Tetrahedral intermediates resulting from the addition of nucleophiles to carboxylic acid derivatives are important, short-lived species in acyl-transfer reactions. [1] As a result of their transient nature, the utility of these compounds in organic chemistry remains limited. The isolation of tetrahedral intermediates could provide insight into the acyl-transfer process as well as useful compounds for organic synthesis. While the adducts formed by the addition of organometallic reagents to N-methoxy-N-methylamides [2] and tertiary amides [3] are relatively stable as their corresponding metal alkoxides (2), [4] their protonated counterparts rapidly decompose to the derived carbonyl derivative 3 [Eq.(1)]. [5] Herein, we report a study of the stability and synthetic utility of the exceptionally stable tetrahedral intermediates 5 and 6 resulting from the addition of nucleophiles to N-acylpyrroles 4 [Eq. (2)].

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A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.

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Most companies establish customer service policies which are then uniformly applied to all customers with the possible exception of providing superior service to the few largest customers. In this article the service provided by the major suppliers in the scientific instrument and supplies industry in Australia is examined. This is contrasted to the service requirements of their customers in toto and by segment. Considerable differences were found between the service provided and the service required. Also service requirements differed significantly between customer segments. Competitive advantage can be obtained by the supplier providing differential service levels by customer segment.