Fig. 4: Model evaluation comparison and visualization of the
backbone model extraction effect
3.2 Case studies for reaction
evaluation
Here, three types of reaction examples are used to illustrate the
effectiveness of RSscore. (Fig. 5 ) First, the synthetic
reactions of the rivaroxaban intermediate (4-phenylmorpholin-3-one) is
employed as an example to evaluate the RSscore for reactions with same
class. (See Fig. 5(a) , Fig. 5(b) ) The substitution
reactions depicted in Fig. 5(a) and 5(b) allow for a
straightforward analysis of reaction superiority through the leaving
group effect. Except for the same leaving part, the basicity of the
chloride leaving group in Fig. 5(a) is lower than the basicity
of the ethyl ester group in Fig. 5(b) . It indicates that the
corresponding anion of the Fig. 5(a) reaction leaving group is
more stable, leading to milder reaction conditions in the Fig.
5(a) reaction. According to the experiment data from the Reaxys
database, the Fig. 5(a) reaction demonstrates the same reaction
temperature, a higher reaction yield and a shorter reaction time
compared to the Fig. 5(b) reaction. It validates the leaving
group effect and indicates that the Fig. 5(a) reaction exhibits
higher superiority. In accordance
of the evaluation metric proposed in this paper, the RSscore achieved
0.7939 in Fig. 5(a) and 0.7651 in Fig. 5(b) . It
indicates that the Fig. 5(a) reaction exhibits a higher
reaction superiority, aligning with the results obtained from the
experimental and mechanistic analyses. This demonstrates that the
RSscore can detect the impact of electronic effects, and effectively
distinguishes the superiority differences among reactions within the
same class.
Synthetic reactions of Pomalidomide intermediate
(4-nitrothalidomide) using different reaction agents
are conducted to determine whether the RSscore can detect the impact of
the reaction agent. The experimental data shows that the reaction usingFig. 5(c) agents exhibit lower reaction time, higher reaction
yield and milder reaction temperature condition compared to the reaction
using Fig. 5(d) agents. After completing the reaction atom
mapping, the RSscore for reactions using Fig. 5(c) andFig. 5(d) agents are calculated as 0.7518 and 0.4812,
respectively. This demonstrates that the RSscore are consistent with
experimental data and provide a better reflection of the reaction agents
influence on chemical reactions.
Finally, as an exploration of the assessment effect of the RSscore in
different reactions, the synthesis reactions Olaparib intermediate
(4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one) are
used as an example for comparison. Although the final product and the
reacted sites for the reactions in Fig. 5(e) and Fig.5(f) are the same, the reaction type are completely different,
with Fig. 5(e) being a hydrolysis reaction and Fig.
5(f) being a condensation reaction. Based on the comparison of the
experimental data between the reactions in Fig. 5(e) andFig. 5(f) , the reaction in Fig. 5(e) is superior in
terms of reaction time, yield, and temperature condition. The calculated
RSscore for Fig. 5(e) is 0.7836 and for Fig. 5(f) is
0.6399. The magnitude relationship of the RSscore supports the
superiority of the reaction in Fig. 5(e) , which aligns with the
experimental data.