3-Bromo-5-chloro-2-pyrazinamine

A 250ml round bottom flask was charged with 5-chloro-pyrazin-2-ylamine (1) (3g, 23mmol, N-bromosuccinimide (4g, 23mmol) and dichloromethane (100ml) under nitrogen. The reaction mixture was refluxed for Ih, then allowed to cool to room temperature and concentrated in vacuo. The compound was purified by flash chromatography, using as eluent pentane/EtOAc 0percent to 50percent, to give the title compound (3g, 62percent). IH NMR (DMSo- d6) 6.8-6.9 (2H, brs), 8.0 (IH, s). MS(ES+): 210, 212.To a solution of 5-chloropyrazin-2-amine (500 mg, 3.86 mmol) in DCM (5mL) was added NBS (686.92 mg, 3.86 mmol), and the brown mixture was stirred at 40 C for 1 hour. After cooling to r.t., the mixture was filtered through silica gel and eluted with EtOAc (20 mL x 3), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20percent to 40percent to 50percent) to give the product (600 mg) as a solid. *H NMR (400MHz, CDC13 ) __ = 7.98 (s, 1H), 5.05 (br s, 2H).A mixture of Zinc dust (activated by the procedure found in WO2011/143365, the disclosure of which is incorporated herein by reference in its entirety) (0.627 g, 9.59 mmol) was charged to a dry flask and suspended in DMA (2.5 mL). 1, 2-Dibromoethane (0.031 mL, 0.36 mmol) and TMSCl (0.092 mL, 0.72 mmol) were added and the reaction was stirred for 25 min. tert-Butyl 3-iodoazetidine-1-carboxylate (2.04 g, 7.20 mmol, Oakwood) in DMA (6.0 mL) was added slowly to the mixture which was immersed in a water bath to keep the temperature below 65 C. The mixture was stirred for 1 hour and was degassed by bubbling a stream of nitrogen through the mixture for 5 minutes. (0976) A separate flask was charged with [1488] Zinc dust (0.627 g, 9.59 mmol) (activated by the procedure described in WO2011/143365, the disclosure of which is incorporated herein by reference in its entirety) was charged to a dry flask and suspended in DMA (2.5 mL). 1, 2-Dibromoethane (0.031 mL, 0.36 mmol) and TMSCl (0.092 mL, 0.72 mmol) were added and the reaction was stirred for 25 min. tert-Butyl 3-iodoazetidine-1-carboxylate (2.04 g, 7.20 mmol) (Oakwood) in DMA (6.0 mL) was added slowly to the mixture which was immersed in a water bath to keep the temperature below 65C. The mixture was stirred for 1 hour and was degassed by bubbling a stream of nitrogen subsurface for 5 minutes.[1489] A separate flask was charged with A mixture of A flask was charged with A flask was charged with The suspension of 18a (3 g, 14.5 mmol), NaCN (0.85 g, 17.4 mmol), CuI (1.3 g, 7.3 mmol) and Pd(PPh3)4 (0.17 g, 0.15 mmol) were stirred in DMF (40 mL) at 120 C for 10 h under nitrogen protection. After cooling to room temperature, 10% aqueous solution of Na2S2O3(10 mL), water (60 mL) and ethyl acetate (200 mL) were added. The resulting mixture was stirred for 10 min, then filtered, and the filter cake was washed with ethyl acetate (150 mL). The organic layer was separated, washed with water (3 × 50 mL), dried over anhydrous Na2SO4and concentrated. The residue was purified by chromatography on silica gel eluting with PE/EA (10:1-2:1) to give a light-yellow solid (1.9 g, yield 85%). 6-Chloro-3-aminopyrazine-2-carbonitrile (19a) Yield: 85%, light-yellow solid, M.p.: 156-158 C. 1H NMR(400 MHz, CDCl3):delta 8.23 (s, 1H), 5.34 (s, 2H). 13C NMR(100 MHz, CDCl3):delta 154.98, 146.84, 137.41, 114.07, 111.16. EI-MS m/z: 154 (M+, Cl35, 100), 156 (M+, Cl37, 35), 127 (M+, Cl35, -H, -CN, 48), 129 (M+, Cl37, -H, -CN, 15).General procedure: 18b (3.0 g, 12 mmol) was added into acetic acid (20 mL) and concentrated sulfuric acid (4 mL) under ice bath. To this mixture was added a pre-prepared solution of NaNO2 (1.65 g, 24 mmol) in water (10 mL). The reaction mixturewas stirred at room temperature for 3 h, and then poured into ice water (100 g). The precipitate was collected by filtrated, washed with water and dried to give an off-white solid (1.8 g, yield 61%).First, into a three-neck flask equipped with a reflux pipe were put 5.01 g of 60 General procedure: Sodium nitrite (3.4 g, 50 mmol, 1.3 eq.) was added in small portionsto 98% sulfuric acid (15 mL) ice bath, and the mixture was allowed towarm up and heated to 60. When getting clear, the solution wascooled in an ice bath again. A solution of 2-amino-pyrazine (9) (4 g, 39.3 mmol, 1 eq.) in 98% sulfuric acid (15 mL) was added dropwise.The reaction mixture was stirred at 40 for 1 h. After cooling to roomtemperature, it was slowly poured onto crushed ice and stirred until nonitrogen run out. The solution was adjusted to pH 6 with a 40% solutionof sodium hydroxide, resulting in lots of sodium sulfate which wasfiltered off whereafter. The filtrate was extracted with EA (50 mL×3), and the combined organics were dried (Na2SO4), filtered and concentratedin vacuo to give the product as a white precipitate (6.38 g, 53%).Next, into a three-neck flask equipped with a reflux pipe were put 3.69 g of 84 10-methoxyphenanthrene-9-boronic acid obtained in Step 3, 3.02 g of 60

Molecular Weight:208.44
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:206.91989
Monoisotopic Mass:206.91989
Topological Polar Surface Area:51.8
Heavy Atom Count:9
Complexity:102
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes