Well-performing empirical models included both LFER methods, such as ACD/pKa Classic (submission ID xmyhm) and Epik Scan (nb007), and QSPR/ML methods such as MoKa (nb017) and S+pKa (gyuhx), all performing with root mean square errors (RMSE) between 0.73 and 0.95 pK a units . These well-established tools thus demonstrated their reliability and quality.