2-Chloro-5-hydroxypyrimidine

2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCOIntermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS0Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS0Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 °C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over NaExample 8 To a stirred solution of 4-Fluorophenylboronic acid (0.72 g, 5.1 mmol) and [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.26 g, 0.35 mmol) were dissolved in toluene (42 mL) and a mixed solvent of ethanol (21 mL), The resulting mixture isAn aqueous solution (7.5 mL) of sodium carbonate (1.7 g, 16 mmol) was added under nitrogen.After stirring for 10 minutes, 5-benzyloxy-2-chloro-pyrimidine 34b (0.76 g, 3.4 mmol) was added, and the mixture was reacted at 80 ° C for 2 hours.The reaction solution was cooled to room temperature and water (20 mL) was added.Extracted with ethyl acetate (30 mL).Dry over anhydrous sodium sulfate, concentrate by suction filtration, and the residue obtained was purified by silica gel column chromatography[ethyl acetate / petroleum ether (v / v) = 1/10] purified to give the title compound34c (0.75 g, yield 78percent) as a white solid.General procedure: Compound 3-(dimethylamino)propan-1-ol (825.28 mg, 8 mmol) and triphenylphosphine (2.517 g, 9.6mmol) were added successively to a suspension of 19 (1.044 g, 8 mmol) in THF (15 mL) under nitrogen.A solution of DIAD (1.67 g, 9.6 mmol) in THF (2 mL) was then slowly added dropwise with ice cooling.The resultant solution was stirred at room temperature for 12 hours. The aqueous phase wasextracted with dichloromethane (40 mL 3). The combined organic layer was washed with H2O (40 mL)and brine (20 mL), and then dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Theresidue was purified by flash chromatography over silica gel (DCM/MeOH = 40:110:1) to give 20a.Compound 3-(dimethylamino)propan-1-ol (825.28 mg, 8 mmol) and triphenylphosphine (2.517 g, 9.6mmol) were added successively to a suspension of 19 (1.044 g, 8 mmol) in THF (15 mL) under nitrogen.A solution of DIAD (1.67 g, 9.6 mmol) in THF (2 mL) was then slowly added dropwise with ice cooling.The resultant solution was stirred at room temperature for 12 hours. The aqueous phase wasextracted with dichloromethane (40 mL 3). The combined organic layer was washed with H2O (40 mL)and brine (20 mL), and then dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Theresidue was purified by flash chromatography over silica gel (DCM/MeOH = 40:110:1) to give 20a.A suspension of tert-butyl 4-(((trifluoromethylsulfonyl)oxy)piperidine-1-carboxylate (6.2 g, 21.1 mmol), [0545] A suspension of tert-butyl 4-(((trifluoromethylsulfonyl)oxy)piperidine-1-carboxylate (6.2 g, 21.1 mmol), To a 50 mL round bottom flask equipped with a stir bar was added 2- chloropyrimidin-5-ol (250 mg, 1.9 15 mmol), 2-(4-fluorophenyl)ethanol (268 mg, 1.9 15 mmol), triphenylphosphine (603 mg, 2.298 mmol) and THF (10 mL). To the stirred solution was added DIAD (0.447 mL, 2.298 mmol). The solution warmed to a mildexotherm, then cooled within 5 minutes. The solution was stirred at r.t. for 2 hrs. The reaction solution was concentrated in vacuo and the resulting oil was purified via silica gel chromatography (40 g column, 5-40percent EtOAc:Hex) to afford the product 2-chloro-5- (4-fluorophenethoxy)pyrimidine (310 mg, 1.227 mmol, 64.1 percent yield) as a white solid. 'H NMR (500 MHz, CDC13) 8.28 (s, 2H), 7.25 (dd, J=8.7, 5.4 Hz, 2H), 7.08 - 7.02 (m, 2H), 4.26 (t, J=6.7 Hz, 2H), 3.13 (t, J=6.7 Hz, 2H). LCMS (M+1) = 252.9.(0220) Under an atmosphere of nitrogen, an ice-cooled solution of a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((2S, 4R)-4-hydroxy-2-(((R)-1, 2, 3, 4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (600 mg, 1.0 mmol), Add K2CO3(5.71 g, 41.3 mmol) to a solution of To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (561 mg, 2.79 mmol) in THF (5 mL) was added (0204) To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (561 mg, 2.8 mmol) in THF (5 mL) was added To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate ( 2.5 g, 12.60 mmol) in THF (30 mL),