If you do not want to use Visual Studio Development Server and use IIS, you can do the following (tested in VS2015 Professional)
1) Application pool in a running state - make sure that used Application Pool is running by accessing a page from your Web app (it may be stopped due to a Idle timeout).
2) Attach to process - Ctrl-Alt-P
or Debug -> Attach to Process
-> lookup your w3wp process that corresponds to your application.
Attach to process can be greatly sped up by using ReAttach extension which creates shortcuts to recently attached processes.
3) Application pool recycle - make sure that the application pool recycles by either entering IIS and recycling it or even faster, by entering web.config, making a no-effect change (put some blank outside of tags) and saving it
4) Start debugging - Perform a request to any page from your web application to force its initialization. You should be able to place and hit breakpoints from any of the startup methods in the Global.asax
protected void Application_Start()
void Application_BeginRequest(Object sender, EventArgs e)
protected void Session_Start(object sender, EventArgs e)