There are a few different ways to set the clock on a W221 S-Class, even if the clock refuses to change.
Method 1 - Easy & Simple
Press and hold the CD eject button until the system resets.
Once you see the COMAND reboot, you have about 1 minute to change the clock in standard system settings. Go to the vehicle on your screen, and you will see the settings.
Method 2 - Permanent Solution
Perform COMAND software update. You can update yourself by following this guide (free) or consult the dealership (cost money). Once the update is performed, you will be able to change the clock at any time.
Try to set the clock first thing in the morning when you get into the car before starting the engine. (Ignition on, no start)
Disconnect the battery in the boot for a short while; then, you could reset it on the command within a minute.
Remove one of the battery terminals before 12:00 and reconnect exactly at 12:00 midday or midnight. Whether you do it at noon or midnight, it doesn’t matter.
Change the language for German; then you can set the clock. After you set the clock, change the language back to English.