3,3-dimethylbutan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (18 mg) was dissolved in DCM, triphenyl phosphine (5.9 eq.). 3,3-Dimethyl-butan-1-ol (excess) added and mixture cooled on ice. DIAD (5.1 eq.) was added and the reaction mixture stirred on ice for 10 minutes and rt for 16 hours. The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4). The resulting residue was hydrolyzed according to General Procedure B and purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH) to give the title compound (11 mg). LCMS (m/z): 769. mixture cooled on ice The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4) purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3,3-dimethylbutanol (26 mg, 0.26 mmol) as the coupling partner. Concentration (no chromatography) yielded 54 mg (85%) of the titled compound. ESI-MS m/z 376 (MH+), 374 (M−H−). Concentration (no chromatography)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (11.09 g, 26.64 mmol), (S)-2-(2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (6.00 g, 24.22 mmol) and K3PO4 (15.42 g, 72.66 mmol) in 2-methyl THF (90 mL) and water (12.00 mL) was purged with nitrogen for 30 minutes. X-Phos (0.92 g, 1.94 mmol) and Pd2(dba)3 (0.44 g, 0.48 mmol) were added and the reaction mixture was heated at 120° C. in a pressure vial for 2 hr. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 10 g of the desired product as a foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.54-8.40 (m, 2H), 8.22 (s, 1H), 8.09-8.00 (m, 3H), 7.29-7.16 (m, 2H), 5.15 (m, 1H), 4.32-4.14 (m, 1H), 3.98 (m, 1H), 3.70 (m, 1H), 2.30 (s, 3H), 1.01 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 502.43 (M+H) RT=1.52 min. was purged with nitrogen for 30 minutes The reaction mixture was cooled to room temperature filtered concentrated in vacuo The residue was dissolved in EtOAc (100 mL) washed with water The organic layer was dried (MgSO4) filtered concentrated in vacuo The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,3-dimethylbutan-1-ol (20.2 g) and triethylamine (41.3 mL) in THF (200 mL) was added methanesulfonyl chloride (24.9 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (36.5 g) as a red-orange oil. cooling the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-2, 200 mg) is reacted analogously to Example I-811 with 3,3-dimethylbutan-1-ol (68.0 mg). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%). This gives, after chromatographic purification, 3,3-dimethylbutyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (98 mg, 40%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium bis(trimethylsilyl)amide (3.95 mL, 7.9 mmol, 2M solution in THF) to a solution of 3,3-dimethyl-butan-1-ol (960 CL, 7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction mixture with saturated aqueous NaHCO3 (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL) and wash the organic layer with brine (100 mL). Dry the combined organic extracts over MgSO4 and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g, 94%). GC-MS m/z: 204 (Me). Stir at room temperature overnight quench the reaction mixture with saturated aqueous NaHCO3 (100 mL) Extract the aqueous layer with dichloromethane (3×100 mL) wash the organic layer with brine (100 mL) Dry the combined organic extracts over MgSO4 concentrate in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (18 mg) was dissolved in DCM, triphenyl phosphine (5.9 eq.). 3,3-Dimethyl-butan-1-ol (excess) added and mixture cooled on ice. DIAD (5.1 eq.) was added and the reaction mixture stirred on ice for 10 minutes and rt for 16 hours. The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4). The resulting residue was hydrolyzed according to General Procedure B and purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH) to give the title compound (11 mg). LCMS (m/z): 769. mixture cooled on ice The reaction mixture was directly purified over silica (DCM-EtOAc 8:2 to DCM-EtOAc 6:4) purified over silica (DCM to DCM+1% MeOH to DCM+7% MeOH)