5-bromo-4-cyclopropylpyrimidine

5-Bromopyrimidine (8 g, 50.3 mmol) was taken in anhydrous THF (160 mL) followed by the addition of cyclopropylmagnesium bromide (106 mL, 52.8 mmol, 0.5 M solution in THF) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and then treated with a solution of 2, 3-dichloro-5, 6-dicyano-l, 4-benzoquinone (1 1.42 g, 50.3 mmol) in THF (26 mL). The resultant brown mixture was allowed to stir at room temperature for 16 hours and then evaporated under reduced pressure. The brown solid was suspended in water and extracted with dichloromethane (3x50 mL). The combined organics were washed with a IN aqueous solution of sodium hydroxide (2x15 mL), water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 160 g BIOTAGE.(R). column eluting with hexanes/EtOAc (9: 1) to provide Intermediate 61 as a pale yellow solid (4.1 g, 41 percent yield). MS (ES): m/z=199.05 [M+H]To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et20 (120 mL) and THF (20ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0°C. The resulting white suspension was stirred at rt for lh and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (IN) and brine. The crude product was purified by Biotage (0-15percent EtOAc/hexanes, 1.2L) to afford the title compound (700 mg, 20percent) as a yellow solid. Preparation 11 A: 5-Bromo-4-cyclopropylpyrimidine [00148] To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et5-Bromopyrimidine (8 g, 50.3 mmol) was taken in anhydrous THF (160 mL) followed by the addition of cyclopropylmagnesium bromide (106 mL, 52.8 mmol, 0.5 M solution in THF) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and then treated with a solution of 2, 3-dichloro-5, 6-dicyano-l, 4-benzoquinone (1 1.42 g, 50.3 mmol) in THF (26 mL). The resultant brown mixture was allowed to stir at room temperature for 16 hours and then evaporated under reduced pressure. The brown solid was suspended in water and extracted with dichloromethane (3x50 mL). The combined organics were washed with a IN aqueous solution of sodium hydroxide (2x15 mL), water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 160 g BIOTAGE.(R). column eluting with hexanes/EtOAc (9: 1) to provide Intermediate 61 as a pale yellow solid (4.1 g, 41 percent yield). MS (ES): m/z=199.05 [M+H]To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et20 (120 mL) and THF (20ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0°C. The resulting white suspension was stirred at rt for lh and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (IN) and brine. The crude product was purified by Biotage (0-15percent EtOAc/hexanes, 1.2L) to afford the title compound (700 mg, 20percent) as a yellow solid. Preparation 11 A: 5-Bromo-4-cyclopropylpyrimidine [00148] To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in EtUnder Ar(g), to a mixture of pyrazin-2-amine (1) (131 mg, 1.4mmol), 5- bromo-4-cyclopropylpyrimidine (2) (250mg, 1.3mmol), Cs2C03 (0.82g, 2.5mmol) was added degassed dry 1 , 4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (58mg, 0.06mmol) and Xantphos (80mg, 0.14mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15mL) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with CH2CI2 (15mL). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4mL) and purified by basic prep LCMS to yield (3) as a solid (104mg, 39%). LCMS (ES): Found 214.3 [M+Hf.Example 25 :[00182] A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (4.45 mg, 3.85 muiotaetaomicron?), Preparation 25A (24.88 mg, 0.077 mmol), sodium carbonate (32.6 mg, 0.308 mmol), and :[00149] A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 muiotaetaomicron?), Preparation 9A (33.9 mg, 0.100 mmol), sodium carbonate (42.4 mg, 0.400 mmol), and Preparation 1 1A (20.90 mg, 0.105 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (Ratio: 2.0, Volume: 373 mu?), EtOH (Ratio: 1.000, Volume: 187 mu?), and water (Ratio: 1.000, Volume: 187 mu?) were added sequentially. The resulting mixture was heated at 90 C overnight. After 16 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3X). The organic phases were combined, dried over a2S04, filtered, and concentrated to afford a residue. