So, there was quite a bit of hubbub over the challenges the 49ers were able to use despite not having timeouts. I haven't re-watched the game and I was barely paying attention by the time the fun was really going, but if I understood correctly the first one went like this

Vikings Run Play

49ers immediately call last timeout to stop clock

Harbaugh notices there was a fumble, attempts to challenge, talks ref into allowing it after 5 minutes

When the review system was bought back into the NFL I remember this being allowed for some time. Then it was changed a couple years later with the reasoning being that they didn't want a team taking a timeout, spending 2 minutes looking at replays, then challenging and getting the timeout back.

It seems to me that there could easily be an exception to the rule under 3 minutes in the halves ( when teams are taking immediate timeouts but the under 2 minute challenges are not in place ) that you have some reasonable time after calling the timeout, say 30 seconds, to decide to challenge. Otherwise the rule is effectively penalizing teams for using the timeouts in the most efficient way by forcing them to put up a 2nd timeout to challenge or not be able to challenge at all.