You can put the motor and transmission on the frame first, but you need to place them according to where the cab needs to sit, not the other way around. Ultimately your wheels need to line up correctly in the wheelwell. Your engine placement should be based around this.
If you place your engine correctly, you shouldn't have to modify the firewall and should have lots of room in front as well. The mounts for a 4.3 may work (they bolt to a small block or big block), but you'll have to see if the stock S-10 location for the frame mounts lines up correctly to get the motor in the right place. If you don't place the motor correctly, you'll be out everywhere else.
