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If your party are all around level 15, you should be able to do the Twisted Rune fight just fine in my opinion.
You can indeed return to the city during chapter 6, a lot of sidequests will still be available, but there are exceptions, there are definitely some that will no longer be available.
If you have a stronghold, their timers will be paused during chapter 4-5, however certain time sensitive quests will be unpaused as soon as you enter chapter 6, this could in some cases cause you to fail those time sensitive quests because the travel time between you and wherever the quest is might be too much.
For example if you have the thief stronghold and fail to pay Renal's cut or is away from the guild for too long he takes the guild away from you. I don't remember the exact day limit, but let's say it's 7 days and you had been away from the guild for 6.5 days and then you went off to Spellhold. It will take more than half a day to get back to the guild after you start chapter 6, so you will lose the stronghold.