2-Bromo-5-iodopyrazine

To a mixture of DME (30 mL) and the product (2) from Part A (1.25 g, 7.2 mmol) was added CsI (1. 86 g, 7.2 mmol), iodine (0.92 g, 3.6 mmol), CuI (0.42 g, 2.2 mmol), and isoamyl nitrite (5.8 [ML, ] 43.2 mmol). The dark mixture was heated to [60°C, ] causing gas evolution. After heating for 35 min, and the mixture was cooled to room temperature, partitioned between saturated aqueous NH4Cl (100 mL) and EtOAc (100 mL), and filtered through celite. The organic layer was separated, washed with 5percent Na2S203, dried over [MGS04, ] and evaporated to afford 1.50 g (74percent yield) of the desired product (3) as an yellow solid. GCMS: [M/Z] = [284, ] 286 [(M+).]To a solution of 5-bromopyrazinamine (3.0 g, 17.2 mmol, 1.0 equiv) in HI ( 1 1.1 mL, 57percent in water) at 0To a mixture of DME (30 mL) and the product (2) from Part A (1.25 g, 7.2 mmol) was added CsI (1. 86 g, 7.2 mmol), iodine (0.92 g, 3.6 mmol), CuI (0.42 g, 2.2 mmol), and isoamyl nitrite (5.8 [ML, ] 43.2 mmol). The dark mixture was heated to [60C, ] causing gas evolution. After heating for 35 min, and the mixture was cooled to room temperature, partitioned between saturated aqueous NH4Cl (100 mL) and EtOAc (100 mL), and filtered through celite. The organic layer was separated, washed with 5% Na2S203, dried over [MGS04, ] and evaporated to afford 1.50 g (74% yield) of the desired product (3) as an yellow solid. GCMS: [M/Z] = [284, ] 286 [(M+).]To a solution of 5-bromopyrazinamine (3.0 g, 17.2 mmol, 1.0 equiv) in HI ( 1 1.1 mL, 57% in water) at 00C was slowly added I2 (3.0 g, 24.1 mmol, 0.7 equiv) over 1 hr, followed by addition OfNaNO2 (5.0 g, 145 mmol, 4.2 equiv) over a period of 3 hr at 0 0C. The reaction mixture was made alkaline by first adding 10% Na2S2Os solution (150 mL), then saturated Na2COs solution (90 mL). The mixture was extracted with diethyl ether (3 x 250 mL). The organic layer was washed with 10% Na2S2Os solution, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, ethyl acetate/hexanes, 0:100 to 10:90, v/v] to give 2-bromo-5- iodo-pyrazine (1.6 g, 32%). 1H NMR (400 MHz, CD2Cl2) delta 8.62 (s, IH), 8.51 (s, IH).EXAMPLE 41B Description 65: Preparation 10: 2-Bromo-5-iodopyrazineTo a solution of 5-bromopyrazin-2-amine (25.95 g, 147.13 mmol) in 1 , 2-dimethoxyethane (500 ml_) was added cesium iodide (38.75 g, 147.13 mmol), copper (I) iodide (8.52 g, 44.74 mmol) and iodine (18.93 g, 74.57 mmol). Isoamyl nitrite (120 ml_, 894.8 mmol) was then added dropwise via a dropping funnel and the reaction mixture was heated at 60 C for 1 hour. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (200 ml_), washed with ammonium chloride (sat. aq .200 ml_), then sodium thiosulphate (sat. aq.3 x 200 ml_). The organic layer was dried over MgS04, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica column (heptane : ethyl acetate, 100:0 to 85:15) to give the title compound as a off-white solid (35.38 g).LCMS (run time = 5 minutes, System D): Rt = 2.09 minutes.H NMR (400 MHz, CDCI3): delta = 8.65 (s, 1 H), 8.50 (s, 1 H).Into a 20-L 4-necked round-bottom flask was placed a solution of 5-bromopyrazin-2-amine (400 g, 2.30 mol) in ethylene glycol dimethyl ether (8 L) , iodocopper (131 g, 687.84 mmol) , diiodane (293 g, 1.15 mol) , iodopotassium (380 g, 2.29 mol) and 3-methylbutyl nitrite (1800 mL, 11.5 mol) . The resulting solution was stirred for 30 min at 60 C, then extracted with 2 x 10 L of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound.5 g (20.1 mmol) of 2-Bromo-5-iodopyrazine (284.9 mg, 1 mmol), lH-imidazole (64.7 mg, 0.95 mmol), toluene (10 mL), and K2CO3 (345.5 mg, 2.5 mmol), Cul (19.0 mg, 0.1 mmol), trans-N, N'- dimethylcyclohexane-l, 2-diamine (0.032 mL, 0.2 mmol) were heated at 100 C overnight. The reaction mixture was then partitioned between H20 and ethyl acetate. The organic layer was dried over MgSCL, filtered, and concentrated under vacuum. Purification by silica gel chromatography (ethyl acetate in hexane, 0-100%), yielded 2-(lH-imidazol-l-yl)-5-iodopyrazine (219.7 mg, 85%) as an off-white solid which contains a small amount of inseparable byproduct 2-(lH-imidazol-l- yl)-5-bromopyrazine. LC-MS 273.1 [M+H]+, RT 0.74 min.2-Bromo-5-iodopyrazine (284.9 mg, 1 mmol), l-(tetrahydro-2H-pyran-2-yl)-4-(4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (306.0 mg, 1.1 mmol), PdCl2(dppf)- dichloromethane adduct (81.7 mg, 0.1 mmol), dioxane (10 mL), and aqueous K2CO3 (1.5 mL, 3 mmol, 2 M) were heated at 80 C for 2 h. The reaction mixture was then partitioned between H20 and ethyl acetate. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (ethyl acetate in hexanes, 0-100%), yielded 2- bromo-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)pyrazine (216.4 mg, 70%) as an off- white solid. LC-MS 225.1, 227.1 [M-THP+H]+, RT 1.32 min.General procedure: 3Cz (0.50 g, 1.0 mmol), 5-bromo-2-iodopyridine (0.29 g, 1.0 mmol), copper (0.07 g, 1.0 mmol) and K2C03 (0.28 g, 2.0 mmol) were combined in a 2-necked flask equipped with a condenser and cycled 3 times with vacuum and nitrogen. Chlorobenzene (15 ml_) was then added and stirred at 120 C under the flow of nitrogen for 19 hours whereupon full consumption of both starting materials was observed. The reaction was then allowed to cool and the copper filtered out over Celite bed and washed with DCM. The solvents were removed under vacuum resulting in an off-white solid (0.63 g, 96%).To a 250 ml_ flask were added Add 30 g of A solution of 3-fluoro-3- (2-fluoro-5- (trifluoromethoxy) phenyl) cyclobutanol (160 mg, 0.597 mmol) in THF (6 mL) was purged with N2 for 5 min, then NaHMDS (1.0 M in THF, 0.597 mL) was added at room temperature. After stirring for 10 min, a solution of

Molecular Weight:284.88
XLogP3:1.5
Hydrogen Bond Acceptor Count:2
Exact Mass:283.84461
Monoisotopic Mass:283.84461
Topological Polar Surface Area:25.8
Heavy Atom Count:8
Complexity:80.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes