Two week drive from Madrid to Lisbon

You'll probably get more useful info by telling us who "we" is (any children?) and what the group is interested in.

Madrid, Seville, Salamanca, Northern Portugal, Lisbon is quite a lot in 2 weeks. For a start I wouldn't drive as you just don't have time for places in between.

Fly in to Madrid - 3 nights (possible day trip to Toledo)
Train to Salamanca - 1 night
Train (via Madrid) to Seville - 3 nights (possible day trip to Cordoba)
Fly to Porto - 3 nights (possible day trip up the Douro Valley)
Train to Coimbra - 1 night
Train to Lisbon - 3 nights (possible day trip to Sintra)
Fly out of Lisbon

It sounds like you want to rent a car in Spain and drop it off in Portugal. There are usually huge (several hundred euros) drop-off charges. Is that okay with you?

Thank you. I have now managed to change my flight to leave from Madrid. Thanks for your warnings!
Cheers
Anne

well done! Have a great trip.

So no Portugal ?

Yes! Portugal looks amazing. We will drive from Madrid, tour Portugal then return to Madrid. Thank you for your feedback.

This is a lot of driving (1900+km) over just 2 weeks. More time would be preferable.

Fly in to Madrid - 3 nights
Salamanca - 1 night
Porto - 2 nights (possible day trip up the Douro Valley)
Coimbra - 1 night
Lisbon - 3 nights (possible day trip to Sintra)
Seville - 2 nights
Cordoba - 1 night
Toledo - 1 night
Fly out of Madrid

That's pretty close to what we've planned. Luckily my husband likes to drive! Thank you so much.
Cheers
Anne