Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@H:9]([C:13]([NH2:15])=O)[CH2:10]2)=[CH:5][CH:4]=1.[ClH:16]>C(O)(C)C>[ClH:16].[NH2:15][CH2:13][C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1)C[C@@H](C(N)=O)CC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)C[C@@H](CN)CC2

Procedure:
(ii') The salt is taken up in 0.1 N HCl, and the obtained solution is then extracted with ethyl acetate. The aqueous phase is made basic by the addition of a sodium carbonate solution and extracted with ethyl acetate. This last organic extract is then dried and evaporated to dryness to afford a residue which is dissolved in isopropanol. The compound of the title is then precipitated therefrom by the addition of hydrogen chloride saturated isopropanol and is recovered by filtration M.p. 228°-230° C.; [α]=-79.0° (c=1.4%, MeOH).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>CCO.O=[Pt]=O.O>[CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:19][CH2:18][CH2:17][NH:16][C:15]=2[N:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1ccc2nccnc2n1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCCCc1ccc2c(n1)NCCN2
Reaction time: 4 h

Procedure:
A mixture of 5-5 (0.83 g, 2.93 mmol), triethylamine (0.222 g, 2.20 mmol), and PtO2.H2O (0.083 g) in EtOH (15 mL) was stirred under a hydrogen balloon for four hours. The reaction was filtered through Celite and concentrated to yield a dark brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:18][CH2:19][CH2:20]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCC2)CC1
Temperature: 50 °C
Yield: 97.8 %

Procedure:
A mixture of Ethyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl) methyl]cyclobutanecarboxylate (4.2 g, 11.9 mmol, Step 5), 2N NaOH (18 mL) and EtOH (12 mL) was heated at 50° C. for 4 hrs. The resulting solution was cooled in ice bath and 2N HCl (ca 19 mL) was added until pH of the mixture was ca 5-6. The whole was extracted with CH2Cl2/iPrOH (3:1, 30 mL×3). Combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated to give 3.8 g (98%) of the titled compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35]Br.[NH4+].[Cl-]>CN(C=O)C>[CH2:28]([O:27][C:25]([C:24]1([C:4]2[CH:5]=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)[CH2:35][CH2:34][CH2:33]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.5 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,3-dibromopropane (0.757 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred for an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: CC(=O)O
Product: O=Cc1cc(F)c(O)c(Br)c1
Temperature: 45 °C
Reaction time: 26 h
Yield: 47.9 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzaldehyde (2 g, 14.3 mmol, 1 eq, Oakwood Products, Inc., West Columbia, S.C., USA) in acetic acid (60 mL), was added a solution of bromine (2.7 g, 17.0 mmol, 1.2 eq) in acetic acid (10 mL), and the mixture was stirred at 45° C. for 26 h. After concentration in vacuo, brine (50 mL) was added to the residue and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by reversed phase semi-preparative .HPLC to afford 1.5 g (48%) of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (26).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)[CH2:16][C:15]([CH3:34])([CH3:33])[CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].BrC1[CH:37]=[C:38]2[C:43](=CC=1)NCC(C)(C)C2.BrC1C=C(S(Cl)(=O)=O)C=CC=1C#N.ClC1C=C(N2C3C(=CC(C4C=CC(C(F)(F)F)=CC=4)=CC=3)C(C)(C)CC2)C=CC=1C1NC(=O)ON=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:43]1([C:2]2[CH:9]=[C:8]([S:10]([N:13]3[C:22]4[C:17](=[CH:18][C:19]([C:23]5[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=5)=[CH:20][CH:21]=4)[CH2:16][C:15]([CH3:33])([CH3:34])[CH2:14]3)(=[O:11])=[O:12])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:38][CH2:37]1
Reactant: CC1(C)CNc2ccc(Br)cc2C1
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(Br)c2)C1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC1(C)CCN(c2ccc(-c3noc(=O)[nH]3)c(Cl)c2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(C3CC3)c2)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
90 mg 2-Bromo-4-[3,3-dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-benzonitrile (derived from 6-Bromo-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline (synthesis described in WO 9629327), 4-(Trifluormethyl)phenyl-ylboronic acid and 3-Bromo-4-cyano-benzenesulfonyl chloride according to the method described for 3-{2-Chloro-4-[4,4-dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-phenyl}-4H-[1,2,4]oxadiazol-5-one in example 3), 153 mg Potassium phosphate (tribasic heptahydrate) 6 mg tricyclohexylphosphine and 42 mg cyclopropylboronic acid were dissolved in a mixture of 30 ml toluene and 0.6 ml water. An argon stream was bubbled through the reaction mixture for twenty minutes. Then 7.4 mg palladium(II)acetate were added and the reaction mixture stirred under microwave irradiation at 120° C. for one hour. The cooled reaction mixture was diluted with 50 ml ethyl acetate and filtered trough a pad of celite. The filtrate was evaporated and purified by chromatography on silica gel to obtain 73 mg 2-Cyclopropyl-4-[3,3-dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-benzonitrile.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:9]=[C:10]([Br:26])[C:11]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1)(=[O:14])=[O:13]>ClCCl>[Br:26][C:10]1[CH:9]=[C:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:7]=[C:6]([Br:5])[C:11]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]([CH3:24])[CH3:25])[CH:16]=1)(=[O:14])=[O:13]
Reactant: COC(=O)Cc1cc(Br)c(S(=O)(=O)c2ccc(OC)c(C(C)C)c2)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(S(=O)(=O)c2ccc(O)c(C(C)C)c2)c(Br)c1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A 1M solution of boron tribromide (17 mL, 0.017 mol) in dichloromethane was added to an ice-cooled solution of methyl 3,5-dibromo-4-(3-isopropyl-4-methoxyphenylsulfonyl)phenylacetate (3.5 g, 0.0067 mol), from Example 1, in dichloromethane. The mixture was warmed to room temperature and allowed to react for 3 hrs. Excess boron tribromide was quenched by the addition of methanol to the ice-cooled reaction mixture and the reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with water and brine, and dried (Na2SO4). The residue obtained after removal of the solvent was purified by flash chromatography (silica gel, 45:45:10 hexane:CH2Cl2 : acetone) to obtain methyl 3,5-dibromo-4-(4-hydroxy-3-isopropylphenylsulfonyl)phenylacetate (2.9 g, 0.0057 mol, 85% yield). MP: 159°-160° C. (hexane/ethyl acetate).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCOc1cnc(Cl)c2ccccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cnc(F)c2ccccc12
Temperature: 145 °C
Yield: 58.8 %

