Preamble: Now, I am aware that directly editing the inchikey is, generally speaking, a bad idea, but...
Can I just change the 2nd block of an inchikey to "UHFFFAOY" to get the correct main-layer-only version of the inchikey of that molecule?
example where this seems to be the case (from pubchem):
BSAIUMLZVGUGKX-BQYQJAHWSA-N = trans-2-nonenal
BSAIUMLZVGUGKX-FPLPWBNLSA-N = cis-2-nonenal
BSAIUMLZVGUGKX-UHFFFAOYSA-N = 2-nonenal
I have seen lots of other examples (100s if not 1000s) to support this hypothesis (both for cis/trans and for sterochemistry) and never a counter-example.