: The mechanism studies of transition-metal-catalyzed reductive coupling reactions investigated using Density Functional Theory calculations in recent ten years have been reviewed. This review introduces the computational mechanism studies of Ni-, Pd-, Cu- and some other metals (Rh, Ti and Zr)-catalyzed reductive coupling reactions and presents the calculated methodology used in these computational mechanism studies. Based on the studies, the mechanisms of the transition-metal-catalyzed reductive coupling reactions normally include three main steps: oxidative addition; transmetalation; and reductive elimination or four main steps: the first oxidative addition; reduction; the second oxidative addition; and reductive elimination. The rate-limiting step is most likely the final reductive elimination step in the whole mechanism diagram. Currently the B3LYP method used in DFT calculations is the most popular choice in the structural geometry optimizations and M06 method is often used to do the single point calculations to refine the energy values. We hope that this review will stimulate more and more experimental and computational combinations and the computational chemistry will contribute more power in the development of future organic synthesis reactions.

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has been attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines(SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good antiproliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM and potently inhibited the SNU-16 and MCF-7 cancer cell with IC50 values of 0.71, 1.26 µM, respectively. And 8e inhibited the grow of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions are quite similar in our molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings 5-amino-1H-pyrazole-1-carbonyl might be served as a promising template of FGFR inhibitor.