HO 221 (CAS NO.: ), with its systematic name of , N-(((4-((5-bromo-2-pyrimidinyl)oxy)-3-chlorophenyl)amino)carbonyl)-2-nitro-, could be produced through many synthetic methods.

Following are some of the synthesis routes:
Route one: 4-Amino-2-chlorophenol (I) is condensed with 5 bromo-2-chloropyrimidine (II) in the presence of K₂CO₃ in hot DMSO to produce 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline (III), which is then condensed with 2-nitrobenzoyl isocyanate (IV) in dioxane.

Route two:
Aminophenol (I) reacts with isocyanate (IV) in dioxane to produce N-(2-nitrobenzoyl(-N-(3-chloro-4-hydroxyphenyl)urea (VII), which is then condensed with pyrimidine (II) by means of KOH in hot DMSO.