2-CHLORO-1,3-THIAZOLE-5-CARBALDEHYDE

To a stirred solution of 2-chlorothiazole E-1 (80 g) in anhydrous THF (1000 ml.) was added n- BuLi (320 ml_, 0.8 mol) drop wise at -78 °C for one hour. Ethyl formate (74 g) was added dropwise to the solution at -78 °C, and stirred for one additional hour. Saturated NH4CI was added to the reaction mixture and stirred for 30 min, then diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed and dried, then concentrated to give the crude product, which was purified by re-crystallized with hexane/ethyl acetate to give 2-chlorothiazole-5-carbaldehyde E-2 (72 g yield: 73 percent, ); 1 H NMR (400 MHz, CDCI3): δ ppm 9.96 (s., 1 H), 8.21 (s, 1 H).Example 53 To a stirred solution of 2-chlorothiazole E-1 (80 g) in anhydrous THF (1000 ml.) was added n- BuLi (320 ml_, 0.8 mol) drop wise at -78 °C for one hour. Ethyl formate (74 g) was added dropwise to the solution at -78 °C, and stirred for one additional hour. Saturated NH4CI was added to the reaction mixture and stirred for 30 min, then diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed and dried, then concentrated to give the crude product, which was purified by re-crystallized with hexane/ethyl acetate to give 2-chlorothiazole-5-carbaldehyde E-2 (72 g yield: 73 percent, ); 1 H NMR (400 MHz, CDCI3): δ ppm 9.96 (s., 1 H), 8.21 (s, 1 H).Example 53 To a solution of 2-bromo-6-(2, 5-dimethylpyrrol-1-yl)pyridine (CAS 198209-31-3, preparation described by U. Kiehne et al, Synthesis 2007, 7, pp 1061-1069) (10.00 g, 39.8 mmol) in anhydrous tetrahydrofuran (320 ml_) under an inert atmosphere and stirred at -78C, was added dropwise a solution of n-butyllithium (1.6 M in hexanes, 26.0 ml_). After 1.5 hours stirring, under an inert atmosphere the resulting solution was added to a well-stirred solution of 45-1 (18.12 mL, 170.53 mmol) was dissolved in dichloromethane (425.00 mL), then pyridine (2.76 mL, 34.11 mmol) was added at -10C, and then phosphorus pentachloride (35.51 g, 170.53 mmol) was added in one time.The reaction mixture was stirred at -10C for 1 hour, and then sodium dicarbonate (42.98 g, 511.59 mmol) was added.The mixture was stirred at -10C for 0.25 hours. The reaction mixture was filtered, the filtrate was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was then concentrated under reduced pressure and evaporated to dryness, giving 45-2. 1H NMR (400MHz, CDCl3) delta 7. 02 (d, J=3. 9 Hz, 1H), 6. 87 (s, 1H), 6. 80 (d, J=4. 0 Hz, 1H).To a solution of 1-methylpyrazol-3-amine (0.2 g, 2.059 mmol) in ethanol (13 mL, 226.5 mmol) General procedure: Thecorrespondingaldehyde(1.0mmol)wasaddedtoasolutionofN, N'-diphenylethylenediamine (424mg, 2.0mmol)inaqueousethanol(50%, 3mL).Thereactionmixturewasstirredatroomtemperature until the complete consumption of aldehydes, as determined by TLC. The mixture was filtered and the filter cake was washed with a small amount of water and cold ethanol to afford the pure product.General procedure: The corresponding aldehydes (1.0 mmol) were added to a solution of N, N'-dibenzyl ethylenediamine (480 mg, 2.0 mmol) in aqueous ethanol (50%, 3 mL). The reaction mixture was stirred at room temperature until the complete consumption of aldehydes, as determined by thin layer chromatography (TLC). The mixture was ltered and the lter cake was washed with a small amount of water and cold ethanol to aord the pure product.To a stirred solution of thiazole compound XVII (1 g, 6.78 mmole) in aq. H2SO4 (70%) (26 g) was added aq. HNO3 (65 %, 4 g) dropwise at 1 10 C. After stirring 1 hour at 1 10C the starting material was consumed. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were dried over anhydrous Na2S04, and concentrated. The was purified by combiflash chromatography (70% ethyl acetate; 30%hexane) to give 870 mg (5.32 mmol) of the product XIV (yield 78%).-NMR (400 MHz, DMSO), delta (ppm): 8.23 (s, 1 H), 13.9 (broad s, 1 H).To a stirred solution of To a stirred solution of 2-chlorothiazole E-1 (80 g) in anhydrous THF (1000 ml.) was added n- BuLi (320 ml_, 0.8 mol) drop wise at -78 C for one hour. Ethyl formate (74 g) was added dropwise to the solution at -78 C, and stirred for one additional hour. Saturated NH4CI was added to the reaction mixture and stirred for 30 min, then diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed and dried, then concentrated to give the crude product, which was purified by re-crystallized with hexane/ethyl acetate to give To a solution of 2-bromo-6-methoxyphenol (5.0 g, 24.63 mmol) in Nu, Nu'- dimethylformamide (50 mL) was added potassium carbonate (6.8 g, 486 mmol) and 2- chloro-5- thiazolecarboxaldehyde (3.6 g , 24.63 mmol) at 0 C. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography using ethyl acetate: hexanes (1 :5) to afford the title compound (5.2 g) as pale yellow solid. H NMR (400 MHz, CDC13) delta 3.80 (s, 3H), 6.98-7.00 (dd, 1H), 7.16-7.20 (t, 1H), 7.23- 7.26 (dd, 1H), 7.87 (s, 1H), 9.84 (s, 1H).

Molecular Weight:147.58
XLogP3:1.7
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:146.9545626
Monoisotopic Mass:146.9545626
Topological Polar Surface Area:58.2
Heavy Atom Count:8
Complexity:100
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes