Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH3:19].C(O)(=O)C(O)=O>O1CCCC1.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([N:23]([CH2:22][CH2:21][N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:24][CH3:25])=[O:12])[CH2:7]1
Reactant: CCNCCN(CC)CC
Reactant: O=C(Cl)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCN(CC)C(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A stirred solution of 7 g (0.024 mole) of 3-(3,5-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 70 ml of tetrahydrofuran was treated with 7 g (0.05 mole) of N,N,N'-triethylethylenediamine (slight exothermic) and stirred at ambient temperature overnight. The mixture filtered to remove a small amount of precipitate. The filtrate was diluted with 200 ml of ice water, extracted with 3×100 ml of benzene and the combined extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil, 8.24 g. The oil was dissolved in acetone, treated with 1.9 g of oxalic acid and heated until dissolved. A fine amorphous gel was removed by filtration and the filtrate diluted with isopropyl ether until cloudy. The salt was allowed to precipitate overnight. After 2 weeks the oil which separated from the acetone/isopropyl ether failed to crystallize. The solvents were removed by decantation and the residual oil converted back to the free base. The free base in methylene chloride was treated with 200 g of florisil and diluted with enough methylene chloride to give a stirrable slurry. After 30 minutes the slurry was filtered and the florisil washed with 2 volumes of methylene chloride. The florisil was suspended in 500 ml of methanol and transferred to a column. The column was washed with an additional 500 ml of methanol. Concentration in vacuo of the combined methanol effluents gave 7.6 g of dark oil which was chromatographed on a 100 g alumina column by eluting with a 0-5% methanol/acetonitrile gradient. The first 2 fractions were discarded and the remainder combined and concentrated to an oil (5.2 g). The oil was dissolved in ethyl ether, filtered to remove traces of alumina, concentrated in vacuo and excess solvent removed by pumping under high vacuum at 55° C. for 18 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(C2(C(=O)N3CCN(C)CC3)CCOCC2)cc1
Yield: 77 %

Procedure:
The title compound (515 mg, 77%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, N-methyl-piperazine and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) similarly to the procedure used for example 166. HRMS ESI+ m/z 319.2009 [MH]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2

Procedure:
To a well-stirred and ice-cooled solution of 1,4-dioxa-8-azaspiro[4.5]decane (34.9 mmol, 5 g) in dichloromethane (200 mL) under an argon atmosphere, was added triethylamine (52.4 mmol, 7.3 mL) and then benzyloxycarbonyl chloride (42 mmol, 5.93 mL) dropwise. The suspension was stirred at room temperature for 24 hours and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give an oily residue which was chromatographed on silica gel eluting with a mixture of ethyl ether and petroleum ether to afford 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro [4,5] decane in quantitative yield. 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 3.89 (s, 4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].C1(C(C)CO)C=CC=CC=1>>[F:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([Cl:14])(=[O:12])=[O:13])=[CH:9][CH:10]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(CO)c1ccccc1
Product: CC(CF)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
Following the procedures analogous to that used for the preparation of 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride, but starting with 2-phenyl-1-propanol in step a.3.g.1, the title compound was prepared.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[CH2:8]([O:15][CH:16]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([O:19]CC1C=CC=CC=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:8]([O:15][CH:16]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([OH:19])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)C(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Yield: 96.9 %

Procedure:
Water (20 ml) and potassium carbonate (10.64 g) were added to a solution of benzyl dibenzyloxyacetate (11.15 g, prepared as described in Step 1 above) in tetrahydrofuran (80 ml) and the mixture heated under reflux for twenty-four hours. It was allowed to cool, poured into water, extracted with ether, acidified with concentrated hydrochloric acid and again extracted with ether. The extract from acidic solution was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (8.12 g), used crude in Step 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>CCOCC.CC#N>[CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][I:34]
Reactant: II
Reactant: COC(=O)COCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)COCCI
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH3CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filtered off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Br:11][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:18])[CH2:1][C:4]=2[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(F)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2cc(F)cc(Br)c2O1
Yield: 77.9 %

Procedure:
Treatment of 2-allyl-6-bromo-4-fluorophenol (25.1 g, 0.109 mol) with 3-chloroperoxybenzoic acid (77%, 56.24 g, 0.326 mol) followed by potassium carbonate (62.19 g, 0.45 mol) generally according to the procedure described for Intermediate 9 provided 20.98 g (78%) of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Rf=0.54 (silica, ethyl acetate:hexanes 1:1); mp 53-57° C.; Anal. calcd. for C9H8BrFO2.0.1 C4H8O2: C, 44.13; H, 3.47. Found: C, 44.17; H, 3.16.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][NH:5][C:6]([CH:8]([CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:9][CH:10]([OH:33])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:7].CN(C1C=CC=CN=1)C.[C:51](OC(=O)C)(=[O:53])[CH3:52]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][NH:5][C:6]([CH:8]([CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])[CH2:9][CH:10]([O:33][C:51](=[O:53])[CH3:52])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COC(CNC(=O)C(CCC(C)(C)O)CC(O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CNC(=O)C(CCC(C)(C)O)CC(OC(C)=O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [4-(2,2-dimethoxy-ethylcarbamoyl)-1-(3-fluoro-benzyl)-2,7-dihydroxy-7-methyl-octyl]-amide (192 mg, 0.336 mmol) in pyridine (0.6 mL) was added dimethylaminopyridine (DMAP) (10 mg, 0.082 mmol) and acetic anhydride (0.093 mL, 0.984 mmol). The resulting solution was stirred for 3 hours then diluted with methylene chloride and washed with 1 M hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (198 mg, 96%).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:30]=[O:31])[CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C=O)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 50 mg, 0.127 mmol) and 4-nitrophenyl formate (29.7 mg, 0.177 mmol) were dissolved in DCM (1.27 mL) and triethylamine (0.021 mL, 0.152 mmol) was added. The RM was stirred at RT for 0.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a white foam (tR 3.25 min (conditions 1), MH+=423).
Reaction SMILES: [Si:1]([C:8]#[CH:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N)CC.[Cl:14]/[CH:15]=[CH:16]\Cl>CCOCC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14]/[CH:15]=[CH:16]\[C:9]#[C:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cl/C=C\Cl
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCCN
Product: CC(C)(C)[Si](C)(C)C#C/C=C\Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of tert-butyldimethylsilylacetylene (14.5 g, 103 mmol, 1 equiv), n-propyl amine (42.5 mL, 517 mmol, 5.00 equiv), and (Z)-1,2-dichloroethene (32.5 mL, 413 mmol, 4.00 equiv) in ether (150 mL) was deoxygenated at -78° C. by alternately evacuating the reaction vessel and flushing with argon (8×). The deoxygenated solution was transferred to an ice bath and copper iodide (2.95 g, 15.5 mmol, 0.15 equiv) was added. The mixture was cooled to -78° C. and was deoxygenated as above. In a similar fashion, bis(triphenylphosphine)palladium(II) chloride (3.64 g, 5.17 mmol, 0.05 equiv) was added at 0° C. and the reaction solution was deoxygenated at -78° C. The deoxygenated reaction mixture was warmed to 23° C. and was stirred at that temperature for 3 h. The product solution was washed with 1:1 saturated aqueous potassium carbonate solution:saturated aqueous ammonium chloride solution (3×150 mL), was dried over sodium sulfate, and was concentrated. The residue was purified by distillation under reduced pressure (bp 60°-65° C., mmHg) to afford (Z)-1-chloro-4-(tert-butyldimethylsilyl)-1-buten-3-yne as a clear oil (12.5 g, 60%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:12])[CH:9]=2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CC(N(C)C)=O>[OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:9]=2)[CH2:4]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OCC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(CO)C3)nc1
Reaction time: 5 h
Yield: 44 %

Procedure:
Combine in a round bottom flask equipped with a stir, Dean Stark Trap filled with toluene, and reflux condenser 2-Hydroxymethyl-indan-5-ol (630.2 mg, 3.84 mmol), K2CO3 (690.0 mg, 5.0 mmol), 6-Chloronicotinamide (600.0 mg, 3.84 mmol) and a solution of DMA:Toluene (15:5 mL). After the reaction refluxes under nitrogen atmosphere for 5 hours, concentrate under reduced pressure and then add ethyl acetate. Wash the organic layer several times with water, then brine, and dry over Na2SO4. After concentrating the reaction mixture under reduced pressure, flash chromatograph using 20% THF, 7% 1N NH3-MeOH, 73% DCM eluent to afforded 481.1 mg, 1.69 mmol (44% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.8-2.2 (4H, m), 2.6-2.8 (3H, m), 3.6-3.8 (2H, br d), 3.9-4.0 (1H, m), 6.1-6.6 (2H, br d), 6.8-7.0 (3H, m), 7.2-7.3 (1H, m), 8.1-8.2 (1H, m), 8.6 (1H, s); MS m/z 285 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH3:12]OS(OC)(=O)=O.C(N(CC)CC)C>[Au].C(Cl)Cl>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:12])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: [Au]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C
Yield: 103.1 %

