2-methoxyethanimidamide;hydrochloride

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (2.00 g, 5.1 mmol), 2-methoxy-acetamidine hydrochloride (0.76 g, 6.1 mmol) and TEA (5.00 mL, 35.9 mmol) in DMF (38 mL) was evacuated and refilled with nitrogen (×3). The reaction was treated with Xantphos (0.15 g, 0.26 mmol) and palladium (II) acetate (57 mg, 0.26 mmol) before the reaction was purged with carbon monoxide gas and the reaction stirred at 60° C. for 3.5 h. The reaction mixture was cooled to RT, purged with nitrogen then treated with isopropyl-hydrazine hydrochloride (1.70 g, 15.0 mmol) and acetic acid (19 mL). After stirring at 60° C. for 1.5 h the reaction was diluted with ethyl acetate (350 mL). The solution was washed with 1N NaOH (2×50 mL) followed by brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-3% methanol in DCM) then triturated with diethyl ether to afford 9-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a pale pink solid (0.85 g, 2.0 mmol, 40%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.44 (1H, d, J=2.57 Hz), 7.94 (1H, s), 7.43 (1H, dd, J=8.74, 2.58 Hz), 6.99 (1H, d, J=8.74 Hz), 5.72-5.63 (1H, m), 4.49 (4H, d, J=3.06 Hz), 4.33 (2H, s), 3.27 (3H, s), 1.44 (6H, d, J=6.60 Hz). was evacuated refilled with nitrogen (×3) was purged with carbon monoxide gas The reaction mixture was cooled to RT purged with nitrogen After stirring at 60° C. for 1.5 h the reaction The solution was washed with 1N NaOH (2×50 mL) dried (Na2SO4) concentrated in vacuo then triturated with diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium metal (0.754 mol) was dissolved in absolute ethanol (100 ml) and the resulting solution was added dropwise to a solution of methoxyacetamidine hydrochloride (0.703 mol) in ethanol (100 ml). After 15 minutes the reaction mixture was filtered and the filtrate was added to a solution of diethyl formylsuccinate (0.703 mol), which was prepared according to H. Nakao et al. Ann. Sankyo Res. Lab., 18, 33-37 (1966). The reaction was refluxed for 15 hours, cooled to room temperature and was then concentrated to obtain a crude solid. This solid was crystallized from isopropanol to obtain the title compound (43% yield), m.p. 142°-143° C. After 15 minutes the reaction mixture was filtered was prepared The reaction was refluxed for 15 hours was then concentrated to obtain a crude solid This solid was crystallized from isopropanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reflux a mixture of malonic acid diethyl ester (7.96 g, 50 mmol), 2-methoxy-acetamidine hydrochloride (6.2 g, 50 mmol), and NaOMe MeOH solution (4.37 M, 22.7 mL, 100 mmol) in MeOH (30 mL) for 24 hours. Concentrate, dilute with H2O (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract with MeOH and concentrate to yield 2-methoxymethyl-pyrimidine-4,6-diol. Reflux Concentrate dilute with H2O (50 mL) wash with EtOAc concentrate the aqueous layer Extract with MeOH concentrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methoxy-acetamidine hydrochloride (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%) as an oil. The mixture is heated to reflux The mixture is concentrated in vacuo the residue is diluted with water (100 mL) extracted with EtOAc (75 mL) extracted thrice with EtOAc (75 mL) dried over magnesium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaOEt (0.088 mol) in EtOH (prepared from 2.0 g of Na and 70 mL of EtOH), methoxyacetamidine hydrochloride (5.4 g, 0.044 mol), and diethyl acetylglutarate (10.0 g, 0.044 mol) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with ether gave 4.6 g (42%) of product as an off-white solid, mp 87°-90° C. was heated under reflux for 24 h The mixture was concentrated extracted with CH2Cl2 The extracts were washed with brine dried (MgSO4) concentrated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methoxy-acetamidine hydrochloride (4.66 g, 0.037 mol) in methanol (20 mL) at 0° C. under vigorous stirring was added dropwise bromine (1.90 mL, 0.037 mol) and a 5.4M sodium methylate solution in methanol (13.7 mL, 0.037 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (3.64 g, 0.037 mol) in methanol (20 mL) over 10 min at 0-10° C. The resulting mixture was stirred for 2 h at 0-10° C. and filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (3.25 g, 60%) as a light yellow solid. filtered The isolated material was washed with methanol dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) crystallized from diethyl ether/hexanes which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reflux a mixture of malonic acid diethyl ester (7.96 g, 50 mmol), 2-methoxy-acetamidine hydrochloride (6.2 g, 50 mmol), and NaOMe MeOH solution (4.37 M, 22.7 mL, 100 mmol) in MeOH (30 mL) for 24 hours. Concentrate, dilute with H2O (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract with MeOH and concentrate to yield 2-methoxymethyl-pyrimidine-4,6-diol. Reflux Concentrate dilute with H2O (50 mL) wash with EtOAc concentrate the aqueous layer Extract with MeOH concentrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methoxy-acetamidine hydrochloride (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%) as an oil. The mixture is heated to reflux The mixture is concentrated in vacuo the residue is diluted with water (100 mL) extracted with EtOAc (75 mL) extracted thrice with EtOAc (75 mL) dried over magnesium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaOEt (0.088 mol) in EtOH (prepared from 2.0 g of Na and 70 mL of EtOH), methoxyacetamidine hydrochloride (5.4 g, 0.044 mol), and diethyl acetylglutarate (10.0 g, 0.044 mol) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with ether gave 4.6 g (42%) of product as an off-white solid, mp 87°-90° C. was heated under reflux for 24 h The mixture was concentrated extracted with CH2Cl2 The extracts were washed with brine dried (MgSO4) concentrated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methoxy-acetamidine hydrochloride (4.66 g, 0.037 mol) in methanol (20 mL) at 0° C. under vigorous stirring was added dropwise bromine (1.90 mL, 0.037 mol) and a 5.4M sodium methylate solution in methanol (13.7 mL, 0.037 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (3.64 g, 0.037 mol) in methanol (20 mL) over 10 min at 0-10° C. The resulting mixture was stirred for 2 h at 0-10° C. and filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (3.25 g, 60%) as a light yellow solid. filtered The isolated material was washed with methanol dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) crystallized from diethyl ether/hexanes which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methoxy-acetamidine hydrochloride (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%) as an oil. The mixture is heated to reflux The mixture is concentrated in vacuo the residue is diluted with water (100 mL) extracted with EtOAc (75 mL) extracted thrice with EtOAc (75 mL) dried over magnesium sulfate filtered concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (2.00 g, 5.1 mmol), 2-methoxy-acetamidine hydrochloride (0.76 g, 6.1 mmol) and TEA (5.00 mL, 35.9 mmol) in DMF (38 mL) was evacuated and refilled with nitrogen (×3). The reaction was treated with Xantphos (0.15 g, 0.26 mmol) and palladium (II) acetate (57 mg, 0.26 mmol) before the reaction was purged with carbon monoxide gas and the reaction stirred at 60° C. for 3.5 h. The reaction mixture was cooled to RT, purged with nitrogen then treated with isopropyl-hydrazine hydrochloride (1.70 g, 15.0 mmol) and acetic acid (19 mL). After stirring at 60° C. for 1.5 h the reaction was diluted with ethyl acetate (350 mL). The solution was washed with 1N NaOH (2×50 mL) followed by brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-3% methanol in DCM) then triturated with diethyl ether to afford 9-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a pale pink solid (0.85 g, 2.0 mmol, 40%). LCMS RT=4.95 min, [M+H]+=418/420. 1H NMR 400 MHz (DMSO-d6) δ: 8.44 (1H, d, J=2.57 Hz), 7.94 (1H, s), 7.43 (1H, dd, J=8.74, 2.58 Hz), 6.99 (1H, d, J=8.74 Hz), 5.72-5.63 (1H, m), 4.49 (4H, d, J=3.06 Hz), 4.33 (2H, s), 3.27 (3H, s), 1.44 (6H, d, J=6.60 Hz). was evacuated refilled with nitrogen (×3) was purged with carbon monoxide gas The reaction mixture was cooled to RT purged with nitrogen After stirring at 60° C. for 1.5 h the reaction The solution was washed with 1N NaOH (2×50 mL) dried (Na2SO4) concentrated in vacuo then triturated with diethyl ether