FileUpload control working on second click but not at first click?

Change  your master page form tag as like this

<form id="form1" enctype="multipart/form-data" runat="server">

FileUpload control not Working in UpdatePanel asp.net

Add this code in UpdatePanel
 <Triggers>
  <asp:PostBackTrigger ControlID="btnSubmit" />
 </Triggers>

Difference between HTTP handlers and HTTP modules

HTTP handlers are the end point objects in ASP.NET pipeline and an HTTP Handler essentially processes the request and produces the response. For example an ASP.NET Page is an HTTP Handler.

HTTP Modules are objects which also participate the pipeline but they work before and after the HTTP Handler does its job and produce additional services within the pipeline (for example associating session within a request before HTTP handler executes, and saving the session state after HTTP handler has done its job, is basically done by an HTTP module, SessionStateModule)

Dynamically changing master in ASP.NET , C#

 protected void Page_PreInit(object seder, EventArgs e)
  {
        this.MasterPageFile = "~/MasterPage.master";
  }