2-Methylthio-4-phenylamino-6,7,8-trifluoro-3H-quinazolin-4-one was synthesized by means of intramolecular cyclizations of S-methyl-N-(tetrafluorobenzoyl)isothiourea followed by a reaction with POCl3 and nucleophilic substitution at the 4-position. The reactions of the synthesized compound with amines proceed, depending on their nature, via substitution of either the F(7) atom or the SMe fragment in the 2-position. The antiviral activity of the obtained 6,7,8-trifluoro-2-ethylthioquinazolin-4-ones was investigated using monkeypox virus, smallpox vaccine, and ectromelia virus. It is shown that fluorinated quinazoline derivatives have good prospects in the search for new active substances