Knowledge-based improvement: simulation and artificial intelligence for identifying and improving human decision-making in an operations system

The performance of most operations systems is significantly affected by the interaction of human decision-makers. A methodology, based on the use of visual interactive simulation (VIS) and artificial intelligence (AI), is described that aims to identify and improve human decision-making in operations systems. The methodology, known as 'knowledge-based improvement' (KBI), elicits knowledge from a decision-maker via a VIS and then uses AI methods to represent decision-making. By linking the VIS and AI representation, it is possible to predict the performance of the operations system under different decision-making strategies and to search for improved strategies. The KBI methodology is applied to the decision-making surrounding unplanned maintenance operations at a Ford Motor Company engine assembly plant

Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam <b>2</b> was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 <i>syn</i>/<i>anti</i>. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate <b>3</b>, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant