Finally, given the interplay of conditions affecting conversion and side product formation, we further refined the reaction conditions in a Design of Experiment (DoE) study. The workflow involved an initial definitive screening of all reaction parameters apart from catalyst loading. This helped confirm the limits of temperature (45 °C) and time (24 h) for a suitable model, as well as demonstrated that the reaction outcome is unaffected by additive loading above 30 mol%. Moreover, aryl iodide loading, Ag2CO3 loading and substrate concentration were found to be the main factors affecting yield and selectivity. These parameters were therefore employed in a subsequent custom design screen aimed at maximizing the predicted yield of 2a whilst minimizing diarylation (see Supporting Information for full workflow). Up to 3 rd order interactions of these parameters were examined, however, under the set temperature and time conditions no 2 nd or higher order interactions were seen. Visualization of 3-dimensional response surfaces of predicted yield against any two of the major factors revealed a defined dome-shaped surface (predicted yield against aryl iodide and base equivalents) with a plateau at 74%. The optimum set of conditions from the plateau gave excellent correlation with the in-situ and isolated yields of 2a (Table , entry 8 and Figure ). Overall, an increased yield and selectivity was achieved at 45 °C along with a reduction in the equivalents of both aryl iodide and silver carbonate base that were required. With the optimized conditions the reaction scope was investigated (Scheme 1). In the presence of 4-iodoanisole, the monocis isomer (2a) was isolated in 68% yield on 0.4 mmol scale, and 70% yield on 4 mmol scale. Changing the N-protecting group from Boc (2) to Cbz (6) gave a similar in-situ yield, although the N-Cbz group led to a more challenging purification. N-Acetyl ( ) and N-mesyl (8) derivatives could also be successfully arylated, albeit in lower yields (10a, 11a). Aryl iodides with various electronic requirements were successfully employed in the reaction, affording piperidines 2b-i in good yield as single diastereoisomers. Halogens were well tolerated (2c-e), providing a useful handle for further functionalization. Bocprotected aniline could be installed in 48% yield (2j). meta-Substituted and electron-rich trimethoxybenzene and benzodioxole derivatives gave high yields (2k, 2l), as did 2-naphthyliodide (2m). 3-Bromo-and 2-fluoro-substituted aryliodides were tolerated (2n, 2o), though the ortho-substitution resulted in a reduced yield. Unprotected benzyl alcohol functionality was compatible with the reaction conditions, providing 2q in 50% yield. Medicinally relevant heterocycles were successfully installed, including N-Ts protected indole (2p), as well as pyridines bearing electron-donating or electron-withdrawing groups (2r, 2s). 2-Iodothiophene exhibited an unusually high reactivity, whereby the monoarylation was observed in only trace amounts and cis-trans diarylated product (2t) was isolated in 55% yield. Similar high reactivity was seen with styryl iodide, leading to an equimolar mixture of all four possible mono-and di-alkenylated piperidines, each isolated in similar yields (19-21%). Minor adaptation of the reaction conditions enabled application to the corresponding tetrahydropyran aminoquinoline amides (Scheme 2). After a screen of additives, 2-mesitylene carboxylic acid (MesCOOH) was also identified as best performing in this case, promoting the highest starting material conversion. A brief DoE study revealed an additive loading of 15 mol% to be optimal in the presence of a similar amount of Ag2CO3 as was required with piperidine. A higher loading of aryl iodide could be tolerated and was employed to enhance reactivity, since high cis-selectivity was observed for this system, with a decreased reactivity towards diarylation. Similarly to the piperidine, higher yields were generally observed for electronrich coupling partners and halogens were well-tolerated.