Maybe you should first of all investigate where the best place to find work or start a business is? It sounds as though you are looking for a Med city. Barcelona is obviously very cosmopolitan, but don't rule out Valencia or Alicante. All are cosmopolitan (to a small degree) and I'm sure you'll be able to find English-speakers to network with.
If you decide to bite the bullet and go to Madrid (where more work opportunities are - relatively speaking) I would recommend living in central Madrid. My experience is that people living in say Malasana or Moncloa areas are more open-minded and less anti-immigrant than say Pozuelo or Somosagauas. Of course you then don't get the benefits of living close to countryside...
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An English Bookseller in Madrid