1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

off-white to light yellow crystals or

A mixture of 4-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 15.5 mmol), bromomethyl-benzene (3.2 g, 18.7 mmol) and KCompound 244.1. l-Benzyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- pyrazole. _:Into a 100-mL three neck round-bottom flask, was placed a solution of 4-(4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (3.60 g, 18.6 mmol) in THF (50 mL). Sodium hydride (742 mg, 18.6 mmol, 60percent dispersion in mineral oil) was carefully added in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C, then benzyl bromide (2.21 mL, 18.6 mmol) was added. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (10 mL). The pH of the mixture was adjusted to 9-10 with aqueous HC1 (2 M) and the aqueous phase was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (2 x 150 mL), dried (Na1 -benzyl-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 H-pyrazole (i34): To a stirred solution of 4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 /-/-pyrazole (3.0 g, 15.46 mmol) in THF (50 ml_), NaH (0.408 g, 17.01 mmol) was added at 0°C and the reaction was stirred for 30 min. Benzyl bromide (2.9 g, 17.01 mmol) was then added at the same temperature and the reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with water and the pH adjusted to 7 using 2 M HCI. The aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using 8percent ethyl acetate in n-hexanes as eluent to afford 1-benzyl-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2- dioxaborolan-2-yl)-1 H-pyrazole (i34) (2.6 g, Yield 59percent). 0.25g 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole was dissolved in 5mL of DMF and 0.63g cesium carbonate was added. To this suspension was added 0.17mL of benzyl bromide and the reaction was stirred overnight at room temperature. The reaction was allowed to settle and the DMF was decanted into a flask. The remaining residue was washed and decanted twice with ethyl acetate and these washes were added to the flask with the DMF. Water was added to the ethyl acetate and DMF and the organic layer removed. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgS0Step 2. 1-Benzyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole; A 1000-mL 3-necked round-bottomed flask was charged with a solution of 1-benzyl-4-iodo-1H-pyrazole (32 g, 112.68 mmol, 1.00 equiv) in N, N-dimethylformamide (500 mL), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 3, 2-dioxaborolane (31.5 g, 124.02 mmol, 1.10 equiv), Pd(dppf)ClA mixture of 1-benzyl-4-iodo-1H-pyrazole (1.05 g, 3.70 mmol) , bis (pinacolato) diboron (1.00 g, 3.94 mmol) , potassium acetate (1.00 g, 9.88 mmol) and Pd (dppf) ClGeneral procedure: In a sealed vial, a mixture of 8-bromo-3-methyl-9-pentyl-6, 9-dihydro-5H-pyrrolo[3, 2-d][1, 2, 4]triazolo[4, 3-a]pyrimidin-5-one (0.015 g, 0.044 mmol). 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (0.017 g, 0.133 mmol), Chloro(2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1, 1'-biphenyl) [2-(2'-amino-1, 1'-biphenyl)]palladium(II) (5.23 mg, 6.65 mumol), potassium phosphate tribasic (0.038 g, 0.177 mmol), 1, 4-dioxane (0.5 ml), and water (0.1 ml) were sparged with N2 for 5 minutes then stirred at 90 C. for two hours. The reaction mixture was cooled to room temperature and diluted with DMF (5 ml). Purification by preparative HPLC (pH 2, acetonitrile/water with TFA) afforded the product (5 mg, 42%). LCMS calculated for C14H20N5O (M+H): 274.2. Found: 274.2.[00781] To a mixture of 3-(5-cyclopropyl-4-iodoisoxazol-3-yl)-1-isopropyl-1H-pyrazolo[4, 3-c]pyridin-4-amine (Example 5, 31 mg, 0.076 mmol), Pd(PPh3)4 (9 mg, 0.008 mmol) and To a solution of 5-(4-chloro-5-isopropyl-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)thiazole (25 mg, 0.067 mmol) (Example 19, Step 4) in dioxane (0.5 mL) were added

Molecular Weight:284.2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:284.1696081
Monoisotopic Mass:284.1696081
Topological Polar Surface Area:36.3
Heavy Atom Count:21
Complexity:353
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes