Abstract: Some substituted acetylpyrazine derivatives were prepared as the starting materials for the subsequent synthesis of N,N-dimethylthiosemicarbazones. General synthetic approach of all newly synthesized compounds is presented. All the N,N-dimethylthiosemicarbazone derivatives of acetylpyrazines were analyzed using the reversed phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using end-capped non-polar C₁₈ stationary RP column. In the present study the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and log P values calculated in various ways is discussed as well as the relationships between the lipophilicity and the chemical structure of the studied compounds.