, J=8.0 Hz, 2H), 4.85 (d, J=4.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 7.55-7.58 (m, 2H).