2-Bromo-5-fluoropyrimidine

Step A: To 2-chloro-5-fluoropyrimidine (2 mL, 22.18 mmol) were added propionitrile (20 mL) and bromotrimethylsilane (6 mL), and the mixture was heated in a sealed vial at 150° C. for 1 h. The mixture was allowed to cool, and then was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCO2-Chloro-5-fiuoro-pyrimidine (1.0 mL) was dissolved in DME (10 mL). TMS-Br (1.5 mL) was added and the mixture stirred at 150 °C in a closed vial for 1.5 h. The mixture was allowed to cool, then concentrated in vacuo. The residue was dissolved in CH2CI2 and filtered through a plug of silica. The filtrate was concentrated in vacuo to give a pale yellow liquid (1.54 g). This compound, 2-bromo-5-fiuoropyrimidine (containing some 2-chloro-5-fiuoro-pyrimidine), (0.75 g) was dissolved in triethylamine (7 mL) under an argon atmosphere. TMS-acetylene (0.6 mL) was added followed by bis(triphenylphosphine)palladium(II) dichloride (15 mg) and copper(I) iodide (30 mg). After heating the mixture at 50 °C 5 h, it was concentrated in vacuo. The residue was purified by flash chromatography (SiC^/Petroleum ether:EtOAc 95:5→5:95) and 5- fluoro-2-[2-(trimethylsilyl)ethynyl]pyrimidine was isolated as a colorless oil (300 mg, 38percent purity).To a mixture of ieri-butyl 3-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)-2, 5-dihydro-lH-pyrrole-l-carboxylate (33.6 g, 113.9 mmol), 2-bromo-5- fluoropyrimidine (20 g, 113.6 mmol) and K2C03 (47.l g, 341 mmol) in dioxane/H20 (500 mL/50 mL) was added PdCl2(dppf)2 (4.6 g, 5.7 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 100 C for 2 h and then concentrated in vacuo. The residue was dissolved with EtOAc (500 mL) and the solution was washed with brine (200 mL x 3). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10: 1 to 5 : 1) to give 2147-A (25.5 g, 85 %) as a gray solid. MS 210.1 [M - 55]+.To a solution of 2303-A (5.0 g, 28.4 mmol) in DCM (70 mL) was added n-BuLi (13.6 mL, 34.1 mmol) dropwise at -78 C and the reaction mixture was stirred for 1 h under N2 atmosphere. Then a solution of SM-A (6.3 g, 34.1 mmol) in DCM (20 mL) was added into the mixture dropwise. The resulting mixture was warmed to room temperature and stirred for 3 h. The mixture was then diluted with saturated NH4Cl (100 mL), extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 to EtOAc) to give 2303-B (550 mg) as a crude product. The crude product was purified by Prep-HPLC to give 2303-B (177 mg, 2.2%) as a brown solid. MS 284.2 [M+H]+.A mixture of 9-[2, 6-dimethyl-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenyl]-3-methoxy-3- azaspiro[5.5]undecane-8, 10-dione (3.60 g, 6.48 mmol), A solution of NiCl2(glyme) (0.084 g, 0.384 mmol), 4-ie/7-butyl-2-(4-ie/7-butyl-2-pyridyl)pyridine, and Ir{dF(CF3)ppy}2(dtbpy)PF6(0.086 g, 0.077 mmol) in DME (80 mL) was sparged with N2for 15 min. The nickel solution was added to a mixture of //77-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (2.03 g, 7.68 mmol), Step 1. //'/- Butyl (2-(4-(5-fluoropyrimidin-2-yl)cyclohex-3-en-l-yl)ethyl)(tetrahydro-2 /7-pyran-4-yl (carbamate. A vial was charged with ieri-butyl (tctrahydro-2/7-pyran-4-yl)(2-(4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)ethyl)carbamate (Intermediate 16, 150 mg, 0.344 mmol), 6-Methyl-N-(1-methylcyclopropyl)-5-[4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 2, 3, 6-tetrahydropyridine-1-carbonyl]furo[2, 3- d]pyrimidin-4-amine (64 mg, 0.15 mmol) and To a solution of the intermediate (S)-4-(difluoromethyl)-N-(3-(2, 5- dihydro- 1 H-pyrrol-3-yl)-6-(3, 4-dimethylpiperazin- 1 -yl)-2, 4-difluorophenyl)-6-oxo- 1, 6-dihydropyridine-3-carboxamide (25 mg, 0.052 mmol, preparation described in Example 33) and 2-Bromo-5-fluoropyrimidine (9.23 mg, 0.052 mmol) in isopropanol (2.5 mL) at RT was added N, N-diisopropylethylamine (0.018 ml, 0.104 mmol). After heating in a microwave reactor at 150C for 1.5 h, the reaction mixture was purified on preparatory column eluting with water (containing 0.1% HCOOH)/acetonitrile (containing 0.1% HCOOH) gradient (90/70). The title compound was isolated as an off white solid (18 mg, 57%). LCMS [M+ljb = 576.6.TBAI (86 mg, 0.23 mmol), nickel(II) iodide (29 mg, 0.09 mmol), ttbtpy (37 mg, 0.09 mmol) and zinc (0.12 g, 1.86 mmol) was added to a vial. The mixture was degassed with N2. Degassed DMPU (3 mE) was added followed by pyridine (7.51 pL, 0.09 mmol). The reaction mixture was stirred for 2 h followed by the addition of the solution of

Molecular Weight:176.97
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Exact Mass:175.93854
Monoisotopic Mass:175.93854
Topological Polar Surface Area:25.8
Heavy Atom Count:8
Complexity:72.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes