1. Do the founders of the first generation count for unique careers/skill challenges/best friends/opportunities like all other heirs, consider I am using two CAS sims? What about spounses?
You have to treat Founders like heirs. If your founder maxed any career, complete any skill challenges, have any best friends, finish any opportunities -- all these will be invalidate for your future generations heirs (all 16 generations).
Spouses for heir #1,2,3,5,6,7,9,10,11,13,14,15 are free to max any career, do any skill challenges without invalidating it for the future generation heirs. Spouses for heir #4,8,12 are different, they fall under the category of founders, so you have to be careful.
2. I assume only unique Maxed Career is needed for requirement rather than unique maxed skill? So it means that anyone can max a skill as long as related challenges are incomplete?
Correct. Only need to max career, you can have multiple heirs max the same skill without completing the skill challenges.
Note: You can't use that particular skill certificate as your moving requirement, since that skill is shared among your heirs.
3. Are townies allowed to be extended of their lives for potential household members/spouses using potions and other methods or is this disallowed?
Allowed. Life extending restriction is only for current active heir before they complete their requirements.
4. Can I purchase empty lots premade in the game if I wish to build a resort?
Yes. It has to be "premade" in the game, not some new lot you place using Edit Town. Remember once you build a resort, you need to owned it fully and upgrade it to 5 stars, part of the moving requirement.