ARI-509 can be obtained by four related synthetic routes (a-d), scheme 16434601a: A key advanced intermediate (VI) was used for the preparation of ARI-509. This intermediate (VI) was prepared by two synthetic routes a and b: In route a, commercially available homophthalic acid diester (I) or homophthalic anhydride (II) was reacted with 4-bromo-2-fluorobenzyl amine to give homophthalimide (IV). Treatment of (IV) with Mander's reagent yielded the key intermediate (VI). In route b, 2-chloro-4-fluorobenzoic acid (III) was converted to diester (V) by the Hurtley reaction. Treatment of (V) with thionyl chloride and further reaction of the generated acid chloride with 4-bromo-2-fluorobenzyl amine gave the key intermediate (VI). Conversion of (VI) to the final product was accomplished by routes c and d: In route c, alkylation of (VI) with tert-butyl bromoacetate, followed by acidic hydrolysis gave acid (VII). Generation of the acid chloride of (VII) with thionyl chloride and treatment with ammonia yielded amide (VIII). In route d, amide (VIII) was obtained in a more direct way, by formation of nitrile (IX) from (VI) with bromoacetonitrile and subsequent acidic hydrolysis. Amide (VIII) was cyclized to the final product (ARI-509), upon treatment with a variety of bases including sodium hydride, sodium methoxide or lithium bis(trimethylsilyl)amide.