I’ll split my ride into two stages on two days (hotel in between):
Day 1: 250km (mostly Netherlands)
Day 2: 130km (or whatever is left; mostly in Belgium)
Question I have is: what is the best way to cross the border from the Netherlands onto Brussels? I heard that cycling can be quite difficult / dangerous in Belgium. Any tips which areas to avoid or which ones are particularly great to ride?
My best advice would be to do that trip the other way around. From Belgium to Groningen. Because 9 out of 10 times the wind is coming from the south 
Unless something has drastically changed, there’s nothing to the border crossing. You’ll know it’s happened because the road quality goes to cr@p. The Dutch will whine about how much road tax they pay (I know I certainly did 
), however, you do get what you pay for! Dutch roads are absolutely excellent (and the cycling infrastructure is probably second to none).
As for routes on the Belgian side, I’m sure there are locals on this forum who can provide some suggestions, though I’ve found Strava’s map routing stuff not too bad.
Enjoy your trip!
This is how I started finding routes in the area:
Site is in Dutch but easy enough to work out what to do.
Some general tips for the Belgian side which I know far better as an expat (I live in Belgium but work across Belgium, Netherlands and Luxembourg):
On the positive side, the scenery can be really beautiful, the country lanes are peaceful and you will rarely find a sunny day when there aren’t loads of other friendly cyclists out with you. E-biking has really gone massive during the pandemic and I’m always being overtaken on hills by old ladies on Decathlon specials 
I’ve never found it difficult and dangerous but you do need to keep your wits about you. Especially if you are planning to go right into Brussels. Lots of drivers are not yet used to the new cycle lanes that were put in due to Covid.
I’m from the US, so my standards for “dangerous to ride” are different, but in my mind, it’s not. Belgium has separated bike paths and bike lanes on a lot of roads. On busy major roads, I’d pick a different route. There are also plenty of little country roads that see little traffic.
I would avoid biking in Brussels. 
While it’s not as direct a path, the LF2 route goes from Dordrecht to Brussels via Antwerp. The LF routes are pretty decent paths. The fact that it takes you over to Leuven is a lot of extra distance, and I can’t say that the stretch from Leuven to Brussels is particularly interesting. But, you could get off LF2 at Boom and take that canalway that runs straight toward Brussels. That looks like it has decent coverage of bike paths.
Unless you actually need to go to Brussels, what I would actually do is ride along the Scheldt from Antwerp to Gent. The ride along the Scheldt is great. You could follow it all the way down to Oudenaarde and take in the hills of De Ronde.
Just something to consider. No idea if they are open right now due to COVID.
I don’t know how and why you heard that crap about cycling being difficult…
The roads for cars are not always in the best shape in Belgium, but then, those are not the ones you’ll be riding. I have rode many Dutch asphalt roads for cyclist, that looked nice from far, but where in a much shittier state than your average Belgian road. Specially when it’s lined with trees, feels like off-roading in paved roads…
The connection bike lanes along the national roads from town to town are mostly sweat in the Netherlands. But the bike paths in little town centers are on crap stone paved roads, usually.
Cyclist don’t get the right of way in Holland. Maybe in city centers.
In Belgium, as long as you’re on a crossing at an area where there’s a pedestrian crossing, you’ll get the right of way. If it’s only a cycle crossing, cars will make you wait, or not.
Technically, the weakest link in public road users, always have the right of way. So at an intersection with no lights, or at a roundabout or a circle, when using the bike lanes, you can just go. Cars will stop. Unless it’s a dutch or other foreign plate, they have no clue.
From plotting a quick route, you have a couple of options.
Once you get into Belgium I recommend taking fietsroutes or fietsostrades for the long boring stretches… Literally cycling highways.
To find more bike friendly roads you can plot a course via a thing called fietsknooppunt. It’s a network of cycle lanes, sometimes along an existing road, usually on it’s own, out in the field. These extend into Holland. You might want to use these to plot a course.
I recommend following canals. Usually the straightest way, with good asfalt. Usually these are bike and pedestrian only.
Brussels became much more bike friendly since the introduction of a 30km speed limit in the center. Not claiming it’s perfect. It is city riding so some level of assertiveness is required to navigate the city jungle.
I am Belgian, cycle all over, in Belgium and Holland.
Do follow the required covid-19 measures.
Enjoy, don’t crash. Good luck.
Thanks for all the feedback. I did it two weeks ago:
Day 1, 250km: Groningen to Son en Breugel via Hoenderloo. 160km → lunch → 90km
Day 2: 145km: Son en Breugel to Brussels (Troonstraat) via Leuven → 110km + 35km
I must say, the roads in Belgium (and the attitude towards cyclists) was way nicer than I am used to in the Netherlands. No craters, just smooth surfaces (mostly).
This was my route to Brussels:
https://www.komoot.com/tour/386704871
In fact, I realized as I was cruising through Brussels that on a bike it is way easier, as you have time enough to analyze traffic situations because on a bike you are way slower than in a car. In addition, people were very mindful… they just braked, waited, and went around me with a big bow (or it was the holidays that people are more relaxed now).
All in all, I would definitely do it again. The scenery was beautiful imho.