First of all, love the smoothie project and I’m looking forward to it’s continued development! I’ve been using smoothie for a few months now and S3D for even longer, so I thought I’d add some details to this thread that might help others.
I’ve talked with the S3D team extensively about the “firmware unresponsive” message that is sometimes displayed when sending gcode files. This message is only displayed when the software sends a command, but the firmware doesn’t respond to it. Because our 3D printing firmwares typically use some type of back-and-forth (ping-pong) communication, it’s important that the firmware acknowledges each command so that the software knows when to send the next command. So that should at least explain why you are seeing this message.
Now from my investigation, there’s several things that can cause it. First, and the easiest to explain, is if the firmware receives a command and truly never responds to it. For example, I remember on a really old build of the Sprinter firmware that I used, whenever I would send a specific style of preheat command, the firmware would just stop responding. It never sent back anything, almost as if the board had reset or something. If this is what’s happening, it’s really easy to confirm in S3D because the Communication tab in the machine control panel records every command that is sent and received (just make sure you have the verbose checkbox enabled). So if you look at the communication traffic and you see something like this:
SENT: G1 X50 F3000
RECEIVED: ok
SENT G1 Y100 F3000
Warning: firmware unresponsive
it means that the software sent the “G1 Y100 F3000” command, but never received a response back. As I’ve seen in some other threads on here, you can actually adjust how long the software will wait for a response by going to Tools -> Firmware Configuration, clicking on the Communication tab, and adjusting the “communication timeout” value at the bottom. So if the smoothie needs more time to respond, you could increase that value. Personally, I’ve had it at 30 seconds and I’ve never seen these unresponsive messages from my smoothieboard, even with some long 10+ hour prints. So if yours is something shorter, maybe try increasing it. But if the software doesn’t get a response in that period of time, it’s going to display a warning saying the firmware is unresponsive.
So next time someone sees that warning in the S3D communication log, check to see if there was a command SENT but nothing RECEIVED. And if that’s the case, maybe we can start investigating that specific command that was sent right before it stopped responding to see if there’s any reason why the smoothie firmware didn’t send back a response.
Just a few ideas to hopefully help get to the bottom of this 
PS - I remember emailing with the S3D team many months ago about smoothie support and they mentioned that they had actually already purchased a few smoothieboards on their own to make sure that the software was compatible with the smoothie firmware. I had quite a few conversations with them about it, and it was pretty clear that they had already spent a lot of effort testing it with the software. I think one of their developers even found a bug that got reported to the smoothie repo and is now fixed. So I think they’ve definitely spent some time helping with the project and trying to make it compatible!