4-(hydroxymethyl)benzohydrazide

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

Procedure: A solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (4.3 g, 19 mmol), 4-(hydroxymethyl)benzohydrazide (3.2 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in dimethylacetamide (100 mL) was stirred at 85° C. until the starting material is all consumed (as followed by LC/MS). The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate (20 mL) and the solid was collected by filtration. The (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol was obtained as a yellow solid (4.8 g, 74%). M.p.=276-278° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.78 (s, 1H), 8.21 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.50-7.33 (m, 6H), 7.17-7.12 (m, 2H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H); LCMS [M+H]: 342. all consumed (as followed by LC/MS) The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase was extracted with dichloromethane (3×100 mL) The combined organic extracts were washed with water (3×100 mL) dried over sodium sulfate concentrated in vacuo The residue was triturated with ethyl acetate (20 mL) the solid was collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 4-(hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was cooled to RT and diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid. 1H NMR (600 MHz, CD3OD) δ 7.90 (ddd, J=0.59, 2.05, 8.51 Hz, 2H), 7.54 (d, J=7.92 Hz, 2H), 4.68 (s, 2H) After heating to reflux for 16 h The mixture was washed with 10% HCl solution and brine dried over magnesium sulfate concentrated Purification of the residue by MPLC (65% ethyl acetate in hexanes)

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

Procedure: To a solution of 4-(hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was cooled to RT and diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid. 1H NMR (600 MHz, CD3OD) δ 7.90 (ddd, J=0.59, 2.05, 8.51 Hz, 2H), 7.54 (d, J=7.92 Hz, 2H), 4.68 (s, 2H) After heating to reflux for 16 h The mixture was washed with 10% HCl solution and brine dried over magnesium sulfate concentrated Purification of the residue by MPLC (65% ethyl acetate in hexanes)

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

Procedure: A solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (4.3 g, 19 mmol), 4-(hydroxymethyl)benzohydrazide (3.2 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in dimethylacetamide (100 mL) was stirred at 85° C. until the starting material is all consumed (as followed by LC/MS). The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate (20 mL) and the solid was collected by filtration. The (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol was obtained as a yellow solid (4.8 g, 74%). M.p.=276-278° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.78 (s, 1H), 8.21 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.50-7.33 (m, 6H), 7.17-7.12 (m, 2H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H); LCMS [M+H]: 342. all consumed (as followed by LC/MS) The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase was extracted with dichloromethane (3×100 mL) The combined organic extracts were washed with water (3×100 mL) dried over sodium sulfate concentrated in vacuo The residue was triturated with ethyl acetate (20 mL) the solid was collected by filtration

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

Procedure: A solution of methyl 4-(hydroxymethyl)benzoate (6.6 g, 40 mmol) and hydrazine hydrate (6 mL) in ethanol (30 mL) was stirred at reflux for 20 hours. The reaction mixture was concentrated to half volume through atmospheric pressure distillation. The solid was collected by filtration and washed with cold ethanol (2×10 mL). The filtrate was further concentrated and a second crop was similarly obtained and combined. The 4-(hydroxymethyl)benzohydrazide was obtained as a white solid (6.1 g, 93%). 400 MHz 1H NMR (DMSO-d6) δ: 9.68 (s, 1H), 7.75 (dd, J=6.4, 1.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.25 (t, J=6.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.43 (s, 2H). at reflux for 20 hours The reaction mixture was concentrated to half volume through atmospheric pressure distillation The solid was collected by filtration washed with cold ethanol (2×10 mL) The filtrate was further concentrated a second crop was similarly obtained

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (4.3 g, 19 mmol), 4-(hydroxymethyl)benzohydrazide (3.2 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in dimethylacetamide (100 mL) was stirred at 85° C. until the starting material is all consumed (as followed by LC/MS). The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate (20 mL) and the solid was collected by filtration. The (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol was obtained as a yellow solid (4.8 g, 74%). M.p.=276-278° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.78 (s, 1H), 8.21 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.50-7.33 (m, 6H), 7.17-7.12 (m, 2H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H); LCMS [M+H]: 342. all consumed (as followed by LC/MS) The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase was extracted with dichloromethane (3×100 mL) The combined organic extracts were washed with water (3×100 mL) dried over sodium sulfate concentrated in vacuo The residue was triturated with ethyl acetate (20 mL) the solid was collected by filtration

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

Procedure: A solution of methyl 4-(hydroxymethyl)benzoate (6.6 g, 40 mmol) and hydrazine hydrate (6 mL) in ethanol (30 mL) was stirred at reflux for 20 hours. The reaction mixture was concentrated to half volume through atmospheric pressure distillation. The solid was collected by filtration and washed with cold ethanol (2×10 mL). The filtrate was further concentrated and a second crop was similarly obtained and combined. The 4-(hydroxymethyl)benzohydrazide was obtained as a white solid (6.1 g, 93%). 400 MHz 1H NMR (DMSO-d6) δ: 9.68 (s, 1H), 7.75 (dd, J=6.4, 1.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.25 (t, J=6.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.43 (s, 2H). at reflux for 20 hours The reaction mixture was concentrated to half volume through atmospheric pressure distillation The solid was collected by filtration washed with cold ethanol (2×10 mL) The filtrate was further concentrated a second crop was similarly obtained

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

Procedure: To a solution of 4-(Hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid. After heating to reflux for 16 h The mixture was washed with 10% HCl solution and brine dried over magnesium sulfate concentrated Purification of the residue by MPLC (65% ethyl acetate in hexanes)

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

Procedure: To a solution of 1.66 g (10.0 mmol) of methyl 4-hydroxymethylbenzoate (19) in 20 ml of ethanol was added 3.0 g (60 mmol) of hydrazine hydrate. The mixture was stirred for 2 h, an additional 3.0 g hydrazine hydrate was added and the mixture was allowed to stand overnight. The precipitate was filtered, washed twice with ethanol and dried in vacuo to yield 20 as a white powder. (Literature references for compound: Yaroshenko, V. V.; Grekov, A. P.; Tkach, V. P.; Yakovenko, A. G. Inst. Khim. Vysokomol. Soedin. Sint. Fiz.-Khim. Polim. 1975, 17 97; and Galiano, R.; Joaquin, A.; Soria, A. (Instituto de Investigacion y Desarrollo Quimico Biologico, S. A., Spain). Span. (1993), 24 pp. CODEN: SPXXAD ES 2039161 A1 19930816) to stand overnight The precipitate was filtered washed twice with ethanol dried in vacuo

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

Procedure: To a solution of 4-(hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was cooled to RT and diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid. 1H NMR (600 MHz, CD3OD) δ 7.90 (ddd, J=0.59, 2.05, 8.51 Hz, 2H), 7.54 (d, J=7.92 Hz, 2H), 4.68 (s, 2H) After heating to reflux for 16 h The mixture was washed with 10% HCl solution and brine dried over magnesium sulfate concentrated Purification of the residue by MPLC (65% ethyl acetate in hexanes)