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge CI 8, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 methanokwater with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanokwater with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (4.0 mg, 11%). ESI MS (M+H) = 332.1. HPLC Peak tr = 2.87 minutes. Purity = 95%. HPLC Conditions: B.Preparation 99A: 4-Cyclopropylpyrimidin-5-ylboronic acid[00334] A vessel capable of sealing was charged with a mixture of Preparation 1 1A (140 mg, 0.703 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi(l, 3, 2-dioxaborolane) (268 mg, 1.055 mmol), potassium acetate (207 mg, 2.110 mmol), PdCi2(dppf)-CH2Ci2 adduct (28.7 mg, 0.035 mmol), and dioxane (6 mL) and was purged with nitrogen for 10 min. The vessel was sealed and heated to 90 C for 3 hours. Upon cooling, the reaction mixture was diluted with EtOAc (20 mL) and filtered with EtOAc. The filtrate was concentrated under reduced pressure. LC/MS: Example 99A (at) 0.52 min (RT)(Condition G). MS (ES): m/z=164.17, [M+H]+.Example 487-(4-Cyclopropylpyrimidin-5- l)-3-(4-fluoro-2-methoxyphenyl)benzo[d]isoxazole[00225] A reaction vial was charged with tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 ?????), Preparation 45A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400 mmol), and Preparation 1 1A (25.9 mg, 0.130 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (Ratio: 2.0, Volume: 373 ??), EtOH (Ratio: 1.0, Volume: 187 ??), and water (Ratio: 1.0, Volume: 187 ??) were added sequentially. The resultant mixture was heated at 90 C overnight. After 14 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3X). The organic phases were combined, dried over a2S04, filtered, and concentrated to afford a brown residue. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge CI 8, 19 x 250 mm, 5-??? particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-??? particles; Mobile Phase A: 5:95 methanokwater with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanokwater with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (10 mg, 28%). ESI MS (M+H)+ = 362.2. HPLC Peak tr = 2.13 minutes. Purity = 99%. HPLC Conditions: E.Example 397- 4-Cyclopropylpyrimidin-5 -yl)-3 -(5 -fluoro-2-methoxyphenyl)benzo [d] isoxazole[00211] A reaction vial was charged with tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 ?????), Preparation 36A (0.037 g, 0.100 mmol), sodium carbonate (42.4 mg, 0.400 mmol), and Preparation 1 1A (29.9 mg, 0.150 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (Ratio: 2.0, Volume: 373 ??), EtOH (Ratio: 1.0, Volume: 187 ??), and water (Ratio: 1.000, Volume: 187 ??) were added sequentially. The resultant mixture was heated at 90 C overnight. After 14 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3X). The organic phases were combined, dried over Na2S04, filtered, and concentrated to afford a brown residue. The crude material was purified via preparative LC/MS with the following conditions:Column: Waters XBridge CI 8, 19 x 250 mm, 5-??? particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-??? particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge CI 8, 19 x 250 mm, 5-??? particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-??? particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-70% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (9.4 mg, 26%). ESI MS (M+H)+ = 362.2. HPLC Peak tr = 2.81 minutes. Purity >99%. HPLC Conditions: B.Example 313-Cyclopropyl-7-(4-c clopropylpyrimidin-5-yl)benzo[d]isoxazole[00192] A reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (2.128 mg, 1.841 muiotaetaomicron?), Preparation 28D (10.5 mg, 0.037 mmol), sodium carbonate (15.61 mg, 0.147 mmol), and Preparation 1 1A (7.70 mg, 0.039 mmol). The mixture was stirred at room temperature for 10 min under N2, then DME (Ratio: 2.0, Volume: 137 mu?), EtOH (Ratio: 1.000, Volume: 68.7 mu?), and water (Ratio: 1.000, Volume: 68.7 mu?) were added sequentially. The resultant mixture was heated at 90 C overnight. After 15 hr, the reaction mixture was allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3X). The organic phases were combined, dried over Na2S04, filtered, and concentrated to afford a yellow residue. The crude material was purified via preparative LC/MS with the following conditions:Column: Waters XBridge CI 8, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (4.0 mg, 39%). ESI MS (M+H)+ = 278.2. HPLC Peak tr = 2.38 minutes. Purity >99%. HPLC Conditions: B.

Molecular Weight:199.05
XLogP3:1.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:197.97926
Monoisotopic Mass:197.97926
Topological Polar Surface Area:25.8
Heavy Atom Count:10
Complexity:125
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes