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The rapid synthesis of diverse substituted polycyclic quinazolinones was achieved by two orthogonal Ugi four-component reaction (Ugi-4CR)-based protocols: the first two-step approach via an ammonia-Ugi-4CR followed by palladium-catalyzed annulation; in the second approach, cyanamide was used unprecedently as an amine component in Ugi-4CR followed by an AIBN/tributyltin hydride-induced radical reaction. Like no other method, MCR and cyclization could efficiently construct many biologically interesting compounds with tailored properties in very few steps.

Hit finding in early drug discovery is often based on high throughput screening (HTS) of existing and historical compound libraries, which can limit chemical diversity, is time-consuming, very costly, and environmentally not sustainable. On-the-fly compound synthesis and in situscreening in a highly miniaturized and automated format has the potential to greatly reduce the medicinal chemistry environmental footprint. Here, we used acoustic dispensing technology to synthesize a library in a 1536 well format based on the Groebcke–Blackburn–Bienaymé reaction (GBB-3CR) on a nanomole scale. The unpurified library was screened by differential scanning fluorimetry (DSF) and cross-validated using microscale thermophoresis (MST) against the oncogenic protein–protein interaction menin–MLL. Several GBB reaction products were found as μM menin binder, and the structural basis of the interactions with menin was elucidated by co-crystal structure analysis. Miniaturization and automation of the organic synthesis and screening process can lead to an acceleration in the early drug discovery process, which is an alternative to classical HTS and a step towards the paradigm of continuous manufacturing.

[2+2+2] cycloaddition reactions are one of the most elegant routes for the construction of six-membered rings. Here, we report initially the alkenone-enol-alkenone [2+2+2] cycloaddition reaction and introduce the cycloaddition into the system of in situbuilding complexes, where three novel coordination polymers (CPs) with functional groups, namely {[CdCl2(L1)]}n(1), {[CdCl2(L2)]}n(2), and {[CdCl2(L3)]}n(3), have been obtained. Particularly, the new 1,2,3,4,5-pentasubtituted cyclohexanols ligands L1, L2, and L3 are created from the starting chalcone derivatives via the [2+2+2] cyclotrimerization. Cadmium chloride not only plays the role of constructing CPs but also acts as a catalyst to promote the cycloaddition reaction. In addition, benefiting from numerous exposed carbonyl and hydroxyl function groups, CPs 1–3are applied to the adsorptive removal of dyes (congo red (CR) and methyl orange (MO)) from aqueous solutions. As a result, 1–3show excellent dye adsorption capacity. 1exhibits maximum CR adsorption capacity of 485.4 mg g–1, and 3has ultrahigh MO uptake capacity of 492.6 mg g–1. Experimental results suggest that the dye removal effect derives from the interactions between dye molecules and the exposed carbonyl and hydroxyl groups.

Miniaturization and acceleration of synthetic chemistry are critically important for rapid property optimization in pharmaceutical, agrochemical, and materials research and development. However, in most laboratories organic synthesis is still performed on a slow, sequential, and material-consuming scale and not validated for multiple substrate combinations. Herein, we introduce fast and touchless acoustic droplet ejection (ADE) technology into small-molecule chemistry to transfer building blocks by nL droplets and to scout a newly designed isoquinoline synthesis. With each compound in a discrete well, 384 random derivatives were synthesized in an automated fashion, and their quality was monitored by SFC-MS and TLC-UV-MS analysis. We exemplify a pipeline of fast and efficient nmol scouting to mmol- and mol-scale synthesis for the discovery of a useful novel reaction with great scope.

To demonstrate its applicability for realistic open systems, we apply the dynamic mean field quantum dissipative theory to simulate the photo‐induced excitation and nonradiative decay of an embedded butadiene molecule. The Markovian approximation is adopted to further reduce the computational time, and the resulting Markovian formulation assumes a variation of Lindblad's semigroup form, which is shown to be numerically stable. In the calculation, all 22 valence electrons in the butadiene molecule are taken as the system and treated explicitly while the nuclei of the molecules are taken as the immediate bath of the system. It is observed that (1) various excitations decay differently, which leads to different peak widths in the absorption spectra; and (2) the temperature dependences of nonradiative decay rates are distinct for various excitations, which can be explained by the different electron‐phonon couplings. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 2083–2092, 2003