The challenge of multi-objective optimization of catalytic reactions is magnified in the field of process chemistry. Due to purity requirements for APIs and the cost of purification on a multikilogram scale, catalysts must impart exquisite chemo-, stereo-, and regioselectivity along with providing a high-yielding reaction. As such, the first two steps of the synthesis of TRPA1 inhibitor 1, an API, is an excellent case study (Fig. ). In the first step, the absolute stereochemistry of the API is set through an enantioselective Pd-catalyzed Hayashi-Heck reaction of 2,3-dihydrofuran (3) with aryl triflate 2 to produce enantioenriched enol ether (R)-4. Besides the demand for high yield and enantioselectivity, this process delivers isomeric alkene 5 in low enantioselectivity. This impurity cannot be readily removed by distillation, the practical method of purification on a manufacturing scale for low molecular weight oils. In the second step, a Rh-catalyzed hydroformylation of (R)-4 sets the second stereocenter of API 1. In this case, regioisomer 7 and C4 epimer (R,R)-6 are generated in addition to the desired aldehyde (R,S)-6. Downstream intermediates stemming from 7 could not be easily purged, leading to unacceptable amounts of the regioisomer and related impurities. Thus, both steps require exquisite control of the reaction outcomes. Regioselectivity was identified as the most important metric targeted for improvement while maintaining high stereoselectivity and overall yield of the desired products. In parallel to the descriptor library construction, a conventional high-throughput experimental campaign was undertaken to examine the performance of a selection of ligands for both reactions (Fig. ). For the Hayashi-Heck reaction, most ligands tested in the first step had a C2-biaryl backbone as ligands of this type have previously proven effective in similar transformations. This is reflected by the relatively narrow region of electronic but broad steric diversity for most of the bisphosphines tested (see steric/electronic chemical space map in Fig. ). The initial results revealed that the use of Segphos L5 furnished (R)-4 in a regioisomeric ratio of 94:6, an enantiomeric ratio of 97:3, and 66% yield. As a wide range of bidentate organophosphorus ligands are known to be effective in alkene hydroformylation, a diverse selection of ligand scaffolds was evaluated including bisphosphines, mixed phosphine-phosphonites, and bisphosphonites. This is illustrated in the chemical space representation by the relatively wide distribution of tested ligands (Fig. ). Bisphosphine (R,R)-Ph-BPE L6 was identified as a top performer for the hydroformylation reaction, providing 50% conversion of (R)-4 to (R,S)-6 with a regioisomeric ratio of 96:4 and a diastereomeric ratio of >99.5:0.5.