We have some long runs in our house. Assuming there isn't too much blockage in the flex duct, would it make sense to reduce some of the very short runs from 6" to 4", for example a bonus room window vent, since the bonus room circulates air extremely well, in order to improve airflow for the longer run to bonus room #2?
Reducing airflow to one or more ducts should help increase airflow to others.
Reducing the duct size is one way to accomplish an airflow reduction in those ducts. However, I would recommend installing dampers at the takeoffs for the flex ducts to achieve your goals. You might want to check and see if you already have them. Here is an example of a takeoff with built-in damper (note: this is not an endorsement for the linked product).
Installing dampers would be much easier than swapping out whole lines of ducting and less of a gamble that downsizing your ducting will meet your airflow needs: You can adjust the dampers to allow multiple levels of airflow and better fine-tune airflow to meet your needs. If you just change to a different sized reduced fixed duct size without dampers, you only get one option and you could find that you no longer have enough airflow to the reduced size ducts.
As a note: The amount by which the airflow will increase as a result of taking either action may not be enough based on what you are looking for. If that is the case, other things to consider are (and potentially contact a professional HVAC contractor for):
Is the return air duct sized appropriately (is there even a return air duct) for bonus room #2?
Air flow requires adequately sized supply and return lines because air needs to circulate in and out of a space in order to be heated/cooled by the HVAC system. However, many people seem think about upsizing supply ducts to increase airflow before they even think about whether there is a return air duct. Without an appropriately sized return air duct, increasing the air supplied into the room will create positive pressure in the room and will not yield significant gains in circulation or comfort.
Do you have an appropriately sized furnace and/or air conditioner?
Oversized equipment can result in decreased comfort because the oversized equipment runs for shorter periods before shutting off which means there is less circulation of air and more concentrated hot/cold spots.
Undersized equipment will run more often (sometimes continuously) and may not be able to hold the desired set temperature, though temperatures will tend to be more even throughout the space because of increased circulation.
Appropriately sized equipment (and multistage HVAC equipement) operates for longer durations and helps to make sure air is circulated more evenly throughout the house.
Is the supply duct size appropriately for bonus room #2? In this case, you may wish to upsize.