1-(5-CHLOROPYRIDIN-2-YL)ETHANONE

2-Bromo-5-chloropyridine (5.8g, 30mmol) was added to dry diethyl ether (100ml). The mixture was cooled to-60°C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2hrs. A solution of N, N- dimethylacetamide (3. 1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgS04 and evaporated to give 1- (5-Chloro-pyridin-2-yl)-ethanone (4. 0g, 85percent).2) 1-(5-chloro-2-pyridyl)ethanone; A 1.56M solution of n-butyllithium in hexane (27 ml) was added dropwise to a solution of the 2-bromo-5-chloropyridine (6.8 g) in diethylether (45 ml) at-78°C, and thereafter, N, N-dimethyl acetamide (5 ml) was added dropwise to the solution. The mixture was stirred for 30 minutes. To the reaction liquid was added saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(5-chloro-2-pyridyl)ethanone (3.26 g, 59percent) as a solid. 2) a) l-(5-Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitxile (10.7 g, 77 mmol) was dissolved in diethyl ether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 a) 1 - (5- Chloropyridin-2-yl)ethanone5-Chloropyridine-2-carbonitrile (10.71 g, 77 mmol) was dissolved in diethylether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was -63 °C. Methyl magnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at -60 To 5-chloro-N-methoxy-N-methylpicolinamide (8.3 g, 41.5 mmol) in THF (100 mL) was added methyl magnesium bromide (3M in THF, 16.6 mL, 49.8 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. Water (200 mL) was added and the mixture extracted with ethyl acetate (200 mL x 3). The combined organicphases were dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica:200-300 mesh, 50 g, petroleum ether I ethyl acetate 9:1) to give 1-(5-chloropyridin-2-yl)ethanone as white solid (6 g, 93percent).LCMS: Rt 1.45 mi MH 156.D100 (32mg, 0.09 mmol) was dissolved in 2-propanol (900 uL), 1-(5-chloropyridin-2-yl) ethanl-one (57.67mg, 0.37 mmol) and HC14N in dioxane (100 uL, 0.40 mmol) were added, and thesolution was stirred at 95C for 4h and overnight at room temperature. The reaction mixture wasdirectly purified by preparative HPLC (HzO/CH3CN+O.l %HCOOH) to afford the title compoundE53 (15.82 mg) as white powder. Method 3; Rt: 3.67 min. m/z: 483.02 (M+Ht. 1H NMR (300MHz, DMSO-d6) 8 ppm 1.81 (s, 3 Hz, 1 H) 10.40 (br s, 1 H).H) 7.13 (d, J=8.70 Hz, 1 H) 7.63 (d, J=8.60 Hz, 1 H) 7.68 -7.83 (m, 2 H) 7.89- 8.03 (m, 2 H) 8.21 (d, J=2.00 Hz, 1 H) 8.38- 8.55 (m, 2 H) 8.59 (d, J=2.201-(5-Chloropyridin-2-yl)ethanone (850 mg, 5.46 mmol) and diethyl ketomalonate (1.9 g, 10.92 mmol) were mixed and stirred at 130C for 24 h. After cooling to rt, the mixture was taken up in ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (MN 617 WA filter paper) and concentrated. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to afford 1.04 g (58%) of the title compound. 1H NMR (400 MHz, DMSO-de) d ppm = 1.17 (t, 6 H), 3.84 (s, 2 H), 4.16 (q, 4 H), 6.44 (s, 1 H), 7.94 - 7.98 (m, 1 H), 8.13 - 8.17 (m, 1 H), 8.80 - 8.82 (m, 1 H).

Molecular Weight:155.58
XLogP3:1.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:155.0137915
Monoisotopic Mass:155.0137915
Topological Polar Surface Area:30
Heavy Atom Count:10
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes