What are aryl chlorides currently used for?

In a recent paper by Gustafson et al. (DOI: [10.1021/acs.orglett.6b02650](http://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b02650)) the authors open with the argument that



> 
> aryl chlorides are both versatile synthetic handles and common functionalities in drug discovery.
> 
> 
> 


However, they fail to give examples of current use in industry and pharmaceutical research.


I know of only one reaction that aryl chlorides are used for, and that would be the Ullmann biaryl (ether) coupling. Are there any other ones for which aryl chlorides are a good starting material?
And then, about the second part of the sentence: Why are aryl chlorides a common functionality in drug discovery? Is it simply that compounds are chlorinated and then compared to their unchlorinated analogues?


All in all, **please provide examples for the quoted statement above**.




1. Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on [this website](http://www.organic-chemistry.org/)). Or make an halogen exchange before coupling your chloro- position.
2. Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see [C. Bissantz et al., *J. Med. Chem.*, **2010**, *53* (14), 5061–5084.](http://pubs.acs.org/doi/abs/10.1021/jm100112j)). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties is
represented here (see [Furet et al., Bioorg. Med. Chem. Lett.
**2012**, 22 (10), 3498–3502](http://www.sciencedirect.com/science/article/pii/S0960894X12004040), which shows the docking model). This is an inhibitor which blocks the binding pocket of the
regulator protein MDM2. The 6-chloroindolyl moiety enables to fill a
subpocket (TRP 23), while the *p*-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.


[![enter image description here](https://i.stack.imgur.com/2IRxr.png)](https://i.stack.imgur.com/2IRxr.png)


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