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The palladium‐catalysed sp3 C−H arylation of a selection of saturated amine scaffolds was investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takes place using unsubstituted picolinamide or 3‐methylpicolinamide, whereas a double C−H arylation occurs with other substituents present, becoming a significant product with 3‐trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of directing groups on the C−H palladation steps which were found experimentally to be irreversible. The substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of other amine scaffolds, the yield of C−H arylation could be improved significantly using 3‐methylpicolinamide as the directing group and/or 3‐methylpentan‐3‐ol as the solvent.

Synthesis of substituted β-carbolines was accomplished by utilizing the catalytic enolate arylation reaction of ketones in conjunction with several 3-bromoindole derivatives. Quenching of the arylation reaction in situ with an electrophile allowed ready incorporation of functionality at the carboline C-4 position in an efficient one-pot protocol.

B(OCH2CF3)3-catalysed direct amidations of challenging substrates (polar heteroycles, poorly nucleophilic anilines) work well in tBuOAc under Dean–Stark conditions., Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficiency, with a measured process mass intensity of 8.

Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficency, with a measured process mass intensity of 8.

Pd-catalyzed α-arylation of methyl-OBO-ketone (OBO = 4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl) gives rise to arylated OBO-protected pyruvates. By appropriate prefunctionalization of the aryl ring or by subsequent functionalization at the α-carbonyl position of the arylated OBO-ketones, useful diketo OBO-protected carboxylates can be generated. Cyclization, aromatization, and OBO deprotection of these intermediates, using two distinct routes, gives access to valuable α-acyl heteroaromatic compounds.

Herein, we report a silver-free Pd(II)-catalyzed C(sp

A protected pyruvate equivalent is described that allows arylation and arylation/alkylation reactions to be performed at the methyl group. Utilization of the OBO derivative of the pyruvate ester allowed the application of palladium catalyzed arylation reactions together with subsequent alkylation, under basic conditions. Moreover, the OBO protecting group could be easily removed in one step to provide access to a wide range of substituted pyruvate derivatives.

A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.

This paper presents an overview of research conducted by the authors and others both experimentally and analytically in the area of blast wave interactions with buildings and structures in an urban landscape. Empirical tools for the assessment of blast wave resultants for simple-geometry situations are first presented before the confining effects of buildings along a street are discussed. Street layouts such a T-junctions and crossroads are then introduced and the way that blast wave characteristics are affected by street width and the height of buildings along the street is assessed. The influence of the location of the explosive charge within the street layout on the blast load experienced by buildings is also reviewed. It is likely that building facades closest to the explosion will fail and the effect on the loading experienced further from the detonation is therefore assessed. A complementary study of the loads developed inside a building whose facade has failed is also discussed. Apart from the blast loads on buildings in a street in which there is an explosion, buildings in adjacent streets will also experience blast loading. Studies concerned with the phenomena of ‘channelling’ and ‘shielding’ are presented and the extent to which both processes occur in any given situation discussed. The various studies reported throughout the paper indicate that simple tools are often inappropriate and the development of empirical rules for more complex geometries may not be reliable. This view is supported by studying blast wave propagation in a realistic cityscape comprising streets of different widths with several layout features all bounded by buildings of different size, shape and height. Such studies conclude that computational fluid dynamics analyses may sometimes be the only satisfactory approach for the engineer seeking a reliable assessment of blast loads experienced by buildings in an urban landscape.

In this paper we propose using experiments with Balanced-Sample Binary Trees (BSBTrees) as assignments and lecture material in intermediate data structures courses (CS2/3). BSBTrees are composite data structures that have a temporarily constructed form that precedes their normal construction. We present them in the context of binary search trees. To do this we first investigate the retrieval properties of randomly generated binary search trees and show how temporary construction can improve both worst case and average case behavior. We provide a brief analysis of BSBTree performance and description of the classes that can be used for BSBTree implementation. Last we discuss the use of BSBTrees in CS2 and CS3 courses and a survey of student opinions about BSBTrees.

The imine Ph2CHNCHCO2Et, generated from benzhydrylamine and ethyl glyoxylate, is an excellent dienophile in aza-Diels–Alder reactions, giving diastereomerically pure cycloadducts in high yield.

The imine Ph2CHNCHCO2Et, generated from benzhydrylamine and ethyl glyoxylate, provides a Diels–Alder adduct with 1,3-pentadiene from which a range of cis-2,6-disubstituted piperidines can be accessed; the benzhydryl group confers high diastereocontrol for derivatising the six-membered ring, allowing access to 2,5,6-trisubstituted piperidines, and to 2,6-disubstituted piperidines such as pinidine.

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

A moment method (MoM) model of a rectilinear edge slot in rectangular waveguide is developed using entire domain trigonometric basis functions. This model has been found to provide an optimum trade-off between computational efficiency and accuracy. The intention behind the analysis is to provide an accurate, computationally fast model for the inclined edge slot radiator for incorporation into an array synthesis program. The basis functions for the ‘three-dimensional’ slot geometries involved in the analysis are generated using a simple transmission line representation of the slot field distribution to identify the resonant ‘slot modes’. The results obtained are compared with alternative modelling approaches to this problem, based on finite element method and finite difference time domain techniques, and also with measurement.

This paper describes a coupled re-entrant cavity system which is designed to provide an electric field distribution capable of generating levitation forces on a conducting plate located in the near-field of two or more non-radiating coupling apertures. Re-entrant cavities are used to maximise the levitation field at these apertures which are placed at the re-entrant cavity gap. The system represents a particularly complex electromagnetic boundary value problem and consequently the arrangement has had to be modelled using a finite element simulation package in order to secure a design. Simulation results from the finite element model are compared with the measured results from the final design.

(2000). The Scientist as Spectator: Musil's Torles and the Challenge to Mach's Neo-Positivism. The Germanic Review: Literature, Culture, Theory: Vol. 75, No. 1, pp. 37-51.

An overview of the main asymmetric routes to substituted piperidines is presented. A wide range of synthetic strategies have been developed, because of the ubiquitous nature of the piperidine sub-unit in natural products, and because of the biological properties of natural and synthetic piperidine derivatives. This review concentrates on general methodologies that provide enantioselective routes to substituted piperidines, but also includes some specific target syntheses that illustrate the power of the methods that have been developed. The three approaches that have been most successful are: the use of the chiral pool, especially amino acids; the use of reagents that utilise a chiral catalyst; and the use of chiral auxiliaries in the asymmetric formation or derivatisation of the piperidine ring.

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure–activity and structure–property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.

This paper describes a series of experiments to measure the penetration depth with time of shaped charge jets as used in the oil industry to perforate well-liners. Targets comprised steel (simulating the well-liner), cement (representing the grout surrounding the liner) and Berea sandstone (in the form of cores) as the oil-bearing material. Results indicated cratering velocities of about 2000 m/s through the sandstone. Jet slow-down was very gradual and performance was found to be consistent with the behaviour of shaped charges penetrating materials such as those used in military armour.

An overview of the main asymmetric routes to substituted piperidines is presented. A wide range of synthetic strategies have been developed, because of the ubiquitous nature of the piperidine sub-unit in natural products, and because of the biological properties of natural and synthetic piperidine derivatives. This review concentrates on general methodologies that provide enantioselective routes to substituted piperidines, but also includes some specific target syntheses that illustrate the power of the methods that have been developed. The three approaches that have been most successful are: the use of the chiral pool, especially amino acids; the use of reagents that utilise a chiral catalyst; and the use of chiral auxiliaries in the asymmetric formation or derivatisation of the piperidine ring.