2-(4-hydroxyphenyl)acetohydrazide

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloro-6-thiazol-2-yl-pyridazine (20 mg, 0.10 mmol) and (4-Hydroxy-phenyl)-acetic acid hydrazide (20 mg, 0.12 mmol) were combined in butanol (5 mL), fitted with water filled condenser and heated to 120° C. overnight. The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min) resulting in the title compound (11.5 mg, 37%) as a white solid. 1H-NMR (CD3OD/CDCl3): δ 8.26-8.24 (1H, d, J=9.6 Hz), 8.17-8.15 (1H, d, J=9.6 Hz), 8.05-8.04 (1H, d, J=3.2 Hz), 7.82-7.81 (1H, d, J=3.0 Hz), 7.32-7.30 (2H, t, J=8.6 Hz), 6.77-6.74 (2H, d, J=8.3 Hz), 4.53 (2H, s). ESI-MS (m/z): Calcd. For C15H11N5OS: 309.07; found: 310.2 (M+H). fitted with water filled condenser The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min)

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

Procedure: A solution containing 3-Chloro-6-thiophene-2-yl-pyridazine (58 mg, 0.29 mmol) Example 17: step a and (4-Hydroxy-phenyl)-acetic acid hydrazide (120 mg, 0.58 mmol) in butanol (5 mL) was heated to reflux overnight. The reaction was cooled to rt and the solids were filtered and washed with MeOH. The solid was recrystallized from MeOH to yield the title compound as a tan solid. 1H-NMR (CD3OD/CDCl3): δ 8.12-8.10 (1H, d, J=9.34 Hz), 7.83-7.82 (1H, d, J=3.7 Hz), 7.78-7.76 (1H, d, J=9.8 Hz), 7.67-7.65 (1H, d, J=5.0 Hz), 7.34-7.32 (2H, d, J=6.5 Hz), 7.22-7.21 (1H, m), 6.77-6.75 (2H, d, J=8.3 Hz), 4.49 (2H, s). ESI-MS (m/z): Calcd. For C16H12N4OS: 308.07; found: 309.2 (M+H). to reflux overnight the solids were filtered washed with MeOH The solid was recrystallized from MeOH

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.08 mmol) in MeOH (20 mL, anhydrous) was added hydrazine (3.77 mL, 120.35 mmol) and then heated to 55° C. for 1 hour. A white precipitate formed during heating. The reaction was then cooled to rt and stirred for an additional hour to facilitate precipitation of solid. The reaction was filtered and the solid was washed with MeOH and dried resulting in the desired product (4.3 g, 86%) as a white solid. 1H-NMR (DMSO): δ 9.20 (1H, s), 9.10 (1H, s), 7.04-7.02 (2H, d, J=8.6 Hz), 6.67-6.65 (2H, d, J=8.6 Hz), 4.17-4.16 (2H, s), 4.11-4.09 (1H, q, J=5.0, 5.5 Hz). A white precipitate formed during heating The reaction was then cooled to rt precipitation of solid The reaction was filtered the solid was washed with MeOH dried

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Solid BrCN 6.059 g (57.2 mmol) was added in one portion into ice-cooled slurry of (4-hydroxy-phenyl)-acetic acid hydrazide 8.642 g (52.0 mmol) and KHCO3 6.510 g (65 mmol) in MeOH (100 mL). The mixture was stirred at 0-5° C. for 1 hour, the ice bath allowed to melt and stirred at room temperature overnight (18 hr). The reaction mixture was diluted with water (100 mL), stirred for 1 hour, the precipitate was collected by filtration, washed with water and dried on high vacuum. A second fraction precipitated after concentrating and cooling the supernatants. stirred at room temperature overnight (18 hr) stirred for 1 hour the precipitate was collected by filtration washed with water dried on high vacuum A second fraction precipitated after concentrating cooling the supernatants

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Neat anhydrous hydrazine 21.0 g (654 mmol) was added to a solution of p-hydroxyphenylacetic acid methyl ester 27.18 g (163.5 mmol) in MeOH (100 mL) and the mixture was heated to 50-55° C. and stirred at this temperature for 90 min (water bath). Cooled, stirred for extra 1 hour, the precipitate collected by filtration, compressed on the frit, washed with MeOH (3×10 mL) and dried on high vacuum. A second fraction was obtained by cooling the supernatants to −15° C. overnight and filtering the formed precipitate. Cooled the precipitate collected by filtration washed with MeOH (3×10 mL) dried on high vacuum A second fraction was obtained by cooling the supernatants to −15° C. overnight filtering the formed precipitate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloro-6-thiazol-2-yl-pyridazine (20 mg, 0.10 mmol) and (4-Hydroxy-phenyl)-acetic acid hydrazide (20 mg, 0.12 mmol) were combined in butanol (5 mL), fitted with water filled condenser and heated to 120° C. overnight. The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min) resulting in the title compound (11.5 mg, 37%) as a white solid. fitted with water filled condenser The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min)

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

Procedure: A solution containing 3-Chloro-6-thiophene-2-yl-pyridazine (58 mg, 0.29 mmol) Example 17: step a and (4-Hydroxy-phenyl)-acetic acid hydrazide (120 mg, 0.58 mmol) in butanol (5 mL) was heated to reflux overnight. The reaction was cooled to rt and the solids were filtered and washed with MeOH. The solid was recrystalized from MeOH to yield the title compound as a tan solid. 1H-NMR (CD3OD/CDCl3): δ 8.12-8.10 (1H, d, J=9.34 Hz), 7.83-7.82 (1H, d, J=3.7 Hz), 7.78-7.76 (1H, d, J=9.8 Hz), 7.67-7.65 (1H, d, J=5.0 Hz), 7.34-7.32 (2H, d, J=6.5 Hz), 7.22-7.21 (1H, m), 6.77-6.75 (2H, d, J=8.3 Hz), 4.49 (2H, s). ESI-MS (m/z): Calcd. For C16H12N4OS: 308.07; found: 309.2 (M+H). to reflux overnight the solids were filtered washed with MeOH The solid was recrystalized from MeOH

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.08 mmol) in MeOH (20 mL, anhydrous) was added hydrazine (3.77 mL, 120.35 mmol) and then heated to 55° C. for 1 hour. A white precipitate formed during heating. The reaction was then cooled to rt and stirred for an additional hour to facilitate precipitation of solid. The reaction was filtered and the solid was washed with MeOH and dried resulting in the desired product (4.3 g, 86%) as a white solid. 1H-NMR (DMSO): δ 9.20 (1H, s), 9.10 (1H, s), 7.04-7.02 (2H, d, J=8.6 Hz), 6.67-6.65 (2H, d, J=8.6 Hz), 4.17-4.16 (2H, s), 4.11-4.09 (1H, q, J=5.0, 5.5 Hz). A white precipitate formed during heating The reaction was then cooled to rt precipitation of solid The reaction was filtered the solid was washed with MeOH dried

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-ylamine 10.182 g (52.7 mmol), water 80 mL and anhydrous hydrazine 20 mL was refluxed under nitrogen on an oil bath (190-200 ° C.) for 23 hours. The mixture was cooled and allowed to crystallize at R.T. under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 mL) and dried on high vacuum. The crude product was re-crystallized from water 60 mL (reflux under nitrogen, than to +4° C. in a refrigerator overnight). The product was filtered, washed with ice-cold water and dried on high vacuum. Y=6.210 g (56.5%) of a large white crystals. 1H-NMR(DMSO-d6, 400 MHz): 7.267 (app d, J=8.6 Hz, J=5.5 Hz, 2H), 7.097 (app t, J=9.0 Hz, 2H), 5.509 (br s, 2H), 5.339 (s, 2H), 3.884 (s, 2H); 19F-NMR(DMSO-d6, 376.5 MHz): −117.14 (m, 1F). The mixture was cooled to crystallize at R.T. under nitrogen overnight The precipitated product was collected by filtration washed with ice-cold water (10 mL) dried on high vacuum The crude product was re-crystallized from water 60 mL ( reflux under nitrogen, than to +4° C. in a refrigerator overnight) The product was filtered washed with ice-cold water dried on high vacuum