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First, the application of QCaRA/AFIR to α,α-difluoroglycine gave a reaction path network, where over 30 reactant candidates were found. Among these candidates, a set of reactants consisting of CF2+NH3+CO2 was selected in consideration of the availability of the species involved. Then, assuming CF3 − and CF 2Br − as sources of CF 2 formation in situ, the reaction path networks for CF3 −+NH 3+CO2 and CF2Br −+NH 3+CO2 were computed by the AFIR method. The results showed that whi le CF3 −+NH 3+CO2 gave CF3CO2 −, CF 2Br −+NH 3+CO2 gave a mixture of the target product and by-products. It was also found that the protons of NH3 promoted the formation of by-products. Then, the reaction path network for CF2Br −+NMe 3+CO2 with the replacement of the proton with the methyl group was obtained by the AFIR method. It was predicted that the desired α,α-difluoroglycine derivatives could be obtained from CF2Br −+NMe 3+CO2 in >99% yield. This article described the reactivity prediction by the AFIR method, which has been developed by the authors, including the latest application results. By applying virtual forces between fragments in a system and inducing chemical changes, the AFIR method gives the reaction paths based on the resulting structural changes. Since the calculated yield of >99% was predicted, the experiment was conducted to confirm the inference. Fig. 5(b) shows the reaction scheme finally discovered experimentally. In the experiment, CF2Br− was generated in situ by mixing Me3SiCF2Br and Ph3SiF2·NBu4. The synthetic experiments afforded α,α-difluoroglycine derivatives from CF2Br −+NMe 3+CO2 in 96% yield. Lastly, we succeeded in isolating the resulting α,α-difluoroglycine derivative as a stable solid after methyl esterification by the treatment with Meerwein reagent. Its three-dimensional structure was confirmed by X-ray crystallography. Furthermore, this three-component reaction proceeded well with various tertiary amines and nitrogen-containing heteroaromatics; hence, it became feasible to synthesize various α,α-difluoroglycine derivatives shown in Fig. 5(c).29 Conclusions This article described the reactivity prediction by the AFIR method, which has been developed by the authors, including the latest application results. By applying virtual forces between fragments in a system and inducing chemical changes, the AFIR method gives the reaction paths based on the resulting structural changes. By systematically testing combinations of various fragment pairs, a systematic automated search for reaction paths is possible. The resulting reaction path network is valuable for elucidating the mechanisms of complicated chemical reactions. The complex reaction path network obtained by the AFIR method can be easily analyzed by the RCMC method based on the kinetics, which is also used to limit the scope of the AFIR search to kinetically accessible paths and to suppress combinatorial explosions. The AFIR method can predict chemical reactions in a system consisting of 30 atoms or less with no previous knowledge. The application to the Strecker synthesis was shown as an example. Even for the system with more than 30 atoms, the reaction mechanism can be analyzed systematically by combining with calculation methods for macromolecular systems such as the semi-empirical quantum chemical calculation method and the QM/ MM method. As examples, this ar ticle presented the structural transition of interfacial amorphous carbon and the conversion of pyruvate to L-lactate by LDH. Lastly, this article introduced the discovery of a synthetic method of difluoroglycine derivatives by QCaRA using the AFIR method as a reaction path search engine. The AFIR method is now widely used in reaction mechanism analysis. This method is implemented in the GRRM20 program and is used by many users.30 The new reaction prediction method combined with QCaRA suggests even more exciting possibilities of the AFIR method. We hope that the new AFIR features in GRRM20 will contribute to many chemical studies in the future. ◆ Acknowledgement This work was partly supported by a grant from JST-CREST (No. JPMJCR14L5), JSTERATO (No. JPMJER1903), and JSPS-WPI. We thank to Ms. Takako Homma for editing a draft of this manuscript.
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