Procedure:
To a solution of 1-chloro-4-ethoxyisoquinolin (4.8 g, 23.12 mmol) in DMSO was added cesium fluoride (6.9 g, 46.24 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (2.6 g, 58.8%) as white solid. MS: MS m/z 192.3 (M++1).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:12][C:11](=[O:13])[O:10][C:8](=O)[CH2:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C1(C)C(C)=CC=CC=1>O>[N:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:8](=[O:10])[CH2:7][C:2]3([CH2:1][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:12][C:11]2=[O:13])=[CH:16][CH:17]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC2(CCCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 25 g of 2,2-cyclohexane diacetic anhydride, 12.92 g of 4-aminopyridine, and 400 ml of xylene is refluxed for 25 hours using a water separator. The hot, supernatant xylene solution is decanted from an oil precipitate (which is discarded), cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(4-pyridyl)-3-azaspiro[5,5]undecan-2,4-dione melting at 213°-215°.
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22]O)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22][Br:26])[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of 3-(2-benzylsulfonylhydrazino)-1-(3-hydroxypropyl)-6-methylpyrazinone, the product of Example 31 (0.429 g, 0.82 mmol) and carbon tetrabromide (0.328 g, 0.99 mmol) in dichloromethane (10 mL), is added triphenylphosphine (0.26 g, 0.99 mmol) portionwise with ice-bath cooling. After the addition is complete, the mixture is stirred for about an additional 2 hours. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography using ethyl acetate/n-hexane as eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 3-bromo-1H-indazole (0.20 g, 1.0 mmol), 4-methoxyphenylboronic acid (0.228 g, 1.5 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.228 g, 0.1 mmol) in ethylene glycol dimethyl ether (5 mL) and 2.0 M sodium carbonate solution (6 mL) under nitrogen was heated at 100° C. for 18 hours. It was quenched by water and extracted with chloroform. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.012 g, 5% yield): 1H NMR (CDCl3) δ 10.4 (br s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 7.46 (m, 2H), 7.22 (m, 1H), 7.06 (d, 2H), 3.89 (s, 3H); EI-MS (m/z) 224 [M]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:13]#[C:14][C:15]2([CH3:29])[CH2:20][CH2:19][C:18]3[C:21]([CH3:28])=[C:22]([OH:27])[C:23]([CH3:26])=[C:24]([CH3:25])[C:17]=3[O:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]2([CH3:29])[CH2:20][CH2:19][C:18]3[C:21]([CH3:28])=[C:22]([OH:27])[C:23]([CH3:26])=[C:24]([CH3:25])[C:17]=3[O:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2]
Reactant: COc1ccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)cc1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)cc1OC(C)=O
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A mixture of 0.7 g of rac-2-{2-[3-(acetyloxy)-4-methoxyphenyl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 0.2 g of 5% palladium on carbon and 50 ml of ethanol was hydrogenated at atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. Crystallization from ether/hexane gave 0.6 g of colorless crystals with m.p. 110°-113°.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.CN([CH:21]=[O:22])C.P(Cl)(Cl)(Cl)=O>>[CH2:6]([CH:1]([N:8]1[C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:17])[CH3:7]
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(CC)n1c2ccccc2c2cc(C=O)c3ccccc3c21
Temperature: 130 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To 11H-benzo[a]carbazole (3.00 g, 9.12 mmol) in DMF (7.02 g, 96.1 mmol) is added phosphoryl chloride (14.0 g, 91.3 mmol) at 0° C. After stirring for 2 hours, the mixture is heated at 130° C., and it is stirred for 1 hour. The mixture is cooled at room temperature, and poured into ice-water. The crude product is extracted with CH2Cl2, and it is washed with water and brine. The organic layer is dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (1.43 g, 43%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.80-0.90 (m), 1.21-1.46 (m), 2.25 (m), 4.68 (m), 7.40 (t), 7.52-7.60 (m), 7.66-7.74 (m), 8.19 (s), 8.61 (d), 8.64 (s), 9.65 (d), 10.39 (s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(C(=O)O)cc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)(c2ccc(-c3cn[nH]c3)cc2)CC1

