2-METHOXYLYPYRIDINE-4-BORONIC ACID PINACOLATE

Nitrogen was bubbled for 5 minutes through a mixture of 4-iodo-2-methoxypyridine (0.099 g, 0.42 mmol), bis(pinacolato)diboron (0.12 g, 0.47 mmol) and potassium acetate (0.13 g, 1.31 mmol) in Λ/, Λ/'-dimethylformamide (1 mL) contained in a microwave vessel. Then [1 , 1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1 :1) (0.017 g, 0.02 mmol) was added and the vessel was sealed and subjected to microwave irradiation for 4 hours at 80 °C. The reaction mixture was diluted with ethyl acetate and filtered through Celite.(R).. The filtrate was washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgS0  4-iodo-2-methoxypyridine (0.099 g, 0.42 mmol), bis(pinacolato)diboron (0.12 g, 0.47 mmol) and potassium acetate (0.13 g, 1.31 mmol) in N, N'-dimethylformamide (1 mL) contained in a microwave vessel. Then [1, 1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (0.017 g, 0.02 mmol) was added and the vessel was sealed and subjected to microwave irradiation for 4 hours at 80 °C. The reaction mixture was diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSOGeneral procedure: A mixture of 4-bromo-2-ethoxypyridine (150 mg, 0.742 mmol), £>/s(pinacolato)diboron (754 mg, 2.97 mmol), PdCI2(dppf) (54.3 mg, 0.074 mmol) and potassium acetate (291 mg, 2.97 mmol) in 1 , 4- dioxane (3 ml.) was heated in a microwave at 1 10 C for 2 x 30 min. The reaction was diluted with EtOAc and filtered through a Celite column. The filtrate was evaporated to give a brown residue. This crude material was used in subsequent steps without further purification and the yield was assumed to be 100% (0.742 mmol, 185 mg).An oven-dried flask was equipped with a magnetic stir bar and charged with 3-methoxy-4- (5-(methyl(2, 2, 6, 6-tetramethylpiperidin-4-yl)amino)pyrazin-2-yl)phenyl (0789) trifluoromethanesulfonate (180 mg, 0.35 mmol), 2-methoxy-4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)pyridine (101 mg, 0.43 mmol, tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.35 mmol), Na2C03 (111 mg, 1.05 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (6 mL) and water (1.5 mL) were added and the reaction was heated to 90 C for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with gradient CH2Cl2/MeOH (0 to 30% MeOH) to afford 5-(2-methoxy- 4-(2-methoxypyridin-4-yl)phenyl)-N-methyl-N-(2, 2, 6, 6-tetramethylpiperidin-4-yl)pyrazin-2-amine (86 mg, 53%) as a tan solid. MS m/z 462.6 [M+H]+; 1H NMR (methanol-^) d: 8.69 (d, 7=1.3 Hz, 1H), 8.20 (dd, 7=5.4, 0.6 Hz, 1H), 8.12 (d, 7=1.3 Hz, 1H), 7.82 (d, 7=8.2 Hz, 1H), 7.41 (dd, 7=8.2, 1.9 Hz, 1H), 7.38-7.40 (m, 1H), 7.32 (dd, 7=5.4, 1.6 Hz, 1H), 7.13 (dd, 7=1.6, 0.9 Hz, 1H), 5.15 (tt, 7=12.6, 3.6 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.01 (s, 3H), 1.67 (dd, 7=12.6, 3.6 Hz, 2H), 1.56 (t, 7=12.6 Hz, 2H), 1.39 (s, 6H), 1.25 (s, 6H); 1H not observed (NH).2-Bromo-4-fluoro-6-(prop-i-en-2-yl)aniline (8.56 g, 37.2 mmol) and 2-methoxy-4- (4, 4, 5, 5-tetramethyl-i, 3, 2-dioxaborolan-2-yl)pyridine (10.5 g, 44.6 mmol) were dissolved in dioxane (10 mL) under N2 atmosphere. Potassium carbonate (15.4 g, 112 mmol) in water (10 mL) was added. Pd(dppf)Cl2-CH2Cl2 (1.52 g, 1.86 mmol) was added and the mixture was stirred overnight at reflux. The dioxane was largely removed by rotary evaporation. Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound (8.0 g, 83%) as a brown oil. (0646) NMR (300 MHz, CDCI3) d 8.20 (d, 1 H), 7.00 (m, 2 H), 6.82 (s, 1 H), 6.72 (d, 1 H), 5-34 (bs, 1 H), 5.09 (bs, 1 H), 3.98 (s, 3 H), 3.80 (bs, 2 H), 2.05 (s, 3 H). (0647) LCMS: m/z 259 (M+H)+ (ES+).2-Bromo-4-fluoro-6-(prop-i-en-2-yl)aniline (8.56 g, 37.2 mmol) and 2-methoxy-4- (4, 4, 5, 5-tetramethyl-i, 3, 2-dioxaborolan-2-yl)pyridine (10.5 g, 44.6 mmol) were dissolved in dioxane (10 mL) under N2 atmosphere. Potassium carbonate (15.4 g, 112 mmol) in water (10 mL) was added. Pd(dppf)Cl2-CH2Cl2 (1.52 g, 1.86 mmol) was added and the mixture was stirred overnight at reflux. The dioxane was largely removed by rotary evaporation. Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound (8.0 g, 83%) as a brown oil. (0640) NMR (300 MHz, CDCI3) d 8.20 (d, 1 H), 7.00 (m, 2 H), 6.82 (s, 1 H), 6.72 (d, 1 H), 5-34 (bs, 1 H), 5.09 (bs, 1 H), 3.98 (s, 3 H), 3.80 (bs, 2 H), 2.05 (s, 3 H). (0641) LCMS: m/z 259 (M+H)+ (ES+).A suspension of 2-methoxy-4-(4, 4, 5, 5-tetramethyl-i, 3, 2-dioxaborolan-2-yl)pyridine (1.08 g, 4.57 mmol, 1 eq), tert-butyl 2-(5-(((trifluoromethyl)sulfonyl)oxy)-2, 3-dihydro- iH-inden-4-yl) acetate (1.74 g, 4.57 mmol, 1 eq) and potassium carbonate (1.90 g, 13.7 mmol, 3 eq) in 1, 4-dioxane (25 mL) was bubbled through with nitrogen for 20 minutes. After that, [i, i'-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 pmol, 0.05 eq) was added and the reaction mixture was heated to 80 C. After stirring overnight, another batch of [i, i'-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 pmol, 0.05 eq) was added and the temperature of the reaction mixture was increased to 100 C. After 2 more hours of stirring, another batch of [1, 1'- bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 pmol, 0.05 eq) was added. After stirring for 20 more hours, another batch of [1, 1'- bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 pmol, 0.05 eq) was added. After 3 more hours of stirring, the reaction mixture was cooled to room temperature and then filtered. The residue was washed with ethyl acetate and dichloromethane. The filtrates were combined and concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (358 mg, 1.05 mmol, 23 %). NMR (300 MHz, CDCI3) d 8.i6 (d, 1 H), 7.19 (d, 1 H), 7.03 (d, 1 H), 6.86 (dd, 1 H), 6.71 (s, 1 H), 3.97 (d, 3 H), 3.46 (s, 2 H), 2.99 (t, 2 H), 2.90 (t, 2H), 2.13 (p, 2 H), 1.42 (s, 9 H).(E)-6-Benzylidene-3-bromo-7-carbonyl-6, 7-dihydro-1H-pyrazolo[3, 4-g]quinoxaline-1, 5, 8-tricarboxylic acid tri-tert-butyl ester (500 mg, 0.76 mmol),

Molecular Weight:235.09
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:235.1379736
Monoisotopic Mass:235.1379736
Topological Polar Surface Area:40.6
Heavy Atom Count:17
Complexity:267
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes