Using CDK's RGroupQuery

Main.java

public static void main(String[] args) throws CDKException {
    IChemObjectBuilder    bldr   = SilentChemObjectBuilder.getInstance();
    SmilesParser          smipar = new SmilesParser(bldr);
    IAtomContainer        root   = smipar.parseSmiles("CC1=CC=NC2=C1C=CC(=C2)C1=CC([R1])=C([R2])C([R3])=C1");

    Map<IAtom, Map<Integer,IBond>> rootAttach = new HashMap<>();
    Map<Integer,RGroupList> rgrpMap = new HashMap<>();
    defineRgroup(root, rootAttach, rgrpMap, "R1", newRGroupList("[H].[CH2]CO.[CH2]Cl", 1));
    defineRgroup(root, rootAttach, rgrpMap, "R2", newRGroupList("[H].[CH2]CN.[CH2]F", 2));
    defineRgroup(root, rootAttach, rgrpMap, "R3", newRGroupList("[H].[CH2]CCl.[CH2]F", 3));

    RGroupQuery query = new RGroupQuery(bldr);
    query.setRootStructure(root);
    query.setRootAttachmentPoints(rootAttach);
    query.setRGroupDefinitions(rgrpMap);

    SmilesGenerator smigen = new SmilesGenerator(SmiFlavor.Isomeric);
    for (IAtomContainer mol : query.getAllConfigurations()) {
        System.out.println(smigen.create(mol));
    }
}

private static IAtom selectAtom(IAtomContainer mol, String label) {
    for (IAtom atom : mol.atoms()) {
        if (atom instanceof IPseudoAtom && label.equals(((IPseudoAtom) atom).getLabel()))
            return atom;
    }
    return null;
}

private static IBond selectBond(IAtomContainer mol, IAtom atom) {
    List<IBond> bonds = mol.getConnectedBondsList(atom);
    if (bonds.size() != 1)
        throw new IllegalArgumentException();
    return bonds.get(0);
}

private static RGroup newRGroup(IAtomContainer mol) {
    RGroup rGroup = new RGroup();
    rGroup.setGroup(mol);
    rGroup.setFirstAttachmentPoint(mol.getAtom(0));
    return rGroup;
}

private static List<RGroup> load(String smi) throws InvalidSmilesException {
    SmilesParser smipar = new SmilesParser(SilentChemObjectBuilder.getInstance());
    IAtomContainer tmp = smipar.parseSmiles(smi);
    return StreamSupport.stream(ConnectivityChecker.partitionIntoMolecules(tmp)
                                                   .atomContainers()
                                                   .spliterator(), false)
                        .map(Main::newRGroup).collect(Collectors.toList());
}

private static RGroupList newRGroupList(String smi, int num) throws
                                                             CDKException {
    RGroupList rlist = new RGroupList(num, false, "1", 0);
    rlist.setRGroups(load(smi));
    return rlist;
}

private static void defineRgroup(IAtomContainer root,
                                 Map<IAtom, Map<Integer, IBond>> attach,
                                 Map<Integer, RGroupList> rgps,
                                 String label,
                                 RGroupList rGroupList) {
    attach.put(atom(root, label),
                   Collections.singletonMap(1, selectBond(root, atom(root, label))));
    rgps.put(rGroupList.getRGroupNumber(), rGroupList);
}

private static IAtom atom(IAtomContainer root, String label) {
    return selectAtom(root, label);
}