5-chloro-1-benzofuran-2-carbaldehyde

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

Procedure: A solution of 5-chlorobenzofuran-2-carboxaldehyde (813 mg, 4.50 mmol) and formylmethylene triphenylphosphorane (1.37 g, 4.50 mmol) in CH2Cl2 (40 ml) was treated as sen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound (640 mg, 3.10 mmol, yield 68.8%) as yellow crystals was obtained. as sen in preparation 1

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

Procedure: LiA1H4 (3.04 g, 80 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (150 ml), then N-methylpiperazine dihydrochloride (6.92 g, 40 mmol) was added portionwise in 10 minutes. N-methylpiperazine (12 g, 120 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of 5-chlorobenzofuran-2-carboxylic acid (2.95 g, 15.0 mmol) in anhydrous THF (50 ml). The mixture was refluxed for 4 hours and after cooling to RT the suspension was diluted with Et2O (400 ml). The resulting mixture was poured into water (500 ml) and the organic phase was decanted. The aqueous phase was extracted with Et2O (2×300 ml) and the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml). After drying (MgSO4) and concentration a brown oily residue was obtained. This was chromatographed on silicagel (n-heptane/EtOAc 3/1). The pooled fractions produced after evaporation pure title compound (850 mg, 4.71 mmol, yield 31.4%) as brown needles. The mixture was refluxed for 4 hours after cooling to RT the suspension the organic phase was decanted The aqueous phase was extracted with Et2O (2×300 ml) the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml) After drying (MgSO4) and concentration a brown oily residue was obtained This was chromatographed on silicagel (n-heptane/EtOAc 3/1) The pooled fractions produced

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

Procedure: To a mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (S)-N-(5-chlorobenzofuran-2-ylmethylene)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (0.137 g, yield 59%) as a light yellow powder. was added followed by extraction with methylene chloride The organic phase was washed with a saturated saline solution dried over sodium sulfate filtered The resulting filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1)

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

Procedure: 1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran-2-aldehyde (34.52 g, 191 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford piperazin-1-yl-(5-chlorobenzofuran-2-yl methylene)amine (49.49 g, yield 98%) as a yellow crystalline powder. was added The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel column chromatography

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

Procedure: 1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran-2-aldehyde (34.52 g, 191 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford piperazin-1-yl-(5-chlorobenzofuran-2-yl methylene)amine (49.49 g, yield 98%) as a yellow crystalline powder. was added The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel column chromatography

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

Procedure: A solution of 5-chlorobenzofuran-2-carboxaldehyde (813 mg, 4.50 mmol) and formylmethylene triphenylphosphorane (1.37 g, 4.50 mmol) in CH2Cl2 (40 ml) was treated as sen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound (640 mg, 3.10 mmol, yield 68.8%) as yellow crystals was obtained. as sen in preparation 1

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

Procedure: LiA1H4 (3.04 g, 80 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (150 ml), then N-methylpiperazine dihydrochloride (6.92 g, 40 mmol) was added portionwise in 10 minutes. N-methylpiperazine (12 g, 120 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of 5-chlorobenzofuran-2-carboxylic acid (2.95 g, 15.0 mmol) in anhydrous THF (50 ml). The mixture was refluxed for 4 hours and after cooling to RT the suspension was diluted with Et2O (400 ml). The resulting mixture was poured into water (500 ml) and the organic phase was decanted. The aqueous phase was extracted with Et2O (2×300 ml) and the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml). After drying (MgSO4) and concentration a brown oily residue was obtained. This was chromatographed on silicagel (n-heptane/EtOAc 3/1). The pooled fractions produced after evaporation pure title compound (850 mg, 4.71 mmol, yield 31.4%) as brown needles. The mixture was refluxed for 4 hours after cooling to RT the suspension the organic phase was decanted The aqueous phase was extracted with Et2O (2×300 ml) the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml) After drying (MgSO4) and concentration a brown oily residue was obtained This was chromatographed on silicagel (n-heptane/EtOAc 3/1) The pooled fractions produced

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

Procedure: LiA1H4 (3.04 g, 80 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (150 ml), then N-methylpiperazine dihydrochloride (6.92 g, 40 mmol) was added portionwise in 10 minutes. N-methylpiperazine (12 g, 120 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of 5-chlorobenzofuran-2-carboxylic acid (2.95 g, 15.0 mmol) in anhydrous THF (50 ml). The mixture was refluxed for 4 hours and after cooling to RT the suspension was diluted with Et2O (400 ml). The resulting mixture was poured into water (500 ml) and the organic phase was decanted. The aqueous phase was extracted with Et2O (2×300 ml) and the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml). After drying (MgSO4) and concentration a brown oily residue was obtained. This was chromatographed on silicagel (n-heptane/EtOAc 3/1). The pooled fractions produced after evaporation pure title compound (850 mg, 4.71 mmol, yield 31.4%) as brown needles. The mixture was refluxed for 4 hours after cooling to RT the suspension the organic phase was decanted The aqueous phase was extracted with Et2O (2×300 ml) the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml) After drying (MgSO4) and concentration a brown oily residue was obtained This was chromatographed on silicagel (n-heptane/EtOAc 3/1) The pooled fractions produced

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 34 (160 mg, 0.89 mmol) was dissolved in EtOH (5 mL). NaBH4 (36 mg, 0.98 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The resulting crude alcohol residue was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (92 μL, 0.98 mmol) was added dropwise over 10 min. The mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 35 (128 mg, 57%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.48 (1H, d, J=2.05 Hz, ArH), 7.37 (1H, d, J=8.70, ArH), 7.25 (1H, dd, J=8.80 & 2.05 Hz ArH), 6.68 (1H, s, ArH), 4.55 (2H, s, 2-CH2). at room temperature for 1.5 h Solvent was evaporated off in-vacuo The resulting crude alcohol residue was dissolved in toluene (5 mL) the solution was cooled to 0° C was then brought up to room temperature stirred for 1 h The solvent was evaporated off in-vacuo purified by flash chromatography eluting with hexane/EtOAc (4:1)

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

Procedure: A stirred solution of 33 (4.10 g, 15.07 mmol) in acetic acid (20 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 34 (550 mg, 20%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 9.91 (1H, s, CHO), 7.76 (1H, d, J=1.85 Hz, ArH), 7.57 (1H, d, J=8.90 Hz, ArH), 7.53 (1H, s, ArH), 7.50 (1H, dd, J=8.90 & 2.10 Hz, ArH). After cooling the solution was evaporated to dryness purified by flash chromatography eluting with hexane/EtOAc (4:1)

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

Procedure: To a mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (S)-N-(5-chlorobenzofuran-2-ylmethylene)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (0.137 g, yield 59%) as a light yellow powder. was added followed by extraction with methylene chloride The organic phase was washed with a saturated saline solution dried over sodium sulfate filtered The resulting filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1)

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

Procedure: 1-Aminopiperazine (29 g, 287 mmol) was dissolved in isopropyl alcohol (173 ml), to which 5-chlorobenzofuran-2-aldehyde (34.52 g, 191 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford piperazin-1-yl-(5-chlorobenzofuran-2-yl methylene)amine (49.49 g, yield 98%) as a yellow crystalline powder. was added The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel column chromatography