hoping to cover Seville, Cordoba, and Granada in 2.5 days
Cordoba and Granada as day trips

This is super tight timing, at best. Maybe even not feasible.

Honestly, I'd either extend Madrid and Barcelona with day trips or maybe make a 2-3 day trip from Madrid to Barcelona to make use of that time.

I don't know Hotel Santo Domingo, but the location is fine and central. Options on the other side of Sol would be closer to the trains and the big museums, but if you take taxis to and from the station the rest of the differences are 6/half-a-dozen.

You have only 2-1/2 days in Seville, which is barely enough for a quick visit to that city alone. It would be a mistake to try to squeeze in Cordoba and Granada as well.

Granada is really too far from Seville to be practical as a day trip. You'd spend over 5 hours just sitting on trains, to which you'd have to add two trips between your hotel and the train station in Seville and two trips between the Alhambra or other sights and the train station in Granada. And you wouldn't be showing up at the departure station right at the time of departure, either. The total travel time would be about 7 hours.

The top day trips from Madrid are Toledo and Segovia, though there are other good ones. I think the top day trip from Barcelona is Girona.

Two weeks is not long enough for the list of destination you've laid out. I'd suggest dropping the geographical outlier, Barcelona, but you can't do that since you're flying into and out of that city.

If you want to keep Barcelona + Madrid + Andalucía, I would remove a day in Madrid - thus keeping Toledo as the only day trip - and add a night in Granada between Sevilla and Barcelona. You would need to leave Sevilla very early to make time for the Alhambra visit, but it will be better than a day trip.
If it were me, I would also remove a day in Barcelona and spend a second night in Granada, but then I do not love Barcelona (it does not match my architectural interests).

I am not sure you will have time for Córdoba either, but Granada takes priority in my opinion.

Granada over Cordoba could go either way. For me, Cordoba over extra days in Madrid is an easy call for travelers not much interested in art who only plan to spend a couple of hours in Madrid's great art museums. Yes, Madrid has other sights, but I don't think it's as interesting as the other listed destinations in Spain, which are just more distinctive. When you have only twelve non-jetlagged days and want to see both Barcelona and Andalucia, some city or cities are going to have to be very quick stops. My vote is for Madrid--again, assuming you are not a big art fan.

Thank you very much acraven, balso, scudder :
I will be adding 1-2 days for Seville, taking a day from Madrid and Barcelona.

Thanks acraven for reminding me, I need to factor in 1 day for jetlag (long flight from San Francisco to Barcelona), I had
not even thought of this earlier :)

A) Madrid
Don't miss the Prado Art Museum in Madrid. Also, take day trips to Toledo and Segovia.
B) 2.5 days to cover Seville (my favorite city in Spain), Cordoba and Granada is ridiculous. You need a week for that.

We just returned from Spain and Portugal. We did one night in Toledo after 4 nights (3 full days in Madrid). I would highly recommend Toledo!

Thank you all very much for your suggestions -- very much appreciated.

I have made following changes to my itinerary:
Day 1 : Reach Madrid hotel around midnight : 5 nights hotel in Madrid
Day 2 : Monday : Madrid - we will be heavily jetlagged. So will only do day-trip to Segovia
Day 3 : Tuesday : Madrid
Day 4 : Wednesday : Madrid
Day 5 : Thursday : Madrid - Complete day-trip to Toledo

Day 6 : Friday : morning train to Seville : 3 nights hotel in Seville
spend remainder day Seville
Day 7 : Saturday : Seville
Day 8 : Sunday : Day trip to CORDOBA

Day 9 : Monday : Train to Barcelona (will take pretty much most of the day) : 5 nights hotel in Barcelona
Day 10: Tuesday : Day Trip to Montserrat
Day 11: Wednesday: Day Trip to Girona or other destination or Barcelona - undecided
Day 12: Thursday : Barcelona
Day 13: Friday : Barcelona
Day 14: Saturday : Flight back to US

With this we are minimizing changing Hotels which can take additional time.

Any suggestions ? Would have preferred to see more around Seville region, but time is short. Also -- Heat seems intense in August, I see each day it reaches 105 F. So not trying to overdo and run to too many places.

Thx for your guidance.

I had missed that the trip was in August. At that time of the year, it makes sense to minimize your stay in Andalucian cities, so i don't think you'll miss much!

Thank you very much balso !

Curious why you don't fly from Sevilla to Barcelona. It's only about 2 hours.

Good question Nestor.

My reasons :
1)
Train from Seville to Barcelona : 5.5 hours
flight may take 2 hours or less -- but adding in extra time to cover security etc. that time saving evaporates

2)
additional cost for checking in even basic carryon
add to risk of baggage not reaching in time ... yikes

Thx

I just stayed in Hotel Santo Domingo (checked out this morning).It was fine, comfortable and good location. Room AC had no problems dealing with 100F temps. Shower controls were a bit overwhelming.

