The initial experiment in MTBO used similar conditions to the optimal conditions from the second case study, with acetonitrile and JohnPhos as categorical variables with 18 minutes residence time with 5 mol% catalyst at 139 °C. This produced a good yield of 71 % but was subsequently improved by using NMP and XPhos, as the MTBO algorithm discovered from the first case study is also a parameter space region of high interest, immediately improving the yield to 83 %. Upon further adjustment of the continuous variables, a yield of 98 % was achieved in only five total experiments. This is the first optimization campaign where one ortho site was blocked for cyclisation, but this variation is seemingly not enough to divert chemical reactivity from what the MTBO algorithm expects, thereby proving the task's applicability to these divergent structures. The entire workflow for optimizing this process used only 250 mg of the starting material, 21, which also resulted in a greater yield, throughput and greener process than other reports in the literature (86 % yield in batch, overnight using fluorinated solvents). This experimental data is displayed at the end of this section in Figure (orange solid line).