What if they created a RtwP kind of button for the player to press? You are watching combat. You see an enemy casting a spell. You hit the "Reaction" button. Game pauses. Your UI comes to life, but only certain Reaction abilities are lit up, like Counterspell. You check the Combat Log. Enemy is casting Bane on Gale. Oh. No big deal. Let that one go. Hit the button again and let the combat resume.
Enemy comes up to attack Astarion. He looks like a baby goblin, so I don't worry about hitting the "Reaction" button to have him use Uncanny Dodge. However, the bugbear with the glowing poison mace comes running up to him. Before the bugbear even starts his swing, I hit the Reaction button to pause time. I quickly click on Astarion's Uncanny Dodge so that it's active in case the bugbear hits. Unpause. Bugbear misses and Uncanny Dodge is refunded to me. I have to remember to click it again if another enemy attacks him that I want to use it on.
Enemy shoves you. You see your character flying off the edge of a cliff. "Reaction" button. Your character is frozen in midair. Your UI is unlocked, and you see your reaction abilities pop up. Feather Fall is highlighted.
Then, on certain actions, like AOO, the game auto-pauses - because you wouldn't have time to respond if it didn't. The animation shows the enemy turn around and start to move away. Game pauses. Combat log pops open and there's a statement, "Enemy has triggered AOO." You see your attack buttons highlighted, including Paladin Divine Smite button. You attack, and it unpauses, showing your character swing at the enemy before they are able to run away.
For multiplayer, the "Reaction" button would only be able to be hit by the active player. So, if the enemy is charging at Player 1's character(s), Player 2 could not hit the "Reaction" button. However, if the enemy is casting an AoE spell, like Fireball, and targeting a location that would hit both Player 1 and Player 2, both players can hit the "Reaction" button and pause the game. Then they could discuss who is going to use their Reaction to stop the spell. To prevent one player from driving another player crazy by taking too long, maybe there could be a timer. Players only have 10, or 20, or whatever, seconds to decide what they are going to do in a multiplayer setting only. Single player wouldn't have a timer. Once the timer runs out, no Reaction occurs. The player took too long to decide.
This method would still be kinda choppy, but no popups. The game would pause only if you are fast enough to react, and only when YOU want it to. There would need to be a Reaction Window providing a set amount of time for a player to be able to react in. As long as they can hit the Reaction Button within that window, they can perform the Reaction. (So, kinda like those games where you have to hit X within a few seconds after it appears on your screen.)
This then forces players to pay closer attention to enemies when they're taking a turn so that you don't miss out on opportunities to React. Any messages that would need to be provided to the player could be done via the Combat Log - like with the AOO example I gave above. For the most party, when you hit the "Reaction" button, the Reactions you can use would simply be highlighted on your UI for you, and you can use them just like you would if it was your normal turn.
So, need to do an AOO? Only the Attack button would highlight indicating that you could click on the target and do an AOO. Once you get familiar with the system, you probably wouldn't even need the log to tell you it's for AOO. You'd see an enemy turn, the game would pause, the Melee Attack would highlight, you'd hover over the enemy and click on him/her, and the game would unpause. You'd watch your character swing at the escaping enemy.