6-Bromo-5-methyl-3-pyridinecarbonitrile

To a -78° C. solution of 2, 5-dibromo-3-methyl-pyridine (1.48 g, 5.89 mmol) in diethyl ether (65 mL) was added n-butyllithium (2.5 M in hexanes; 2.59 mL, 6.48 mmol) dropwise. After 40 min, p-toluenesulfonyl cyanide (1.17 g, 6.49 mmol) was added and the mixture was warmed to 0° C. The reaction was quenched with satd. aq. NaHCOThe crude 128b (432 mg), The crude 126d (64 mg), copper(I) iodide (6 mg, 0.03 mmol), and trans- dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.02 mmol) were mixed in a round bottom flask and placed under a nitrogen atmosphere. THF (2 mL) and triethylamine (0.06 mL, 0.43 mmol) were added, and the reaction mixture was stirred at 60 C for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with saturated aqueous NH4CI, dried over MgSO/t, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% EtOAc in heptane) gave product of insufficient purity. The impure product was slurried in MeOH and filtered to give (1S, 5S, 6S)-3 -amino-5 -(5 -((5 -cyano-3 -methylpyridin-2-yl)ethynyl)-2-fluorophenyl)-5 - methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-l-carbonitrile (126, 10 mg, 0.025 mmol, 11% yield) as a tan solid. LC/MS (ESI+) m/z = 402.0 [M+H]+. NMR (400 MHz, CHLOROFORM-d) delta ppm 8.70 (s, 1H) 7.79 - 7.84 (m, 2H) 7.53 (m, J = 7.24, 3.72 Hz, 1H) 7.10 (dd, J = 11.54, 8.41Hz, 1H) 2.56 (s, 3H) 2.47 (t, J = 8.71Hz, 1H) 1.83 (s, 3H) 1.68 (dd, J = 9.68, 6.16 Hz, 1H) 1.14 (t, J = 7.04 Hz, 1H). NH2 peak was not observed.A mixture of (1S, 5S, 6S)-3-amino-5-(5-ethynyl-2-fluorophenyl)-N, N, 5-trimethyl-2- thia-4-azabicyclo[4.1.0]hept-3-ene-l-carboxamide (123d, 90 mg, 0.27 mmol), 2-bromo-5- cyano-3-picoline (Matrix Scientific, Columbia, SC, USA) (80 mg, 0.41 mmol), bis(triphenyl- phosphine)palladium (II) dichloride (19 mg, 0.027 mmol), and copper(I) iodide (8 mg, 0.041 mmol) were mixed in a round bottom flask and placed under a nitrogen atmosphere. THF (2.5 mL) and triethylamine (0.08 mL, 0.54 mmol) were added, and the reaction mixture was stirred at 60 C for 1 hour. The reaction mixture was cooled to room temperature and then concentrated in vacuo to give an oil. The oil was purified via silica gel chromatography (30 to 100% ethyl acetate in heptane) to give (1S, 5S, 6S)-3-amino-5-(5-((5-cyano-3- methylpyridin-2-yl)ethynyl)-2-fluorophenyl)-N, N, 5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept- 3-ene-l-carboxamide (123) (74 mg, 0.17 mmol, 61% yield) as a yellow solid. LC/MS (ESI+) m/z = 448 [M+H]+. NMR (400 MHz, CHLOROFORM-) delta ppm 8.70 (d, J = 131Hz, 1H) 7.85 (d, J = 6.65 Hz, 1H) 7.80 (s, 1H) 7.49 (ddd, J = 8.36, 4.55, 2.15 Hz, 1H) 7.07 (dd, J = 11.54, 8.22 Hz, 1H) 3.07 (br. s., 6H) 2.56 (s, 3H) 2.32 (t, J = 8.02 Hz, 1H) 1.83 (s, 3H) 1.27 - 1.37 (m, 1H) 0.88 (t, J = 6.46 Hz, 1H). NH2 peak was not observed.A mixture of 116a (46 mg, 0.11 mmol), 1, 4-Dioxane (4.14 mL) and ethynyltributylstannane (Sigma- Aldrich, St. Louis, MO, USA) (0.18 mL, 0.62 mmol) were added to a flask charged with ((1S, 5S)-3-amino-5-(5- bromo-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en- 1- yl)(mophiholino)methanone (136c, 0.18 g, 0.41 mmol) and bis(tri-t- butylphosphine)palladium(O) (Sigma-Aldrich, St. Louis, MO, USA) (0.02 g, 0.04 