it is hard to discuss such large patch on GitHub since diffs and comments to all files are shown on one page. Rietveld is more appropriate since it shows only one file at the time. I suggest you Oren to provide the next version of your patch as a patch for reviewing on Rietveld and make PRs only for ready patches.

Even after withdrawing some changes or extracting them as separate issues the patch can be too large. I suggest to commit first the part that relates to PyArg_Parse* ang PyLong_As*.