Finally, we explore a carbonyl reduction reaction with NaBH 4 , where the distinction between aldehyde and ketone is familiar to chemists but can be challenging to infer from literature examples. The reaction proceeds via a nucleophilic addition of borohydride to the carbonyl carbon, which therefore depends on the electrophilicity of the carbonyl group. Hence, we use the MAA ML model to predict the most electrophilic site of the reactant. As seen in Figure , we can successfully predict the aldehyde as the most reactive site given the higher MAA value of 168 kJ/mol compared to 140 kJ/mol for the ketone. Having demonstrated that our ML models can successfully predict chemical selectivity in challenging examples, we now explore how the ML models can improve retrosynthetic route predictions by identifying potential selectivity issues. Figure shows a synthetic pathway for Ciprofloxacin generated using Manifold by PostEra. All structures are presented in their major protonation state as determined by MarvinSketch based on the expected reaction conditions. The predicted pKa values and protonation states at different pH levels are shown in the Supporting Information. For the first reaction step in Figure , the ML models predict the most nucleophilic and electrophilic sites to be in the quinoline derivative. This could lead to an undesired product where the quinoline derivative reacts with itself instead of reacting with piperazin-1-ium as proposed by Manifold. The second most nucleophilic site is the neutral nitrogen atom in piperazin-1-ium with an MCA value of 438 kJ/mol compared to 462 kJ/mol for the most nucleophilic site. As a result, this could lead to low yields of the target product, if this reaction occurs. The chemoselectivity of the second reaction step is correct according to the ML predictions. The assumption here is that triflate acts as a good leaving group forming a cyclopropyl cation, which will have the highest MAA value. The most nucleophilic site is the nitrogen atom in the quinoline derivative highlighted in green in Figure . However, as this route has potential selectivity issues, we suggest a modified retrosynthetic route as shown in Figure . Here, the two reaction steps are switched around such that the nucleophilic substitution with amine is the first reaction step and the Buchwald-Hartwig amination is the second reaction step. In this modified retrosynthetic route, the ML-predicted MAA and MCA values agree with the suggested chemoselectivity. In fact, the second reaction step in Figure combining fluoroquinolonic acid and piperazine is reported in the literature with a high yield of around 90 % under acidic conditions. Figure : Correlation plots comparing QM-calculated and ML-predicted MAA values against experimental hydrolysis rates for 33 esters and carbamates under basic conditions. The calculated MAA values are obtained at the r 2 SCAN-3c SMD(DMSO)//GFN1-xTB ALPB(DMSO) level of theory. All of the predicted MAA values have estimated errors below the predefined cutoff of 30 kJ/mol.