Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:18]2[C@:19]3([CH2:36][CH2:35][C@H:34]4[C@@H:24]([CH2:25][CH:26]=[C:27]5[C@:32]4([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]5)[C@@H:21]3[CH2:22][CH:23]=2)[CH3:20])[CH:5]=1
Reactant: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Yield: 83.9 %

Procedure:
The method followed that described in Example 1, using in step (b) diethyl(3-pyridyl)borane (0.88 g, 6.0 mmol), androsta-3,5,16-trien-17-yl trifluoromethanesulphonate (2.01 g, 5.0 mmol), prepared in step (a), THF (25 ml), bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol), and aqueous sodium carbonate (2M, 10 ml). Chromatography, on elution with dichloromethane, afforded the title compound (1.39 g, 84%) which crystallised from hexane, m.p. 110°-112° C. 1H-NMR (CDCl3) inter alia δ1.02(3H,s,19-CH3), 1.07(3H,s,18-CH3), 5.44(1H,m,6-H), 5.61(1H,m,3-H), 5.95(1H,dm, J 9.8 Hz, 4-H), 6.01(1H,m,16-H), 7.23(1H,m,Py 5-H), 7.66(1H,m,Py 4-H), 8.46(1H,m,Py 6-H), 8.63(1H,m,Py 2-H); MS m/z 331 (M+).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[CH:16][CH:15]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (648 mg, 2.43 mmol) and 2-aminothiazole (487 mg, 4.86 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 14.0 mL, 9.72 mmol) was heated under reflux at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (286 mg, 35%) as a white solid: mp 156.6–159.8° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0910.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=[C:18]([C:19]([NH2:21])=O)[C:13]=2[N:12]=[C:11]1[C:28]([F:31])([F:30])[F:29].COC(OC)[N:35]([CH3:37])C.O.[NH2:41]N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:17]=[C:18]([C:19]3[N:21]=[CH:37][NH:35][N:41]=3)[C:13]=2[N:12]=[C:11]1[C:28]([F:29])([F:30])[F:31]
Reactant: NN
Reactant: NC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Reactant: COC(OC)N(C)C
Solvent: O
Product: FC(F)(F)c1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 105 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
A suspension of 1-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxamide, prepared as described in Example 56, step a (389 mg, 0.822 mmol) in N,N-dimethylformamide dimethyl acetal (9 mL, 67.2 mmol) was stirred at 105° C. for 1 hour. The reaction was concentrated under reduced pressure and the residue was suspended in Acetic Acid (7 mL). After the addition of hydrazine monohydrate (0.181 mL, 5.75 mmol) the reaction mixture was heated at 100° C. for 1 hour. The solvent was concentrated under vacuum and the residue was dissolved in DMSO and purified by reverse phase-HPLC (20-95% AcCN in water plus 0.1% TFA) (some residual solid filtered off). The fractions containing product were combined, neutralized by the addition of aq NaHCO3 sat sol and the organic evaporated (some compound lost during transfer). The precipitate in the aqueous residue was collected by filtration, washed with water and dried in a vacuum oven (45° C.) overnight to give the desired product (115 mg, 0.227 mmol, 27.6% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.05 (br. s., 1H), 8.12 (s, 1H), 8.00 (d, J=2.27 Hz, 1H), 7.47 (dd, J=8.08, 1.26 Hz, 1H), 7.10 (t, J=7.96 Hz, 1H), 6.59 (d, J=2.27 Hz, 1H), 6.37 (dd, J=7.83, 1.01 Hz, 1H), 5.62 (s, 2H), 3.79-3.92 (m, 4H), 3.17-3.30 (m, 4H). MS (ES+) m/e 497 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O-])([O-])=O.[K+].[K+].[C:19](#[N:21])C>>[Cl:1][C:2]1[CH:7]=[C:6]([N:21]([CH3:19])[CH3:13])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: [K+]
Product: CN(C)c1cc(Cl)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-chloro-4,5-difluoro-2-nitro-benzene (Preparation 1) (20.0 g, 103.3 mmol), K2CO3 (31.4 g, 227.3 mmol) and dimethyl amine. HCl (9.3 g, 113.6 mmol) in acetonitrile (200 mL) was heated to reflux for 2 h. The solution cooled to room temperature, quenched with water and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 22.1 g (98%) of 1-chloro-5-dimethylamino-4-fluoro-2-nitro-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J=14.2 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 3.09 (d, J=2.2 Hz, 6H), 3.77 (br s, 2H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.O.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=O.C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=[N:23][NH:22][C:20](=[O:21])[C:5]1[CH:4]=[C:3]([N:2]([CH3:24])[CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1
Reactant: O=CC(F)(F)C(F)(F)F
Reactant: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00088 mol) was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.29 g, 0.00088×2.0 mol) and benzene, and further with a small amount of concentrated hydrochloric acid. The obtained mixture was refluxed and dehydrated for about 8 hours using a water separator. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][NH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31]([N:10]3[C:5]4[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ccc2c(n1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4nc(Cl)ccc43)ncn2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
20a (36 mg, 0.23 mmol) was dissolved in DMF (1.5 mL) with NaH (60% suspension, 9.6 mg, 0.24 mmol). 3a (75 mg, 0.24 mmol) was added slowly. The mixture was stirred at 90° C. for 8 h then cooled down to room temperature, diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was isolated, dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 20-1, LCMS 432.1 (MH+). tR=5.21 (Method 5). EC50: 751 nM.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]=O.[CH3:15][NH:16][NH2:17].Cl>C(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:15][N:16]([CH3:13])[N:17]=[C:3]1[C:2]([F:12])([F:11])[F:1])=[O:6])[CH3:9]
Reactant: CNN
Reactant: C=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CN(C)N=C1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (120 g, 0.65 mol) was dissolved in 650 ml of ethanol and the solution was cooled down to 0° C. A 37% aqueous solution of formaldehyde (53 g, 0.65 mol) was added and the mixture was stirred for 15 minutes at 0° C. Methylhydrazine (30 g, 0.65 mol) was added and the reaction mixture was heated to reflux. After reaching the reflux temperature, 2.5 ml of concentrated hydrochloric acid were added, and refluxing was continued for 16 h. Subsequently, the mixture was cooled down and the solvent was removed in vacuo. The remainder was taken up in water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, yielding 90 g of 1-methyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:12][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=1[O:2][CH3:1]
Reactant: BrP(Br)Br
Reactant: COc1c(CO)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A solution of 14.7 g of (2-methoxy-3-nitro-phenyl)-methanol dissolved in 140 ml of dichloromethane and 5.5 ml of pyridine was cooled in an ice bath and slowly added 6.48 ml of phosphorus tribromide. After 45 minutes at 5° C., the reaction mixture was diluted with dichloromethane, washed with water, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (5:95) giving 7.3 g of 1-bromomethyl-2-methoxy-3-nitrobenzene as a yellow solid. ##STR158##
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34])(=O)=O>CN(C=O)C>[CH3:32][O:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:25]([N+:33]([O-:35])=[O:34])[CH:26]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: COCc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A stirred solution of bis(1,1-dimethylethyl) propanedioate (1.672 g, 7.73 mmol) in anhydrous DMF (25 mL) under argon was cooled to 0° C. and treated, portionwise with sodium hydride (0.297 g, 7.42 mmol) which was added over 10 mins. The resultant mixture was stirred at 0° C. for 15 mins and then allowed to warm to rt. After 1 hr the mixture was cooled back to 0° C. and treated with a solution of 4-[(methyloxy)methyl]-2-nitrophenyl trifluoromethanesulfonate D122 (1.95 g, 6.19 mmol) in DMF (5 mL) which was added slowly over 10 mins. After the addition was complete the cooling bath was removed and the mixture allowed to warm to rt. After 1 hr TLC indicated little or no reaction. The mixture was then warmed to 70° C. for 16 hr, then cooled to room temp and the solvent was removed under vacuum. The dark brown oily reside was dissolved in EtOAc (100 mL) and washed thoroughly with water (6×50 mL) and brine (50 mL), dried (MgSO4) and concentrated to dryness under vacuum. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound as a yellow oil (1.32 g, 55.9%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43]Br>C(#N)C>[CH2:24]([N:23]([CH2:26][CH3:27])[C:21](=[O:22])[C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([C@@H:9]([N:3]2[CH2:4][C@@H:5]([CH3:8])[N:6]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[C:40]([F:39])[CH:41]=3)[CH2:7][C@@H:2]2[CH3:1])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:19]=1)[CH3:25]
Reactant: Fc1cccc(CBr)c1
Reactant: CCN(CC)C(=O)c1cccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)NC[C@@H]2C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1cccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)c1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A solution of 3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide (0.49 g, 1.20 mmol) in acetonitrile (10 mL) was added to sodium iodide (100 mg), sodium carbonate (0.70 g, 6.64 mmol) and stirred under nitrogen at room temperature during the addition of 3-fluorobenzyl bromide (0.16 mL, 1.32 mmol). The reaction was complete in 3 hours. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride twice more, and the combined organic extracts were dried (Na2SO4/MgSO4) and concentrated under reduced pressure. The residual brown oil was purified by chromatography on silica gel (EtOAc/CH2Cl2) to give 0.37 g (0.71 mmol) of the desired product as a light brown amorphous solid. The salt was made by dissolving the amine in ethanol and titrating to pH 3.92 with 0.2 M HCl in ethanol. The salt was redissolved in water and lyophilized to obtain a light brown powdery solid. 1H NMR (300 MHz, CDCl3): δ 1.04–1.22 (m, 12H); 1.93–2.08 (m, 2H); 2.51–2.76 (m, 5H); 3.10–3.60 (m, 4H); 3.78 (s, 3H); 3.84–3.89 (d, J=13.3 Hz, 1H); 5.11 (s, 1H); 6.76–7.46 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([C:38]2[CH:39]=[C:40]([NH2:43])[NH:41][N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C.C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:41]4[N:42]=[C:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:39]=[C:40]4[N:43]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 1 (250 mg, 0.59 mmol) and 5-Phenyl-2H-pyrazol-3-ylamine (96 mg, 0.59 mmol) in acetic acid (0.4 mL) and ethanol (1.6 mL) was heated under reflux for 6 hours. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 9-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH2:19][C:20](O)=[O:21])[N:9]=2)=[CH:4][C:3]=1[CH3:23].CCN(C(C)C)C(C)C.[N:33]1([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]([CH2:19][C:20]([N:36]3[CH2:37][CH2:38][N:33]([C:39]4[N:40]=[CH:41][CH:42]=[CH:43][N:44]=4)[CH2:34][CH2:35]3)=[O:21])[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1cc(-c2cc(-c3ccccc3)n(CC(=O)O)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cc(-c3ccccc3)n(CC(=O)N3CCN(c4ncccn4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg 3-(4-fluoro-3-methyl-phenyl)-5-phenyl-pyrazol-1-yl acetic acid was dissolved in 2 mL DMF. 83 mg PFTU and 33 μL DIPEA were added to this solution and the mixture was stirred for 15 min at RT. Then, 25 μL 2-(1-piperazinyl)-pyrimidine was added and stirring was continued for 8 h. Then, 1 mL of a K2CO3 solution (5%) and 10 mL CH2Cl2 were added, the organic phase was separated and washed two times with water. The solvent was removed and the residue was crystallized from ACN to yield 46 mg of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([N:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[C:25]([OH:34])(=[O:33])[C@H:26]([C@@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CO>[C:30]([C@H:28]([C@@H:26]([C:25]([O-:34])=[O:33])[OH:27])[OH:29])([O-:32])=[O:31].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:24])[C@@H:9]([N:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CC(C(O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Solvent: CO
Product: C[C@@H]([C@@H](O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To an appropriate flask maintained under a nitrogen atmosphere, 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (189.5 g, 0.58 mol) and methanol (3.8 L) were added. The mixture was heated to 50-55° C. and then D-(−)-tartaric acid (87.0 g , 0.58 mol) was added. The mixture was heated at reflux (˜65° C.) for 5 hours. The slurry was cooled at 30-35° C. and then granulated for 1 hour at 30-35° C. The product was filtered and the cake was washed with fresh methanol (135 mL). The wet cake was sampled for a chiral HPLC assay to determine enantiomeric impurity levels. The wet cake was suspended in methanol (1.6 L), and the resulting slurry was heat at reflux (˜65° C.) under a nitrogen atmosphere for 5 hours. The slurry was cooled to 30-35° C., granulated for 1 hour at 30-35° C. and then filtered. The filter cake was washed with methanol (136 mL) and then dried in vacuo at 40-45° C. for 18-24 hours. A sample was assayed by chiral HPLC. The D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (118.0 g) was obtained in 43% weight yield. At times, as the results show in Table 1 above an additional methanol reslurry is required to decrease the amount of the (1R,2R)-enantiomer impurity below 2.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(NCCc2cccc(OC)c2)cc1

Procedure:
A solution of (3-methoxy-phenyl)-acetyl chloride (5.0 g) in ethyl acetate (85 mL) was added to a solution of 4methoxy-phenylamine (3.33 g) in ethyl acetate (50 mL). After 18 h the reaction was poured into water (150 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofurane (100 mL) then lithium aluminum hydride (5.2 g) was added in small portions over 30 minutes. After 18 h the reaction was slowly poured onto 200 mL of ice. The mixture was filtered through a pad of celite and the collected filtrate was extracted with ethyl acetate (300 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated to give the title compound. MS: 258.3 (MH+); HPLC tR: 1.98 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.S(Cl)([Cl:23])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([Cl:23])=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Product: O=C(Cl)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 10C (3.5 g, 11.36 mmol) in thionyl chloride (25 mL) was heated at 90° C. for 4 hours. The solution was allowed to cool to ambient temperature and then the mixture was evaporated to dryness to provide the title compound.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.CC[N:16]([CH:20]([CH3:22])[CH3:21])C(C)C.C[N:24](C)[CH:25]=[O:26]>CO>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([NH:16][C:20]1[CH:22]=[CH:8][CH:2]=[C:3]([CH2:4][CH2:22][C:20]2[C:21]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:25](=[O:26])[NH:24][N:16]=2)[CH:21]=1)=[O:7]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(CCC(=O)c1ccccc1)Nc1cccc(CCc2n[nH]c(=O)c3c2CCCC3)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-oxo-4-phenylbutanoic acid (50 mg, 0.28 mmol), 2-(3H-(1,2,3)triazolo(4,5-b)pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V) (106 mg, 0.28 mmol) and Hunig's base (120 mg, 0.9 mmol) in anhydrous N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 10 minutes, and EXAMPLE 260 (50 mg, 0.18 mmol) was added in one portion. The reaction mixture was stirred at room temperature for another 1 hour, and was diluted with 5 mL of methanol. The solid material was collected by filtration, washed with methanol, and dried to provide the title compound. MS (DCI/NH3) m/z 430 (M+H)+. 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 1.54-1.77 (m, 4H), 2.30-2.42 (m, 2H), 2.42-2.49 (m, 2H), 2.65-2.79 (m, 4H), 2.79-2.89 (m, 2H), 3.30-3.38 (m, 2H), 6.90 (d, J=7.80 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.38-7.49 (m, 2H), 7.54 (t, J=7.46 Hz, 2H), 7.61-7.69 (m, 1H), 7.99 (t, J=6.61 Hz, 2H), 9.96 (s, 1H), 12.52 (s, 1H).