Procedure:
4-(4-Carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, to obtain the title compound. LCMS (PS-A2) Rt 2.92 min [M+H]+ 448.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1.[BH4-].[Na+]>O1CCCC1CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC1CCCO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Reaction time: 20 h

Procedure:
253 mg (0.53 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]quinoline-2-carboxylic acid amide is dissolved in 10 ml of tetrahydrofuran-methanol (50%) and mixed with 101 mg (2.65 mmol) of sodium borohydride. After 20 hours, the solvent is removed in a vacuum. The subsequent recrystallization of the residue from ethyl acetate-methanol and purification of the mother liquor that is concentrated by evaporation on silica gel with hexane-ethyl acetate (0-50%) yield 116 mg (46% of theory) of the product.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24]([N:10]2[CH2:9][CH2:8][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)([OH:13])[CH2:12][CH2:11]2)=[O:25])[C:21]=1[CH3:22]
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)O
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Reaction time: 14 h
Yield: 30.2 %

Procedure:
To a 20 mL vial equipped with a magnetic stirring bar was added 63 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.3 mmol, 1.2 equiv.), 62 mg of (4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetic acid (0.26 mmol, 1.0 equiv), and 138 mg of benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.27 mmol, 1.0 equiv). The reagents were dissolved in 0.6 mL of DMA and to the resultant solution was added 0.18 mL of DIPEA (1.0 mmol, 3.8 equiv.). The reaction solution was stirred for 14 h and then poured into 50 mL of EtOAc. The organic extracts were washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 34 mg of 2-(4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (30% yield): MS (ES) M+H expected=413.2, found 413.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.69 (s, 1H), 7.27 (s, 1H), 7.11-7.14 (m, 2H), 6.98-7.03 (m, 2H), 5.06 (d, J=16.0 Hz, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.32-4.35 (m, 1H), 3.66-3.69 (m, 1H), 3.43-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.30 (s, 3H), 1.55-1.63 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:13][CH:12]=[N:11][C:10]=1[CH2:14][OH:15].[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.ClCCl.CO>[CH3:8][C:9]1[N:13]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[N:11][C:10]=1[CH2:14][OH:15]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1[nH]cnc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
230 ml (1.659 mole) of triethylamine are added in the course of 15 minutes to a solution of 100 g (0.673 mole) of 5-methyl-1H-imidazole-4-methanol in 1.5 liter of dimethylformamide maintained between 10° and 14° C. Subsequently, a solution containing 192 g (0.69 mole) of triphenylmethyl chloride in 2 liters of dimethylformamide is introduced between 8° and 11° C. The reaction mixture is stirred for 2 hours and then poured on 14 liters of ice. Stirring is continued for 1 hour, whereafter the precipitate obtained is filtered off, washed with 6 liters of water and dried. This precipitate is then again taken up in 4 liters of boiling ethanol and the insoluble material is separated by hot filtration. Thus, a first crop (19 g; M.P.: 255°-260° C.) of the desired product is recovered. The alcoholic filtrate is filtered hot on Norit, then concentrated and cooled while stirring. A second crop of the desired product crystallizes. It is filtered off, the yield being 28.3 g; M.P.: 255°-262° C. Finally, the filtrate is distilled under reduced pressure and the residue obtained is dissolved in 1 liter of a 95:5 v/v dichloromethane-methanol mixture and the solution obtained is purified by passage through a column of 1.8 kg of silica (0.2-0.5 mm) (eluent: a 80:20 v/v dichloromethane-methanol mixture). A further 72.1 g of the desired product are thus recovered. In total, 119.4 g are recovered containing practically only one of the two possible isomers in the 4- and 5-positions, namely, the 5-methyl-1-triphenylmethyl-1H-imidazole-4-methanol. The yield is 50.1% of theory. The product obtained is used as such in the following step.