One thing we noticed is that on some machines Simplify3D will start to connect but then stop. This is usually caused by the firmware serial start command not matching exactly what Simplify3D is looking for. The easiest way to get around this is to just uncheck the firmware start check by following the steps below.
Open the Tools menu and select Firmware Configuration
Uncheck "Wait for startup command" and click Save
Verify that the "Wait for startup command" is unchecked