4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

To a solution of 2, 4, 6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40percent water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00 equiv) and triethylamine (16 mL) at -78° C. To a solution of 2, 4, 6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40percent water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00equiv) and triethylamine (16 mL) at -78 °C. The resulting mixture was stuffed for 30 mm at -78 °C and then 2h at 0 °C. After completion the reaction was concentrated under vacuum without heating. Then ethyl acetate was added and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum without heating. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford 6 g (78percent) of4, 6-dichloro-1-methyl-1H-pyrazolo[3, 4-d]pyrimidine as a white solid. LC-MS (ES, m/z): 203 [M+H] .To a stirred solution of 2 4 6-trichloropyrimidine-5-carbaldehyde (18.5 g 88.1 mmol) in EtOH (250 mL) was added methyl hydrazine (6.8 g 88.1 mmol 60in water) and Et1 -methyl- 1 H-pyrazolo-[3, 4-d]pyrimidine-4, 6(5H, 7H)-dione 4 (2.1g, 13 mrno) was dissolved in POCIPhosphorus pentachloride (15 g, 0.072 mol) was added to a mixture of 1-methyl-1, 7-dihydro-pyrazolo[3, 4-i/] pyrimidine-4, 6-dione 4 (6 g, 0.04 mol) in phosphorus oxychloride (10 ml, 0.12 mol). The reaction mixture was heated to reflux for 18 h. Excess of phosphorus oxychloride was distilled off under reduced pressure. The residue was poured on ice. The resulting mixture was extracted with DCM (3X). The combined organic layers were washed with water, dried over MgSOTo a solution of 4, 6-dichloro-1H-pyrazolo[3, 4-d]pyrimidine (110 mg, 0.58 mmol) in DMF (8 mL) was added K2C03 (160 mg 1.16 mmol). The reaction mixture was stirred for 30 mm at rt, and iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction, and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na2504 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (48 mg, 41 percent).‘HNMR (400 MHz, CDC13) (ppm): 8.16 (s, 1H), 4.13 (s, 3H).To a solution of 4, 6-dichloro-1H-pyrrolo[3, 4-d]pyridine (110 mg, 0.58 mmol) in DMF (5 mL) was added K2C03 (160 mg, 1.16 mmol). Then the reaction mixture was stirred for 30 mm maintaining at temperature, then iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction, and the resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous Na2504, filtered, and the filtrate was concentrated in vacuo.The residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/i) to give the title compound as a yellow solid (48 mg, 41 percent).‘HNIVIR (400 IVIFIz, CDC13) (ppm): 8.16 (s, 1H), 4.13 (s, 3H).General procedure: To a solution of 2, 4-dichloropyrrolo[1, 2-f][1, 2, 4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2, l-f][l, 2, 4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): delta 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl).General procedure: To a solution of 2, 4-dichlorofuro[3, 2-d]pyrimidine (la) (0.71 g, 3.74 mmol; CAS 956034- 07-4) in 2-Propanol (20 mL) was added DIPEA (1.63 mL, 9.36 mmol), 1-methyl-1H-imidazol-4-amine hydrochloride (0.5 g, 3.74 mmol) and heated at reflux for 24 h. The reaction mixture was concentrated in vacuum to dryness and the residue obtained was triturated with water. The solid obtained was collected by filtration and dried in vacuum to afford 2-chloro-N-(l-methyl-lH-imidazol-4-yl)furo[3, 2-d]pyrimidin-4-amine (lb) (550 mg, 59 % yield) as brown solid; NMR (300 MHz, DMSO-^) delta 10.89 (s, 1H, D20exchangeable), 8.35 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 1.3 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 3.71 (s, 3H); MS (ES+): 250.3 (M+l), 272.3, 274.3 (M+Na), (ES-): 248.2 (M-l).Step 1:

Molecular Weight:203.03
XLogP3:2.1
Hydrogen Bond Acceptor Count:3
Exact Mass:201.9813015
Monoisotopic Mass:201.9813015
Topological Polar Surface Area:43.6
Heavy Atom Count:12
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes