$x = "<tr><td>1</td><td>2</td><td><font>3</font></td><td>4</td><tr>";

$x =~ s{<td>(?!<td>)3(?!</td>)</td>}{<td>($1)a($2)</td>}; 
print $x;
#output must be: <tr><td>1</td><td>2</td><td><font>a</font></td><td>4</td><tr>

##</code><code>##

$text =~ s/(<td>)((?:(?!<td>).)*)3((?:(?!<\/td>).)*)/<td>$1$2a$3/;
OR
$text =~ s{(?<=<td>)((?:(?!<td>).)*)3((?:(?!</td>).)*)(?=</td>)}{$1a$2};