If I have 2 Karthus and I kill a Ruined Rex with sacrifice and get 3 triggers of the Rex 4 damage, do I have to choose all targets first then opponent can decide which one they "not so fast," or can I do them one by one and wait for each to resolve the damage before targeting the next one? Could I target a unit with GA so it first dies and GA goes off and then target it again to actually kill the unit, or do I target first 2 times and then it still dies? Or do all damage from the Deathknells resolve and then GA procs? The main question is if the targets for multiple Deathknells need to be chosen before opponent reacts to any specific one in the stack.

To address your question, we must look at how the chain, Deathknell triggers, and targeting work.

The Short Answer

No, you do not choose all targets upfront. Each Deathknell trigger is a separate item on the chain. You will place them on the chain, and then resolve them one by one. You choose the target for a specific Deathknell trigger at the moment that specific trigger is finalized and placed on the chain.

Because each trigger is a separate chain item, you resolve the first one completely (choosing a target, dealing damage) before the next one is even addressed. Your opponent has priority to react to each trigger individually as they appear on the chain.

The Sequence of Events

Following your scenario (2 Karthus on board, sacrificing Ruined Rex):

1. Playing Sacrifice: You announce Sacrifice, killing Ruined Rex as an additional cost.
2. Deathknell Creation: Because you have 2 Karthus, Eternal on the board, Ruined Rex’s Deathknell triggers 3 times total (1 for the death + 2 bonus triggers). Per Rule 808.1.d.2, these become Pending Items.
3. Sacrifice Resolution: Sacrifice finishes its instructions (Draw 2, channel 1).
4. Finalization: With Sacrifice resolved, the game moves to the Finalize step. The 3 Deathknell triggers are placed onto the chain.
   • Note: You place them one by one. You choose a target for the first, then the second, then the third.
5. Chain Resolution:
   • Trigger 1: Resolves. You deal 4 damage to your chosen target. If this kills a unit with Guardian Angel, the Guardian Angel trigger goes on the chain on top of the remaining Deathknell triggers.
   • Opponent's Opportunity: After Trigger 1 resolves, the state becomes OPEN. Before Trigger 2 resolves, your opponent has an opportunity to react.
   • Trigger 2: Resolves. You deal 4 damage to your chosen target.
   • Trigger 3: Resolves. You deal 4 damage to your chosen target.

Clarifying Your Specific Questions

• "Do I choose all targets first?" No. You choose the target for each Deathknell trigger as you place that specific trigger onto the chain during the Finalization step (after Sacrifice resolves).
• "Can I do them one by one and wait for each to resolve?" Yes. Each trigger is a distinct item on the chain. You fully resolve the first, then the next, and so on.
• "Can I target a unit with GA so it dies, GA goes off, and then target it again?" If you kill a unit with Guardian Angel with the first Deathknell trigger, the Guardian Angel effect (e.g., "Heal me...") is a triggered ability that goes on the chain. You would have to resolve the Guardian Angel effect (or wait for it to resolve) before you could use your second or third Deathknell triggers to target that same unit again.
• "Do all damage from the Deathknells resolve and then GA procs?" No. If a unit dies during the resolution of a chain item, its triggered abilities (like Guardian Angel) are placed on the chain immediately, on top of any existing chain items.

Summary of Rules

• Targeting: Per Rule 355.14.b, targets are chosen when the spell or ability is finalized on the chain. Since your triggers are separate items, you choose targets sequentially.
• Priority: You and your opponent have priority to add reactions to the chain after every item resolves.
• Guardian Angel: If a unit dies, its triggered abilities (like Deathknell or Guardian Angel) enter the chain as items to be resolved. They do not all "proc" at once after everything else is done; they interact with the chain order (LIFO).