Procedure:
Into a 3-neck 1 liter round bottom flask equipped with a magnetic stirrer, reflux condenser fitted with a drying tube, addition funnel with a septum and a nitrogen inlet, 100 g (0.659 mole) 2-carboxybenzaldehyde, about 140 ml methylene chloride and 162.8 g [122.2 ml (1.291 moles)] dimethylsulfate were placed. The mixture was heated to reflux 135.89 g [187.2 ml (1.343 moles)] triethylamine was added dropwise, maintaining a brisk reflux. After the addition was complete, the resulting gold-colored solution was allowed to cool to room temperature, and then washed with 400 ml water. After the layers were separated, the aqueous phase was extracted with 400 ml methylene chloride. The organic layers were combined and washed with 500 ml of a saturated aqueous sodium bicarbonate solution and with 500 ml water. The organic phase was dried over magnesium sulfate and then concentrated to give 111.5 g of the product as a gold liquid.
Reaction SMILES: O.[NH2:2]N.[N:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:13][CH2:12]2)=[S:10])C=CN=C1>C(O)C>[F:26][C:25]([F:28])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([NH:4][NH2:2])=[S:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: NN
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(C(=S)n2ccnc2)CC1
Solvent: O
Solvent: CCO
Product: NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
The mixture of hydrazine hydrate (0.584 mL, 12.03 mmol) and [4-(imidazole-1-carbothioyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (4.03 g, 10.94 mmol) in anhydrous ethanol was refluxed for 3 hours. The reaction mixture was cooled to room temperature and kept in the fridge overnight. The precipitate formed was collected by filtration and washed with ethanol, dried in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioic acid hydrazide in 60% yield (2.20 g). 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.55 (dd, J=7.5, 7.5 Hz 1H), 7.33 (d, J=7.5 Hz, 1H), 3.70-4.00 (m, 8H). MS (ES+) m/z 333 (M+1).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][C@@H:6]([CH2:8][OH:9])[C@H:5]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:30][C:2]1([F:1])[CH2:7][C@@H:6]([C:8]([OH:33])=[O:9])[C@H:5]([C:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:13][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2CO)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexyl}methanol (1.64 g, 3.63 mmol) in acetone (40 mL) was treated at 0° C. with Jones reagent (3.8 mL) followed by stirring at rt for 30 min. Water was added and the mixture was extracted with two portions of ethyl acetate. The combined organics were washed twice with water then with a saturated aqueous solution of NaCl before drying over Na2SO4. Concentration in vacuo gave (1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxylic acid as a faint-yellow foam.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH:10]=[CH2:11]>CC(C)=O>[CH2:11]([O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH3:3])[CH:10]=[CH2:9]
Reactant: CN(C)CCO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOCCN(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17.5 g) and dimethyl formaldehyde (400 mL) were added to a 2-L round-bottom flask. After cooling the flask to 0° C. by immersing in an ice bath, 2-dimethylaminoethanol (0.398 mol) was added. After stirring for about 30 minutes and adding allyl bromide (0.4378 mol), the mixture was stirred for 3 hours after raising the temperature of the reactor to room temperature. Upon completion of reaction, the reaction was terminated by adding water to the flask and the product was extracted using diethyl ether. The extract was concentrated under reduced pressure and used in the next step without further purification. After filtration under reduced pressure, 2-(allyloxy)-N,N-dimethylethanamine was obtained through fractional distillation. Structural analysis was performed by NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)([CH3:4])([CH3:3])[CH3:2].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:38]([O:40][C:41]([C@@H:43]([NH:53][C@H:54]([C:56](O)=[O:57])[CH3:55])[CH2:44][S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:42])[CH3:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:56](=[O:57])[C@H:54]([CH3:55])[NH:53][C@H:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:44][S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCSC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C

Procedure:
In 25 ml of DMF were dissolved 2.6 g of the β-isomer of N-[(R)-1-ethoxycarbonyl-2-heptylthioethyl]-alanine prepared in Reference Example 29, 2.5 g of (S)-prolyl-(S)-proline t-butyl ester prepared in Reference Example 28, 1.7 g of WSCD.HCl and 1.1 g of HOBt. To the solution was added 3.6 ml of triethylamine while being stirred with ice cooling. The solution was stirred overnight. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 30:1 mixture of chloroform and methanol as an eluent), giving the title compound as a colorless oil. Yield 3.5 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:32][CH:31]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccccc2OCc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Yield: 96.3 %

Procedure:
A solution of 5 g (12.87 mmol) of methyl 4-({tert-butoxycarbonyl-[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoate from Example 3A in 100 ml of dry acetonitrile is mixed with 3.89 g (15.57 mmol) of 4-bromobenzyl bromide and 2.69 g (19.46 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). 6.88 g (12.4 mmol, 89% yield) of a solid are obtained.