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When a breakpoint is added to an add-in project in Visual Studio, the breakpoint is not hit when debugging the program. (For more information on breakpoints, refer to Debugging Basics: Breakpoints.)
This issue occurs because the supported runtime version in the configuration (.config) file for the ArcMap add-in application does not match the targeted .NET framework of a Visual Studio project.
In the extensible markup language (XML) code of the ArcMap.exe.config file, lines 4 and 5 state the supported runtime versions for the .NET framework of a Visual Studio project. The compiler reads version 2.0 in line 5, instead of version 4.0 in line 4 as the supported runtime version because line 4 is commented.
.NET 3.0 and 3.5 frameworks support runtime version 2.0 while .NET 4.0 and 4.5 support runtime version 4.0. For more information on .NET frameworks, refer to How to: Determine Which .NET Framework Versions Are Installed.
Additionally, do the same when targeting the .NET 3.5 (or under) framework.
Save a copy of the file in a different folder and use it to overwrite the original file if the following error is returned, "The file cannot be saved and it may be protected."