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Compound 8, (44 g), 200 mL toluene, and 475 g of 20% dipotassium oxalate are stirred vigorously and the mixture comprising Compound 8-A is cooled to 5C. Thiophosgene (1.5 L) is added over 1 hour. The mixture is filtered through celite and the cake is washed with toluene. The filtrate is collected and the toluene is removed in vacuo. The residue is dissolved in 16: 1 Hexanes: Ethyl acetate and the mixture is filtered through silica gel. The filtrate is collected and the solvents removed in vacuo to provide Compound 9 as a solid (69 g). [0339] 6 g of Compound 9 is suspended in 12 mL acetonitrile and the mixture is heated to 35C. 1.68 g of formyl hydrazide is added in three portions over twenty minutes and the mixture is stirred for 2 h at 35C, then cooled to 4C and stirred overnight. The reaction mixture is filtered, the cake is washed with 5: 1 hexane:ethyl acetate and dried at 40C to provide 5.85 g of
6; 4 Example 6: Synthesis of Compound 11 - method 1
[0345] Under this route, cyclopropylmagnesium bromide was added to a solution of bromonaphthalene in tetrahydrofuran stirred at 0-5 °C in the presence of a catalytic amount of [l,3-bis(diphenylphosphino)propane]dichloronickel(II) to form cyclopropylnaphthalene, which was diluted with ethyl acetate and washed. [0346] Cyclopropylnaphthalene (Compound 6) was dissolved in dichloromethane or 1 ,2- dichlorobenzene, then nitric acid was added at 0 °C and the reaction mixture was allowed to warm to ambient temperature. After reaction completion, the mixture was neutralized with sodium bicarbonate then washed with water, and l-cyclopropyl-4-nitronaphthalene (Compound 7) was used in the next step without further purification. [0347] Compound 7 was dissolved in ethanol or methanol, and hydrogenated in the presence of palladium on charcoal. The resulting l-amino-4-cyclopropylnaphthalene (Compound 8) was crystallized as an oxalate salt (Compound 8 -A) then dissolved in dichloromethane or toluene and treated with thiophosgene in the presence of potassium hydroxide to generate the corresponding isothiocyanate intermediate (Compound 9). [0348] l-Cyclopropyl-4-isothiocyanatonaphthalene (Compound 9) was solvent exchanged with DMF and condensed with aminoguanidine hydrochloride to generate the corresponding substituted thiosemicarbazide (Compound 13). This intermediate Compound 13 was heated in the presence of aqueous sodium hydroxide to form Compound 11 , which was purified by crystallization from a mixture of ethanol and water or a mixture of methanol, DMF and water.