The reaction time for the 1,2-addition step was also analyzed for the asymmetric system. In this case, the ketone 2 addition time was fixed at 1 h, while the time after the addition of 2 was varied from 5 to 60 min, then followed by the quenching of the reaction mixture (Table ). At the shorter reaction time of 5 min, the overall assay yield of the syn + anti diastereomers mixture was good (81 %), however, the reaction was not able to reach equilibrium in that time and suffered from lower stereoselectivity (9:1 d.r. and 19 % ee) resulting in 43 % assay yield of BDQ (3) (Table , Entry 1). As the reaction time was increased (10 to 30 min) a considerably higher stereoselectivity was achieved (up to 15:1 d.r. and ~50 % ee) without noticeably sacrificing conversion (Table , Entries 2-4). The lower overall yield of 69 % at 20 min did not reflect the trend, and this outlier might serve to highlight the high sensitivity of the reaction (e.g. moisture in the system or unintended increase in temperature during reaction quench). At the longer reaction time of 60 min, a decrease in d.r. (9:1) was observed leading to the conclusion that 20-30 min post-completion of ketone 2 addition corresponds to the optimal reaction time. Under this optimized condition, BDQ (3) was synthesized with high levels of stereoselectivity, and it was ultimately achieved in 56 % assay yield (Table , Entry 4). Understanding the impact of concentration on the reaction outcome. After achieving the developed reaction conditions with high stereoselectivity toward BDQ (3), the process was intensified to improve further practical applications and, with that in mind, reducing the amount of solvent would be essential. Different reaction concentrations were therefore studied to understand how concentration would affect the course of the reaction. Initially, the reaction in THF was observed to proceed better when carried out in a more diluted range of 20 30 volumes (V = mL solvent ÷ g of solute) (Graph 3). Exploring this trend with 2-MeTHF at 15, 20, and 25 V, it was observed that the reactions in the range of 15-20 V of 2-MeTHF produced similar amounts of the syn-diastereomer pair, 3 and ent-3, as compared to 30 V of THF, around 70 % (HPLC A %). Changes in concentration also impacted the purity profile of this reaction. Additional experiments have shown that when the quinoline 1 solution was further concentrated from 5 to 3 V of THF, a higher amount of the desbromoquinoline 17 was observed due to a competing Li-halogen exchange, indicating that a concentrated medium is not ideal for the lithiation step (Scheme 8) (see Supporting Information Tables ). The lithiated compound 17a can react with 2 leading to the undesired 1,2-addition product 18 as a mixture of stereoisomers. Higher dilutions tend to slow down these side reactions. For instance, when 30 V of THF was used instead of 15 V, only trace amounts of the desbromoquinoline 17 was formed, and compound 18 was not observed at all under these conditions. Moreover, the enolization of ketone 2 leads to a facilitated elimination of its dimethylamine moiety, resulting in the side product 19 (Scheme 8). The lithium amide base 11 can also react in a 1,4-addition with enone 19 yielding the impurity 20. Based on HPLC analysis, the amount of the side product 20 did not follow a specific trend with the variation in reaction concentration, and it was observed in varying amounts from 1 to 9 % (HPLC A %) (see Supporting Information Table /S5).