Suggest changing your travel tactics to potentially gain better journey effectiveness.
Rent apartments instead of staying at hotels. Having a kitchen allows controlling your breakfast, ability to keep snacks at hand and even fix a light dinner. You can spend some time shopping in a market or local grocer and have a place to prep the food. Apartment also provides extra space to spread out and relax and landlord can serve as excellent local resource for information. It has been 17 years since we stopped staying in hotels. Seek apartment with terrace located on third floor or above and with a lift. Stay off main streets in order to obtain quieter environment.
August is hot and humid. Keep your meat out of the heat in order to prevent baking your mind. Up early with itinerary set to have mid day visits to indoor experiences. STAY HYDRATED! Even though you are intent on seeing so much, strongly recommend taking a mid day siesta in your room. Nothing worse than being in a crush of sweaty tourists. TIP: interior window shopping at Cort El Ingles is an excellent AC experience. Many of their dept stores (think Macy's) have a food market in their basement with toilets on top floor by customer service.
Seek to adapt to Spain time with following mentality............In Spain the next day starts at 10 pm.......meaning so much happens just as most Americans are use to going to bed.
Suggestion, Arrive in Barcelona and stay there in order to better adapt to jet lag. Head for your apartment and take a long walk around where you are staying in order to get your body in motion and shake out the "stiffs" of a long flight. TIP: start hydrating 24 hours prior to your flight. Bring with you the small drink packets you can mix with water and seek items providing electrolytes. Wear hats!
Sun sets quite late in August and you will find families out strolling and evening in the twilight. Take the walk, take a nap and then get back out with the locals for an evening stroll after sunset. Buy a few tapa for a late dinner. The sooner you adapt to Spain Culture Time the more you will get out of your journey. Stay minimum of 5 nights in Barcelona, I advocate for 6 including a dat trip to Montserrat (be sure to learn how to take the trip to Montserrat, lots of options).
Take an evening train to Madrid so you can enjoy the countryside during sunlight hours. Strive to arrive by 9 pm. If you love art and museums then stay in Madrid for four days including a day trip to destination of your choice. NOTE: Madrid is third largest city in Europe, but has one of smallest "old Towns" where tourists congregate. Madrid is also highest elevation and sun.................We stayed in Madrid for three nights, but we are NOT museum lovers.
Continue onto Seville for remainder of journey then travel back to Barcelona evening prior to leaving for home. NOTE: we only travel with one carry on suitcase and a personal bag each. Do all you can to travel light. What time does your flight depart for home from Barcelona? If you have a late departure I would consider an early flight from Seville to Barcelona. We fly the Iberia subsidiaries and find them economical and effective with meeting our travel needs. Yep, this is sort of a crazy travel year and think I understand the risks. However, having a last late night in Seville and the efficiency of minimizing travel modes (all by airline) is a tactic we have successfully previously utilized.
We have been in Spain in August, which is why we now only go in October or April. Don't wear out your bodies as the heat will sap your energy and impact enjoyment of your journey.
Day trip suggestions: it all depends on the heat. Crazy as it may sound, we suggest taking a half day to enjoy the Barcelona beaches and soak in the Mediterranean; especially if super hot. Barcelona offers excellent transport connections between subway and trains, Montserrat is a favorite. Toledo is better enjoyed with an overnight stay.

Thank you Archimedes for feedback on Hotel Santo Domingo

Hi Marbleskies :
Thank you very much for taking the time for your feedback -- you make several good points -- specially as we travel in extremely HOT weather.

• agree on Apartments, our reasoning for hotels was to central location and importantly having breakfast covered
  But apartments give additional advantage - specially having clothes washer/dryer - I will search for these again on each of the three locations where we are staying (Madrid - Seville - Barcelona)

• wonderful tip on managing during HOT conditions and on 'Cort El Ingles' stores, we will be on the lookout for them

• already paid for train journeys (Barcelona-Madrid, Madrid-Seville, and Seville-Barcelona). On taking Madrid train in 2 hours after landing in Barcelona, our reasoning was to sleep-relax on the train and get to Madrid the same day (Sunday night). Next day (Monday) we will be heavily jet-lagged -- we will do only a slow paced trip to Segovia. Hopefully by Monday evening we will be over our jetlag

• very good tip on traveling light - we will do everything possible to not have to check in any bags ( saves $$ too )

• we have 4 full days in Barcelona (reaching Monday around 3pm and then Tues-Wed-Thurs-Friday). We have Montserrat as a day trip .. and maybe Girona if we are not tired. Other times fully in Barcelona

• our flight back to San Francisco on Saturday is at 2pm .. for this we need to be at the airport by 11am, so will not leave us much time for anything else.

Thx again -- much appreciated