mmol) under an argon atmosphere. The reaction mixture was heated to 80 C and stirred for 2 hours. The reaction mixture was then cooled to ambient temperature, diluted with EtOAc and 1 M aqueous KF, and stirred for 15 min. The biphasic mixture was filtered through celite. The organic layer was separated, washed with brine, dried over MgSO/t, filtered, and concentrated to yield 136d as a brown oil that partially solidified upon standing. The crude 136d was taken on directly assuming 100% yield without further purification orcharacterization. Crude alkyne 136d (155 mg, 0.41 mmol), Preparation of (l , 5 , 6S)-methyl 3-((teri-butoxycarbonyl)((2- (trimethylsilyl)ethoxy)methyl)amino)-5-(5-(( )-2-(5-cyano-3-methylpyridin-2-yl)-2- fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-l- carboxylate (24A). A mixture of A suspension of 2-{4-[2-(3-fluoromethyl-azetidin-l-yl)-ethoxy]-phenyl}-4-methyl-3- (4, 4, 5, 5-tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-2H-chromen-6-ol (82.5 mg, 0.17 mmol), 2- bromo-3-methyl-5-cyano-pyridine (50 mg, 0.25 mmol), potassium carbonate (46 mg, 0.33 mmol) and bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.017 mmol) in N, N- dimethylformamide (3 mL) and water (1 mL) was heated at 90 C in a sealed tube under argon for 2 hr. The reaction mixture was allowed to cool to room temperature and loaded onto a 10 g SCX-2 cartridge. The cartridge was washed with methanol and the crude product eluted with 2 M ammonia in methanol. The eluent was concentrated in vacuo and the resultant residue was purified by reverse-phase HPLC (XSELECT CSH Prep CI 8 5 um OBD, 19x250 mm, mobile phase: acetonitrile in water gradient 10% to 98%). Appropriate fractions were combined and evaporated and the residue obtained was further purified by silica gel chromatography (Phenomenex Luna Si 5um, 21.4 x 250 mm steel column, mobile phase: 5% of 2 M ammonia in methanol solution in dichloromethane). Appropriate fractions were combined and evaporated to afford the title compound as a beige glass (26.8 mg, 33%). 1H NMR (300 MHz, DMSO-J6): delta 9.04 (s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.15 (broad d, 1H), 6.78 (s, 1H), 6.73 (d, / = 8.8 Hz, 2H), 6.59 (m, 2H), 5.93 (s, 1H), 4.54 (d, / = 6.1 Hz, 1H), 4.42 (d, / = 6.1 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.27 (dt, / = 1.2 Hz, / = 7.5 Hz, 2H), 2.95 (t, / = 6.8 Hz, 2H), 2.76-2.68 (m, 1H), 2.65 (t, J = 5.8 Hz, 2H), 2.15 (broad s, 3H), 1.80 (s, 3H). LCMS: 486.2 [M+H]+.To a -78 C. solution of 2, 5-dibromo-3-methyl-pyridine (1.48 g, 5.89 mmol) in diethyl ether (65 mL) was added n-butyllithium (2.5 M in hexanes; 2.59 mL, 6.48 mmol) dropwise. After 40 min, p-toluenesulfonyl cyanide (1.17 g, 6.49 mmol) was added and the mixture was warmed to 0 C. The reaction was quenched with satd. aq. NaHCO3(50 mL) and extracted with CHCl3 (100 mL). The organic layer was dried (Na2S2O5) and concentrated to obtain the crude residue which was purified by FCC (EtOAc/hexanes) to give 310 mg (27%) of a white solid.

Molecular Weight:197.03
XLogP3:2
Hydrogen Bond Acceptor Count:2
Exact Mass:195.96361
Monoisotopic Mass:195.96361
Topological Polar Surface Area:36.7
Heavy Atom Count:10
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes