Palladium-Catalyzed C–H Functionalization Using Guanidine as a Directing Group: Ortho Arylation and Olefination of Arylguanidines

Palladium-catalyzed C–H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively

Substrate-Controlled Synthesis of Spirocyclo­propyl­pyrazolones and Bicyclic 4,5-Dihydropyrazoles from 1,2-Diaza-1,3-dienes with Sulfur Ylides

Substrate-controlled reactions have been developed for the synthesis of spirocyclo­propyl­pyrazolones and bicyclic 4,5-dihydropyrazoles from 1,2-diaza-1,3-dienes and sulfur ylides. These protocols were carried out under mild reaction conditions without any additives in generally moderate to good yields. Plausible mechanisms for the transformations were proposed

Tuning the Annulation Reactivity of Vinyl Azides and Carbazates: A Divergent Synthesis of Aza-pyrimidinones and Imidazoles

A divergent cascade annulation has been developed using readily available vinyl azides and carbazates with a wide range of substituents. Vinyl azides were successfully applied as bifunctional partners to prepare aza-pyrimidinones via 6-ring closure with carbazates as well as to construct polyfunctionalized imidazoles via 5-ring closure with <i>N</i>-substituted carbazates. The aza-heterocycles were obtained with high levels of chemoselectivity and excellent yields

One-Pot Three-Component Approach to the Synthesis of Polyfunctional Pyrazoles

A simple, multicomponent, and straightforward reaction of vinyl azide, aldehyde, and tosylhydrazine affords the construction of 3,4,5-trisubstituted 1<i>H</i>-pyrazoles regioselectively in the presence of base with moderate to excellent yields. A range of functionality could be tolerated in this methodology, and a possible mechanism is proposed

Direct Access to 3‑Thioether-Substituted Dihydrofuro[2,3‑<i>b</i>]benzofurans via Tandem Reactions of Sulfur Ylides and 2‑Nitrobenzofurans

The synthesis of 3-thioether-substituted dihydrofuro[2,3-b]benzofurans involving the [3 + 2] coupling of sulfur ylides with 2-nitrobenzofurans has been realized in moderate to good yields under mild conditions without any precious catalysts or additives. It is worth mentioning that the reutilization of the departed nitro-anion in the reaction process facilitates this new chemical transformation and presents a manner of high atom economy to provide products with a complex structure

Synthesis of Pyrimidopyrrolopyridazines via a Tandem Reaction of Heterocyclic Ketene Aminals with 1,2-Diaza-1,3-dienes

A tandem reaction of heterocyclic ketene aminals and 1,2-diaza-1,3-dienes was developed for the expedient synthesis of pyrimidopyrrolopyridazine derivatives. This process involved an intramolecular conjugate addition followed by CuCl₂-catalyzed hydrazone formation

A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles

Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound <b>5a</b> was validated against EGFR^WT, EGFR^T790M as well as A431 and H1975 cancer cell lines. Additionally, compound <b>5a</b> displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of <b>5a</b> at a dose of 30 mg/kg induced tumor regression in a murine-EGFR^L858R/T790M driven H1975 xenograft model. Also, <b>5a</b> exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance