2-FLUORO-5-(4 4 5 5-TETRAMETHYL-(1 3 2)&

Pd(dppf)Cl2 (4.16g, 5.68mmol) was added in one batch to a solution of 5-bromo-2-fluoro-pyridine (10g, 56.82mmol), bispinacolatoboronate (21.64g, 85.23mmol), potassium acetate (16.73g, 170.46mmol) in dioxane (100mL)at room temperature under nitrogen atmosphere, and the mixture was stirred for 10 minutes and heated to reflux for 6hours. Upon the completion of the reaction, the solvent was evaporated off directly and the residue was purified by flashsilica gel column chromatography to give the title compound (10.5g, yield 82.85percent). 1H NMR (400 MHz, CHLOROFORMd)ppm 8.59 (s, 1H), 8.15 (dt, J=1.76, 8.41 Hz, 1H), 6.91 (dd, J=2.26, 8.28 Hz, 1H), 1.35 (s, 12H).5-bromo-2-fluoropyridine (2.0 g, 11.3 mmol), K2CO3 (4.46 g, 45 mmol) and bis(pinacolato)diboron (3.17 g, 12.4mmol) were dissolved in 38 mL of DMF and charged with nitrogen gas for 5 minutes. After addition of catalytic amountof PdCl2(dppf)-DCM, the mixture was stirred at 80°C for 3 hours. Solids were filtered and purified by column chromatographyto obtain the title compound (1.59 g, 60 percent).1H-NMR (DMSO-d6) δ 8.45 (1H, d), 8.16 (1H, m), 7.20 (1H, dd), 1.30 (12H, s)To a stirred solution of 5-bromo-6-methoxy-3-nitropyridin-2-amine (2.5 g, 10.09 mmol, 1.0 eq) and 2- fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine (2.70 g, 12.104 mmol, 1.2 eq) in dioxane (40 mL) was added a 2M solution of NaiCCb (2.14 g, 20.18 mmol, 2.0 eq) in water (10.09 mL) at rt. The resulting mixture was purged with nitrogen for 10 min followed by addition of Pd(dppf)Cl2.DCM (0.083 g, 0.100 mmol, 0.01 eq), again purged with nitrogen for 10 min. The reaction mixture was heated at l20C for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL), with brine (50 mL), dried over Na2S04, concentrated and purified by combi flash chromatography [silica gel 100-200 mesh: elution 0-10 % EtOAc in Hexane] to afford the desired compound (1.30 g, 48.87%) as yellow solid. LCMS: (M+l)+ 265.1General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1, 1'-biphenyl) (1, 1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2', 4', 6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%To a flask was charged 3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1, 5-a]pyridin-4-yl trifluoromethanesulfonate (36) (3.00 g. 7.91 mmol), To a flask was charged 3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1, 5- a]pyridin-4-yl trifluoromethanesulfonate (36) (3.00 g. 7.91 mmol), 2-fluoro-5-(4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridine (1.85 g, 8.30 mmol), and THF (60 mL, 20 vol). The solution was purged with nitrogen for 15 minutes and PdCl2(dppf)DCM (452 mg, 0.553 mmol) was charged and the mixture was purged with nitrogen for an additional 5 minutes. To a separate flask was added KOAc (1.55 g, 15.82 mmol) and water (15 mL). This mixture was purged with nitrogen for 2 minutes and then added to the reaction mixture, which was purged with nitrogen for an additional 5 minutes. The reaction stirred overnight at ambient temperature. The reaction mixture was poured onto MTBE (60 mL) and water (45 mL). The layers were separated and the organic layer was washed with water (30 mL) followed by 3:1 water/brine (30 mL). The first and second aqueous layers were combined and back extracted with MTBE (30 mL). The organic layers were combined and concentrated to a solid. The solid was taken up in MTBE (30 mL) and after stirring for 2 hours at ambient temperature the suspension was filtered, the cake washed with n- heptanes (3 x 6 mL) and the solids dried under vacuum to give 13 (1.69 g, 65% yield).2-Fluoro-5-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)pyridine (325 mg) was dissolved indimethylsulfoxide (5 mL). (.S)-(l, 4-Dioxan-2-yl)methanamine hydrochloride (246 mg) was added, followed by N-ethyl-N-isopropylpropan-2-amine (753 mg). The solution was heated to 120 C for six hours and was cooled. The solution was added to water (15 mL) and brine (3 mL). The solution was extracted with dichloromethane (20 mL) three times. The extracts were combined, dried on anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using a 0% to 10% gradient of methanol in dichloromethane. 'H NMR (500 MHz, dimethylsulfoxide-do) 6 ppm 8.22 (d, IH), 7.52 (dd, IH), 6.95 (t, IH), 6.47 (d, IH), 3.73 (dd, 2H), 3.66- 3.61 (m, 2H), 3.55 (td, 1H), 3.46 (td, lH), 3.31 (m, 2H), 3.23 (dd, 1H), 1.31 (s, 3H), 1.25 (s, 6H), 1.07 (s, 3H). MS (ESI) m/z 321.3 (M+H), 319.1 (M-H).General procedure: Under N2 atmosphere, a mixture of 6 (100.0 mg, 0.26 mmol), Pd(pph3)4 (30.0 mg, 0.026 mmol), 2.0M aq Na2CO3 (0.29 ml, 0.78 mmol) and 1-Methyl-1H-pyrazole-5-boronic acid pinacolester (108.2 mg, 0.52 mmol) in 1, 4-Dioxane (0.65 ml) was heated to90 C and stirred for 6 h. The reaction mixture was cooled, dilutedwith ethyl acetate, washed with water, dried over anhydrousNa2SO4, filtered and concentrated under vacuum. Purification onsilica using a solvent gradient of 10-30% ethyl acetate in hexanesyielded the desired compound 1j (77.0 mg, 77.5%). Compounds 1akwere prepared according to general procedure as described forcompound 1j using corresponding aryl bromide 2-4 and theappropriate boronic acid or boronic acid pinacol ester. The characterizationdata for compounds 1a-k were provided below.

Molecular Weight:223.05
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:223.1179870
Monoisotopic Mass:223.1179870
Topological Polar Surface Area:31.4
Heavy Atom Count:16
Complexity:257
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes