Evidence-based transit and land use sketch planning using interactive accessibility methods on combined schedule and headwaybased networks.

An asymmetric synthesis of (S)-mirtazapine has been achieved from the synthesis of the racemate by using (S)-1-methyl-3-phenylpiperazine as the starting material. Unfortunately, significant racemization was encountered in the final step, which involved an electrophilic aromatic ring closure of a alcohol by concentrated sulfuric acid. A significantly higher ee was observed when polyphosphoric acid (PPA) was used instead. A remarkable correlation between the amount of PPA used and the ee of the product was revealed, namely, an increase in the ee upon decreasing the amount of PPA.

The discovery synthesis of asenapine that was used for the manufacture of drug substance batches up to 10 kg contained two chemical steps that were major bottlenecks for scale-up. One of these steps involved a magnesium/methanol reduction of an enamide moiety that was severely hampered by safety and efficiency problems. The other step was a laborious chromatography and isomerization cycle that was marked by a poor yield and extremely low throughput. The safety issues of the magnesium/methanol reduction could be solved by adding portions of magnesium to a solution of the enamide. In addition, an alternative process for the conversion of the mixture of cis- and trans-lactam into the desired trans-isomer was developed, circumventing the chromatographic separation.

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