Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Br[CH2:10][C:11]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:12]1>CN(C=O)C.O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[O:12][C:11]1([CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[I:3])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Ic1ncc[nH]1
Reactant: Fc1ccc(C2(CBr)OC2c2ccccc2Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(C2(Cn3ccnc3I)OC2c2ccccc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
At 3° C., sodium hydride (60% by weight strength dispersion in mineral oil, 56.7 mg, 1.41 mmol) was added to a stirred solution of 2-iodoimidazole (242 mg, 1.25 mmol) in dry DMF (8 ml). The reaction mixture was stirred at room temperature for 20 min, and 2-(bromomethyl)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxirane (300 mg, 0.83 mmol) in dry DMF (4 ml) was then added. The resulting mixture was stirred at 50° C. for 20 h and then at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with AcOEt, and the extracts were dried and concentrated to dryness under reduced pressure. The filtrates were combined and concentrated to dryness under reduced pressure. Purification of the residue on silica gel gave 1-{[3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-2-iodo-1H-imidazole as a 55/45 mixture of diastereoisomers [298 mg, colourless solid, yield 72%; HPLC/MS: m/z=473 (M+H); log P(HCOOH)=2.92 (major diastereoisomer), 3.31 (minor diastereoisomer)].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[C:3]=1[C:4]#[N:5].[BrH:13].C([O-])(O)=O.[Na+].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(O)(=O)C.ClCCl>[Br:13][C:4]1[C:3]2[C:6](=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[CH:10]=[C:11]([NH:12][C:26](=[O:28])[CH3:27])[N:5]=1
Reactant: Br
Reactant: N#CCc1cccc(Cl)c1C#N
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc2cccc(Cl)c2c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
2-Chloro-6-(cyanomethyl)benzonitrile (3.12 g, 17.7 mmol) was added to a solution of HBr in acetic acid (20 mL) and stirred at room temperature overnight. The reaction mixture was added drop wise to a saturated solution of NaHCO3. The resulting precipitate was collected by filtration to give a yellow solid, which was stirred in dichloromethane (100 mL). Triethylamine (3.7 mL, 26.5 mmol) and acetyl chloride (1.9 mL, 26.7 mmol) were added and the reaction mixture was stirred overnight at room temperature. Solvents were evaporated and residue was triturated with water, then ether, to the title compound as a pale yellow solid (2.67 g, 8.91 mmol, 51%). 1H NMR (d6-DMSO, 400 MHz) δ 8.47 (s, 1H), 8.00 (dd, 1H, J=8.6, 1.3 Hz), 7.74-7.72 (m, 1H), 7.67-7.64 (m, 1H), 2.14 (s, 3H). LC-MS (1) Rt=2.05 min; m/z (ESI+) 299 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].C([N:24]1C=CC2C(=CC=C(F)C=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:24][C:17](=[O:19])[CH:16]=[C:5]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2C=CN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate (70.6 g, 206 mmol), triethylsilane (176 g, 1517 mmol) and trifluoroacetic acid (121 mL, 1568 mmol) in 1,2-dichloroethane (500 mL) was stirred at 80° C. for 3.5 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (250 mL) and brine (200 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (200 mL) to yield the title compound as white crystals (47.6 g). UPLC-MS: MS 344.1/346.1 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1C=CC3N=C(C)OC=3C=1)C=2)=O)CCC.P(Cl)(Cl)([Cl:63])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:63])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4nc(C)oc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(C)oc4c3)cc2c1O
Temperature: 120 °C

Procedure:
A solution of the regiosomeric mixture of 1,4-dihydroxy-6-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7-(2-methyl-benzooxazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester synthesized as described above (2.5 g, 6.12 mmol), and phosphorus oxychloride (685 μL, 7.35 mmol) in dichloroethane (30 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was stirred at ambient temperature with a saturated sodium bicarbonate solution for thirty minutes. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give a solid (1.72 g). It was recrystallized from ethyl acetate (130 mL) to give the title compound as a white solid (844 mg): MS: (+) m/z 427.16 (M+1).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[NH4+].[NH4+].[N+:7]([O-])([O-])=O.[La+3].[N+:12]([O-])([O-])=O.[N+:16]([O-])([O-])=O>O>[NH3:7].[C:1](=[O:3])=[O:2].[C:1](=[O:2])([O-:4])[O-:3].[NH4+:12].[NH4+:16]
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [La+3]
Agent: [NH4+]
Solvent: O
Product: N
Product: O=C=O

Procedure:
FIGURE shows an embodiment of the process according to the invention. The sodium zeolite is treated in an ion exchanger stage first with an aqueous ammonium carbonate solution, then with an aqueous lanthanum nitrate solution. Thereafter, treated zeolite and mother liquor are separated by a suitable process, for example filtration, and optionally dried. The zeolite thus pretreated is calcined in a furnace, releasing ammonia. These stages can be conducted twice or more in succession. The mother liquor from the removal stage is supplied to a column which comprises a stripping section and is heated at the bottom with an evaporator or by direct addition of steam. The temperature increase drives out ammonia and carbon dioxide, entraining water in the form of steam. The vaporous mixture is condensed in a direct or indirect condenser, and ammonia and carbon dioxide recombine with water to give aqueous ammonium carbonate. The ammonium carbonate solution thus obtained is recycled into the ion exchange stage. Via the bottom of the column, an aqueous sodium carbonate solution is discharged. The ammonia from the calcining furnace is optionally conducted with supplementary ammonia and carbon dioxide into the column upstream of the condenser.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[CH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>O1CCCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[CH:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2ncnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To the mixture of 4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one (19 mg, 0.077 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (20 mg, 0.12 mol) at rt. The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (3.10 mg, 12.4%). LCMS calculated for C11H14BrN6O (M+H): 325.0. found: 325.0, 327.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: BrCc1ccccc1
Product: Cc1c(C)n(Cc2ccccc2)c2c(Cl)nccc12
Yield: 42 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 42%)
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.Cl.[NH2:9][OH:10].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>O.Cl>[OH:10][N:9]=[CH:2][C:3]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[O:5]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NC(=O)C=NO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloral hydrate (38 g, 0.223 mol), hydroxylamine hydrochloride (41 g, 0.594 mol) and sodium sulphate (40 g, 0.281 mol) in water (800 mL) was heated to 90° C. To this mixture was added a solution of p-toluidine (20 g, 0.1866 mol) in conc. HCl (30 mL) The resulting mixture was stirred for another 2 h. After the reaction is completed, the reaction mixture was cooled to room temperature, the precipitate was filtered and washed with water (100 mL). The solid was dried in a vacuum oven to get the required product as a grey coloured solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:28])[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][C:24]([F:27])([F:25])[F:26])[CH:18]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)Cc1cccc(SC(F)(F)F)c1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc(SC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of diisopropylamine (1.5 mL, 10.5 mmol) in dry tetrahydrofuran (27 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (4.2 mL, 10.5 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester (2.50 g, 10.0 mmol) in a small amount of tetrahydrofuran. The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.10 g, 10.0 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (50 mL) and then partitioned between water (75 mL) and ethyl acetate (75 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 8/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromethylsulfanyl-phenyl)-propionic acid methyl ester (2.95 g, 89%) as a colorless oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1047.
Reaction SMILES: [CH3:1][NH2:2].O.C(O[C:7]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Br:16])[N:10]=1)=[O:8])C>CO>[NH2:15][C:14]1[C:9]([C:7]([NH:2][CH3:1])=[O:8])=[N:10][C:11]([Br:16])=[CH:12][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)c1nc(Br)ccc1N
Solvent: CO
Solvent: O
Product: CNC(=O)c1nc(Br)ccc1N
Temperature: 100 °C

Procedure:
A 10M solution of Methylamine in H2O (30.0 mL, 386 mmol) was added to a stainless steel reactor containing 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester (Compound 6E, 7.614 g, 31.07 mmol) in MeOH (20.0 mL). The reactor was sealed and heated to 100° C. for 16 hours. The cooled reaction mixture was transferred to a round bottom flask and concentrated in vacuo forming a yellow precipitate which was collected by filtration. Further precipitate formed in the filtrate which was also collected. The combined precipitates were dried in vacuo to afford the title compound as 6.18 g of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (br. s., 1H), 7.27 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.02 (br. s., 2H), 2.97 (d, J=5.1 Hz, 3H).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.C(OCC)(=O)C>[CH2:17]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[N:1]=[CH:2][N:3]=1)=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(C(=O)O)ncn1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)ncn1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
Pyrimidine-4,6-dicarboxylic acid is dissolved in dichloromethane (DCM) at 24° C. To the solution is added three equivalents of thionyl chloride. The reaction mixture is stirred at 24° C. for 1 hour. The reaction mixture is concentrated by evaporation of the solvent under reduced pressure to give an oil. The oil is dissolved in ethyl acetate, and three equivalents of benzylamine are added. The reaction mixture is stirred at 24° C. for 3 hours. The solvent is than removed by evaporation under reduced pressure to give an oil. The oil is purified by chromatography over silica gel, eluting with hexane-ethyl acetate (9:1) to 100% ethyl acetate. The fractions shown by thin layer chromatography to contain a single product component are combined and concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1>CN(C)C=O>[ClH:17].[CH3:10][C:11]1[N:16]=[C:15]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1
Reactant: Cc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 58.1 %

Procedure:
After 2-methyl-4-fluoroaniline(0.8 ml, 7.2 mmol) was added to a mixture solution of 6-methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(1.0 g, 3.8 mmol) and dimethylformamide(10 ml), 0.85 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH3:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:17][C:16]([F:19])([F:18])[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:21])([F:33])[F:34])(=[O:26])=[O:27])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: CCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 96 h
Yield: 37.7 %

Procedure:
To a solution of 2.7 g of 3-(trifluoromethyl)pentyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 1.2 g of potassium carbonate at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for four days, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.20 g of methyl 5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)heptanoate (hereinafter referred to as the present compound (4)).
Reaction SMILES: C(OCC)(=O)C.C[O:8][C:9](=[O:35])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[C:27]([CH2:28][CH2:29][CH3:30])=[CH:26][C:25]3[C:24]([CH3:32])([CH3:31])[CH2:23][CH2:22][C:21]([CH3:34])([CH3:33])[C:20]=3[CH:19]=2)=[O:17])=[CH:12][CH:11]=1>[OH-].[K+].CO>[CH2:28]([C:27]1[C:18]([C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([OH:35])=[O:8])=[CH:15][CH:14]=2)=[O:17])=[CH:19][C:20]2[C:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][C:24]([CH3:31])([CH3:32])[C:25]=2[CH:26]=1)[CH2:29][CH3:30]
Reactant: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C

Procedure:
3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (prepared from Friedel-Crafts alkylation/cyclization of n-propylbenzene with 2,5-dichloro-2,5-dimethylhexane) was combined with monomethylterephthalate acid chloride in dichloromethane and treated portionwise at ambient temperature with aluminum chloride until the spontaneous reflux had subsided and the solution become dark red/brown in color. After stirring at room temperature for 10-15 min, the reaction was poured into ice water and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The crude product was crystallized (CH2Cl2/hexanes) to give 4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid methyl ester as white crystals (95%): TLC (20% ethyl acetate: 80% hexanes) Rf 0.7; mp 112-114° C.; 1H-NMR (400 MHz, CDCl3) δ8.19 (½ABq, J=8.0 Hz, 2H, ArH); 7.89 (½ABq, J=8.0 Hz, 2H, ArH), 7.22 (s, 1H, ArH), 7.20 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 2.64 (t, J=8.0 Hz, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.55 (m, 2H, CH2), 1.31 (s, 6H, 2CH3), 1.20 (s, 6H, 2CH3), 0.89 (t, J=7.5 Hz, 3H, CH3), Anal. (C23H32O3) C, H. The ester was hydrolyzed in excess KOH/MeOH at ambient temperature for 24 h. The methanol was removed in vacuo. The residue was taken-up in water and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted 3 times with EtOAc; the organic layers were combined, and washed with water (2×) and brine. The organic solution was dried (Na2SO4), filtered, and concentrated to give 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (101). Crystallization gave a white powder (93%): TLC (10% MeOH: 90% CHCl3) Rf 0.3; mp 252-254° C.; 1H-NMR (400 MHz, CDCl3) δ8.20 (½ABq, J=8.0 Hz, 2H, ArH), 7.90 (½Abq, J=8.0 Hz, 2H, ArH), 7.20 (s, 1H, ArH), 7.25 (s, 1H, ArH), 2.64 (t, J=8.0 Hz, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.55 (m, 2H, CH2), 1.31 (s, 6H, 2CH3), 1.20 (s, 6H, 2CH3), 0.89 (t, J=7.5 Hz, 3H, CH3), Anal. (C25H30O3) C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cn1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 4-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (15-3, 0.40 g, 1.22 mmol) in THF (6.1 mL) was added triethylamine (0.370 g, 3.65 mmol) followed by isonicotinoyl chloride hydrochloride (0.430 g, 2.42 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was purified by column chromatography on silica gel (EtOAc:hexanes=5:1 as eluant) to give N-(4-(4-(5-methoxypyrazin-2-yloxy)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (15, 0.12 g) as yellow solids in 23% yield: 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J=5.0 Hz, 2 H), 8.03 (d, J=6.5 Hz, 2 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 6.81 (s, 3 H), 3.97 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:21](O)=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:21]2[C:20]([F:23])=[C:19]([F:24])[C:18]([F:25])=[C:17]([F:26])[C:16]=2[F:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Fc1c(F)c(F)c(OC2CCN(Cc3ccccc3)CC2)c(F)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A stirred mixture of 10.33 g of 1-benzyl-4-hydroxypiperidine, 9.93 g of pentafluorophenol, and 15.58 g of triphenylphosphine in 200 ml of benzene was cooled to 10° C. At this temperature, a solution of 10.35 g of diethyl azodicarboxylate in 50 ml of benzene was added, dropwise, over one hour. After stirring for 20 hours at ambient temperature, the reaction mixture was filtered and concentrated to an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with ethylacetate/dichloromethane 1:1). Evaporation of the appropriate fractions afforded 14.5 g of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. Conversion of the free base to the corresponding hydrochloride salt afforded 8.2 g (42%) of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride, m.p. 244°-246° C.