To spend hours creating a perfect road network, with an absurdly high availability of all municipal services.
It can be very tempting to activate the mod for endless money to build the perfect city from scratch. The production of goods comes with a price. It means you will have to take some breaks to ensure everything is running smoothly (to avoid embarrassments like garbage or dead bodies piling up in the streets), but it's worth the effort when you notice how much money is pouring in while you're working on a specific project. In those cases leaving the simulation on can lead to city-wide chaos, but in other cases there's rarely a downside to letting your citizens live out their lives.
The only examples I can think of where the pause button should be used is when you're working on the road connections leading into your city, or when you're altering basic services such as electricity or water and sewage. Every minute the simulation is paused, is a new minute of money lost for ever. On the contrary, I would advice you to keep the simulation running as much as possible, to ensure a steady income. If needs be you can pause the entire simulation in Cities: Skylines, but that doesn't mean you should do that all the time. Always run the simulation (with a few exceptions)