Ethyl pyrazole-3-carboxylate

To solution of ethanol (50 mL) and 3-pyrazolecarboxylicacid (1.112 g 10 mmol) at 80 °C was added concentratedsulfuric acid (2 mL), and after 2 h of stirring theethyl 1H-pyrazole-3-carboxylate was obtained (1.350 g, 9.6 mmol, 96 percent).Ethyl 1H-pyrazole-3-carboxylate (6) A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H1H-pyrazol-3-formic acid (7.25 g, 64.7 mmol) was dissolved in absolute ethanol (100 mL), and concentrated sulfuric acid (0.7 mL) was added. 1 H-Pyrazole-3-carboxylic acid (2.0 g, 17.84 mmol) was dissolved in ethanol (20 ml_), sulfonic acid (1 ml_) was added and the reaction mixture was heated to reflux overnight. Evaporation in vacuo followed by addition of water and aqueous sodium carbonate gave a white precipitate. Filtration followed by wash with water gave 1 H- pyrazole-3-carboxylic acid ethyl ester (2.0 g, 80percent) as white crystals.General procedure: To a suspension of 4-methoxy-3, 5-dimethylbenzoic acid (4 g, 22.2 mmol) in MeOH (60 mL) sulphuric acid was added (1 mL) and mixture stirred at reflux for 1 day. Water was added and it was extracted with AcOEt, organic layers were put together and dried over sodium sulphate and concentrated. The oil thus obtained was purified by normal phase chromatography with 5percent MeOH/DCM to yield the title compound as a colorless oil (99percent yield). LRMS: m/z 195 (M+1)Example 14A1 lH-Pyrazole-3-carboxylic acid ethyl ester To a solution of lH-pyrazole-3-carboxylic acid (2.0 g, 17.8 mmol) in anhydrous ethanol (20 mL) was added concentrated H2SO4 (1 mL) at room temperature. The mixture was refluxed for 12 hours. TLC (neat EtOAc) indicated that the reaction was completed. The mixture was concentrated, the residue was washed with aqueous NaHC0a. A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MHExample 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.Example 15.[00151] presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6, 7-dihydro-4H-pyrazolo[4', 3':5, 6]oxepino[4, 3-d][1 , 3]thiazol-2-amine (Table II, Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.Step 2: lH-Pyrazole-3-carboxylic acid ethyl ester[0164] 4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester (195 g, 1.14 mol) and hydrazine dihydrochloride (119.7 g, 1 eq) were dissolved in EtOH (1 L) and stirred at room temperature overnight. The mixture was then heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with water three times and dried. The filtrate was concentrated to a thick oil and added dropwise into a flask with stirred EtOAc (200 mL). The resulting solid was filtered and rinsed with a small amount of EtOAc. The filtered solids were combined to give the product (62 g, 39percent yield). MS (ES) mlz 141.1 (M+ H8. Preparation of 3-difluorochloromethyl-NH-pyrazole from 4-butoxy-1-chloro-1, 1-difluorobut-3-en-2-oneOver a period of 10 minutes, hydrazine hydrate (80percent pure, 0.52 g, 0.008 mol) was added dropwise to a solution of 4-butoxy-1-chloro-1, 1-difluorobut-3-en-2-one (1.2 g, 0.005 mol) in ethanol (6 ml). The mixture was then stirred under reflux conditions for 5 h. The resulting yellow-brown suspension was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (20 ml) and water (20 ml). After separation of the phases, the aqueous phase was re-extracted with ethyl acetate (20 ml). The organic phases were combined, dried over MgSOTo a mixture of compound B82 (1 g, 7.14 mmol), Cs2C03 (5.81 g, 17.8 mmol) in DMF (15 mL) was added compound B83 (6.14 g, 35.68 mmol). The mixture was stirred at 20C for 12 hours to give a yellow suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the aqueous phase was extracted with EtOAc (80 mL x 2), the combined extracted phase was washed with water (80 mL), dried over Na2S04, filtered, concentrated under reduced pressure to give a yellow oil, which was purified by Combi flash to give compound B84 (1.9 g) as a white solid.

Molecular Weight:140.14
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:140.058577502
Monoisotopic Mass:140.058577502
Topological Polar Surface Area:55
Heavy Atom Count:10
Complexity:127
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes