Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)[CH:34]=1
Reactant: O=Cc1cccnc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2cccnc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 3-pyridine carboxaldehyde (8.6 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Pyridin-3-ylmethyl)-piperidin-3-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 12 as a colorless oil (15.6 mg, 76%). LRMS338.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21]>C(O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: Cc1ccc(O)c(Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C

Procedure:
The product from Example 1d (893 mg, 5 mmol) and 2-Amino-4-methyl-phenol (616 mg, 5 mmol) in ethanol (20 mL) were refluxed for 4 hours. The mixture was cooled to room temperature and evaporated. The residue was triturated with hexane/ethyl acetate (3:1) to give the title compound in quantitative yield as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH2:4][CH2:5]C(Cl)=O.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH2:4][CH3:5]
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: CCC(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In the second step, a solution of 3-oxo-4,10-oxa-tricyclo[5,2,1,02,6]nonan-(8)9-ol (21.3 g, 125.0 mmol) in 200 mL acetonitrile was added to the 5-bromo-4,4,5,5-tetrafluoropentanoyl chloride solution. To the mixture was added 9.93 g (125.5 mmol) pyridine and the reaction was stirred at ambient temperature under nitrogen for 16 h. The solvent was removed under reduced pressure and the resulting oily residue was dissolved in 250 mL dichloromethane. The later solution was washed once with 200 mL 1 N HCl, washed once with 200 mL saturated aqueous NaHCO3, dried over MgSO4 and the solvent removed under reduced pressure to produce 3-oxo-4,10-oxa-tricyclo[5,2,1,02,6]nonan-(8)9-oxycarbonyl]-4-bromo-3,3,4,4-tetrafluorobutane as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([CH2:20][C:21]([OH:23])=O)=[CH:13][CH:12]=1.[OH-].[NH4+:25]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([CH2:20][C:21]([NH2:25])=[O:23])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Combine {4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetic acid (0.920 g, 2.872 mmol), and 1,1-carbonyldiimidazole (2.365 g, 14.585 mmol) in tetrahydrofuran (15 ml), and stir for 1 hour under nitrogen. Cool the mixture to 0° C., and add concentrated aqueous ammonium hydroxide (2 ml). Remove the ice bath, and stir the mixture at room temperature for 16 hours. Dilute the mixture with ethyl acetate, wash with water and brine, dry over sodium sulfate, filter, and concentrate. Purification using flash chromatography and eluting with hexane:ethyl acetate gives 0.732 g (80%) of the title product as a white solid. Mass spectrum: electrospray (m/z) 236 (M++1-85).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:16]1([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)N1CCCC(c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCCC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner analogous to Example 60; 1 equivalent of (4-Bromo-phenyl)-(3-phenyl-piperidin-1-yl)-methanone would be combined with 1.5 equivalents of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 equivalents of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would then be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]([CH2:15][OH:16])[CH2:12][C:13]2=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N2CC(C(=O)O)CC2=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCc1ccc(N2CC(CO)CC2=O)cc1
Yield: 81.1 %

Procedure:
1-(4-Ethylphenyl)-5-oxo-3-pyrrolidinecarboxylic acid (5.00 g) is suspended in carbon tetrachloride (15 ml) and thereto is added thionyl chloride (2.32 ml). The reaction mixture is heated with stirring under refluxing for 1 hour and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (25 ml) and thereto is added dropwise a solution of sodium boron hydride (1.61 g) in dimethylformamide (about 16 ml) under ice-cooling. The mixture is further stirred for 1 hour. Methanol (13 ml) and conc. hydrochloric acid (1.87 ml) are successively added dropwise into the reaction mixture and the mixture is concentrated under reduced pressure. Ethyl acetate (120 ml) is added to the residue and the mixture is washed with water three times, dried over anhydrous magnesium sulfate, and then concentrated again under reduced pressure. To this residue is added a mixed solvent (about 50 ml) of ethyl acetate/hexane [1:20 (v/v)]. The mixture is allowed to stand and the precipitated crystal is collected by filtration to give the desired product (3.81 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-(2,6-difluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (236 mg), (R)-pyrrolidin-3-ol (2 eq.), HATU (1.2 eq.) and TEA (0.2 mL) in DMF (3 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 16 mg of the titled compound as a yellow solid.
Reaction SMILES: CO.ClCCl.C(OC([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH:26]=[CH2:27])[C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.C(O)C.[IH:35]>C(OCC)C>[IH:35].[CH2:25]([N:24]1[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[N:21]=[C:20]1[N:16]1[CH2:17][CH2:18][CH2:19][NH:13][CH2:14][CH2:15]1)[CH:26]=[CH2:27]
Reactant: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol). After about 30 minutes, when the gas evolution ceases, add allyl bromide (0.35 mL 4.0 mmol). Heat to 75° C. After 4 hours, dilute with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.83 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.9 g, 2.5 mmol) and ethanol (10 mL). Add aqueous hydriodic acid (10 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][SH:25])=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:25][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: C#CC(=Nc1ccccc1)SCc1ccccc1
Reactant: Fc1ccc(CS)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CSC=CC(=Nc2ccccc2)SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Benzyl N-phenylpropynthioimidate (0.30 g) and 4-fluorobenzylmercaptan were dissolved to chloroform (15 ml), catalytic amount of potassium t-butoxide was added thereto under ice-cooling and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain benzyl 3-(4-fluorobenzylthio)-N-phenyl-thioacrylimidate (0.15 g) as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[CH2:17][CH2:16]1
Reactant: ClCC1CC1
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.2 %

Procedure:
A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol), (chloromethyl)cyclopropane (4.3 g, 32 mmol) and K2CO3 (8 g, 58 mmol) in acetone (80 mL) was stirred at 80° C. for 5 h. The mixture was quenched with water (40 mL). Extractive work up with ethyl acetate and purification by preparative HPLC gave the title compound (2.5 g, 28.6%). 1H NMR (CDCl3, 400 MHz) δ 8.12 (d, J=2.3 Hz, 1H), 7.84 (dd, J1=2.3 Hz, J2=8.7 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 3.99 (d, J=6.7 Hz, 2H), 3.05 (s, 3H), 1.23-1.43 (m, 1H), 0.70 (d, J=7.9 Hz, 2H), 0.44 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[S:13][C:14]([CH:17]=[N:18]O)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CS(Cl)(=O)=O>N1C=CC=CC=1.ClCCl>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cn1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a 0° C. solution of Example 68E (464 mg, 1.66 mmol) in pyridine (10 mL) was added methanesulfonyl chloride (0.53 mL, 6.64 mmol). The reaction was warmed to 25° C., stirred for 4 hours and diluted with dichloromethane (50 mL). The mixture was washed with 10% HCl (2×50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 20% ethyl acetate in hexanes to provide 363 mg of the title compound (84%) as a off-white solid, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.25 Hz, 6H) 5.14-5.30 (m, 1H) 6.89 (d, J=9.19 Hz, 1H) 7.87 (dd, J=9.01, 3.13 Hz, 1H) 8.23 (s, 1 H) 8.31 (d, J=2.57 Hz, 1H); MS (ESI) m/z 262.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:22])([CH3:21])[CH2:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=1.[Na].[I-].[CH3:25][S+](C)(C)=O>CS(C)=O>[CH3:21][C:13]([C:9]1[CH:8]=[C:7]([CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:12]=[CH:11][CH:10]=1)([CH3:22])[CH2:14][C:15]1([C:16]([F:18])([F:19])[F:17])[CH2:25][O:20]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: [I-]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(C2OCCCO2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one (1 g, 3 mmol) in 4.1 mL of anhydrous DMSO was added the sodium ylide of trimethylsulfoxonium iodide (3.0 mL of a 0.8M solution in DMSO) over 5 minutes. The reaction was stirred 2 hours and quenched with water and ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded 2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-[1,3]dioxane as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.I[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]I>>[O:20]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:14][C:9]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:16])[O:3]2)=[CH:10][CH:11]=1)[CH2:19][CH2:18][O:15][CH2:12][CH2:13][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: ICCOCCOCCOCCI
Product: CC1(C)OB(c2ccc(OCCOCCOCCOCCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)OC1(C)C

Procedure:
By following the process described in Example R65, Example R66 is prepared by dimerization of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol with 1-iodo-2-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}ethane (Example R4). A white powder is obtained.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[N:13][N:14]([CH:23]([F:25])[F:24])[C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[S:9][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[F:25][CH:23]([F:24])[N:14]1[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[C:11]([C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[N:7]=2)[CH:12]=[N:13]1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(F)F)c2-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(-c2cnn(C(F)F)c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of the compound (0.380 g, 1.00 mmol) obtained in step 5 in ethanol (4.0 mL) was added 6N aqueous sodium hydroxide solution (0.500 mL, 2.99 mmol) at room temperature, and the mixture was heated under reflux for 30 min. After cooling to room temperature, concentrated hydrochloric acid was added until the mixture became pH 6. The reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give (2-[1-(difluoromethyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl)acetic acid (0.320 g, 91%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N,N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-{(1-hydroxycyclohexyl)-[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=1[CH2:57][C:58]([OH:60])=O>>[Cl:56][C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([Cl:49])[C:51]=1[CH2:57][C:58]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:60]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2c(Cl)cccc2Cl)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,6-dichlorophenylacetic acid, mp 203°-205° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32]O)=[CH:29][C:23]=3[CH2:22][S:21](=[O:39])(=[O:38])[C:20]=2[CH:40]=1)=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][O:36][CH2:35][CH2:34]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:38])(=[O:39])[C:20]=2[CH:40]=1)=[O:15]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCO)CCO)cc(Cl)c1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCOCC3)cc(Cl)c1O2

Procedure:
Catalytic amount of p-toluene sulphonic acid (PTSA) was added to a stirred solution of compound of Example 13 (1 g, 2.19 mmol) in xylene (50 mL). Reaction mixture was refluxed in Dean-Stark apparatus for 6 h and xylene was removed by distillation. Reaction mixture was diluted with 50 mL water, neutralized using 10% sodium bicarbonate solution and extracted using ethyl acetate (3×50 mL), washed with brine (2×10 mL), dried on sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet. ether) to obtain the title compound. Yield: 0.32 g, (33%); mp: >320° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.68 (s, 3H, CH3), 3.15 (s, 4H, 2CH2), 3.74 (s, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.76 (s, 1H, Ar), 6.88 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.44 (s, 1H, Ar); MS: m/e (EI) 437 (M+).
Reaction SMILES: C[O:2][C:3]1([CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[N:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:16]N1C(=O)CCC1=O>CN(C)C(=O)C.C(OCC)(=O)C>[Br:16][C:13]1[CH:12]=[N:11][N:10]([CH2:9][C:3]2([OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:14]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1(Cn2nccc2C)CCCCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnn1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 165B (10.6 g) in N,N-dimethylacetamide (30 mL) was added N-bromosuccinimide (9.72 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (400 mL) and washed with aqueous sodium bisulfite, water, and brine. Evaporation of the solvent gave the crude product which was used in the next reaction without further purification.