(I use both of the innermost thumb buttons as a space bar on my split keyboard, with the left one also acting as a layer shift which gives me arrow keys on hjkl while holding it down. If you're a vim user, this arrangement becomes second-nature startlingly quickly, I found)
I'm on a 42-key keyboard; two 6x3 halves plus three thumb keys on each side. I would dearly love to try living with a (5x3+3)*2 keyboard for a week but I just can't see how I would replace the outside columns; I just need my tab, shift, control, and quote keys too much, and I'm pretty doubtful about the prospects of putting those keys onto separate layers or otherwise chording them. (backspace and enter are likely to be issues as well, although I could maybe adapt to ctrl-h and ctrl-m for those the same way I've adapted to ctrl-] for escape. And now that I've mentioned it, I could do tab on ctrl-T. So that brings down the number of extra keys I need to just shift, control, and quote. I guess I could do 'shift' with a hold of z or / and a tap of the opposite-side key to be capitalised. Not sure what I'd do about quote or enter, though.)