What is an appropriate way to write a recursive SMARTS that excludes trifluoromethyl groups as a potential R group?
I'm not sure if I correctly understand your intent.  My assumptions are

you have a set of molecules, e.g., as a list of SMILES strings (say FC(c1ccccc1)(F)F, CCCC(F)(F)F, CC(Cl)(Cl)Cl, and CCCO) in a file like probe.smi
you want to identify the molecules without the $\ce{-CF3}$ group

If so, I would i) search for the molecules with said group in a first step and then ii) remove this sub-set of positives from the set to know about the molecules without the $\ce{-CF3}$ group.

OpenBabel's positives: obabel -ismi probe.smi -s'C(F)(F)F' -osmi -O positives.smi.  In the present example, this yields only FC(c1ccccc1)(F)F and CCCC(F)(F)F, regardless of the different notation of the trifluormethyl group in the entries concerned.

The molecules lacking the $\ce{-CF3}$ group are just the complementary sub-set to the sub-set of the positives.  To start, one could opt for a Python script like:


#!/usr/bin/python3
&quot;&quot;&quot;Report molecules lacking the -CF3 group.&quot;&quot;&quot;


def reporter():
    &quot;&quot;&quot;Report .smi of molecules without -CF3 group.&quot;&quot;&quot;
    # prepare lists about the molecules:
    all_mols = []  # all molecules, no discern
    positives = []  # molecules with -CF3
    negatives = []  # molecules without -CF3

    with open('probe.smi', mode='r') as source:
        for line in source:
            all_mols.append(line.strip())

    with open('positives.smi', mode='r') as source:
        for line in source:
            positives.append(line.strip())

    # truncate the set to yield the sub-set about molecules without -CF3 group:
    set_all_mols = set(all_mols)
    set_positives = set(positives)
    set_negatives = set_all_mols.difference(set_positives)

    # convert the sub-set (back) into a list of entries:
    negatives = list(set_negatives)

    with open('negatives.smi', mode='w') as newfile:
        newfile.write('\n'.join(negatives))


if __name__ == &quot;__main__&quot;:
    reporter()

which in file negatives.smi correctly reports CC(Cl)(Cl)Cl and CCCO as molecules without the $\ce{-CF3}$ group.

Of course it would be nice to identify how to negate OpenBabel's search filter (-s'C(F)(F)F') to shorten the route traveled here.