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# Created by Greg Landrum, Nov 2008
""" Implementation of the BRICS algorithm from Degen et al. ChemMedChem *3* 1503-7 (2008)

"""
from __future__ import print_function
import sys, re, random
from rdkit import Chem
from rdkit.Chem import rdChemReactions as Reactions
from rdkit.six import iteritems, iterkeys, next
from rdkit.six.moves import range

# These are the definitions that will be applied to fragment molecules:
environs = {
  'L1': '[C;D3]([#0,#6,#7,#8])(=O)',
  #
  # After some discussion, the L2 definitions ("N.pl3" in the original
  # paper) have been removed and incorporated into a (almost) general
  # purpose amine definition in L5 ("N.sp3" in the paper).
  #
  # The problem is one of consistency.
  #    Based on the original definitions you should get the following
  #    fragmentations:
  #      C1CCCCC1NC(=O)C -> C1CCCCC1N[2*].[1*]C(=O)C
  #      c1ccccc1NC(=O)C -> c1ccccc1[16*].[2*]N[2*].[1*]C(=O)C
  #    This difference just didn't make sense to us. By switching to
  #    the unified definition we end up with:
  #      C1CCCCC1NC(=O)C -> C1CCCCC1[15*].[5*]N[5*].[1*]C(=O)C
  #      c1ccccc1NC(=O)C -> c1ccccc1[16*].[5*]N[5*].[1*]C(=O)C
  #
  #'L2':'[N;!R;!D1;!$(N=*)]-;!@[#0,#6]',
  # this one turned out to be too tricky to define above, so we set it off
  # in its own definition:
  #'L2a':'[N;D3;R;$(N(@[C;!$(C=*)])@[C;!$(C=*)])]',
  'L3': '[O;D2]-;!@[#0,#6,#1]',
  'L4': '[C;!D1;!$(C=*)]-;!@[#6]',
  #'L5':'[N;!D1;!$(N*!-*);!$(N=*);!$(N-[!C;!#0])]-[#0,C]',
  'L5': '[N;!D1;!$(N=*);!$(N-[!#6;!#16;!#0;!#1]);!$([N;R]@[C;R]=O)]',
  'L6': '[C;D3;!R](=O)-;!@[#0,#6,#7,#8]',
  'L7a': '[C;D2,D3]-[#6]',
  'L7b': '[C;D2,D3]-[#6]',
  '#L8': '[C;!R;!D1]-;!@[#6]',
  'L8': '[C;!R;!D1;!$(C!-*)]',
  'L9': '[n;+0;$(n(:[c,n,o,s]):[c,n,o,s])]',
  'L10': '[N;R;$(N(@C(=O))@[C,N,O,S])]',
  'L11': '[S;D2](-;!@[#0,#6])',
  'L12': '[S;D4]([#6,#0])(=O)(=O)',
  'L13': '[C;$(C(-;@[C,N,O,S])-;@[N,O,S])]',
  'L14': '[c;$(c(:[c,n,o,s]):[n,o,s])]',
  'L14b': '[c;$(c(:[c,n,o,s]):[n,o,s])]',
  'L15': '[C;$(C(-;@C)-;@C)]',
  'L16': '[c;$(c(:c):c)]',
  'L16b': '[c;$(c(:c):c)]',
}
reactionDefs = (
  # L1
  [
    ('1', '3', '-'),
    ('1', '5', '-'),
    ('1', '10', '-'),
  ],

  # L3 
  [
    ('3', '4', '-'),
    ('3', '13', '-'),
    ('3', '14', '-'),
    ('3', '15', '-'),
    ('3', '16', '-'),
  ],

  # L4
  [
    ('4', '5', '-'),
    ('4', '11', '-'),
  ],

  # L5
  [
    ('5', '12', '-'),
    ('5', '14', '-'),
    ('5', '16', '-'),
    ('5', '13', '-'),
    ('5', '15', '-'),
  ],

  # L6
  [
    ('6', '13', '-'),
    ('6', '14', '-'),
    ('6', '15', '-'),
    ('6', '16', '-'),
  ],

  # L7
  [
    ('7a', '7b', '='),
  ],

  # L8
  [
    ('8', '9', '-'),
    ('8', '10', '-'),
    ('8', '13', '-'),
    ('8', '14', '-'),
    ('8', '15', '-'),
    ('8', '16', '-'),
  ],

  # L9
  [
    ('9', '13', '-'),  # not in original paper
    ('9', '14', '-'),  # not in original paper
    ('9', '15', '-'),
    ('9', '16', '-'),
  ],

  # L10
  [
    ('10', '13', '-'),
    ('10', '14', '-'),
    ('10', '15', '-'),
    ('10', '16', '-'),
  ],

  # L11
  [
    ('11', '13', '-'),
    ('11', '14', '-'),
    ('11', '15', '-'),
    ('11', '16', '-'),
  ],

  # L12
  # none left

  # L13
  [
    ('13', '14', '-'),
    ('13', '15', '-'),
    ('13', '16', '-'),
  ],

  # L14
  [
    ('14', '14', '-'),  # not in original paper
    ('14', '15', '-'),
    ('14', '16', '-'),
  ],

  # L15
  [
    ('15', '16', '-'),
  ],

  # L16
  [
    ('16', '16', '-'),  # not in original paper
  ], )
import copy
smartsGps = copy.deepcopy(reactionDefs)
for gp in smartsGps:
  for j, defn in enumerate(gp):
    g1, g2, bnd = defn
    r1 = environs['L' + g1]
    r2 = environs['L' + g2]
    g1 = re.sub('[a-z,A-Z]', '', g1)
    g2 = re.sub('[a-z,A-Z]', '', g2)
    sma = '[$(%s):1]%s;!@[$(%s):2]>>[%s*]-[*:1].[%s*]-[*:2]' % (r1, bnd, r2, g1, g2)
    gp[j] = sma

for gp in smartsGps:
  for defn in gp:
    try:
      t = Reactions.ReactionFromSmarts(defn)
      t.Initialize()
    except Exception:
      print(defn)
      raise

environMatchers = {}
for env, sma in iteritems(environs):
  environMatchers[env] = Chem.MolFromSmarts(sma)

bondMatchers = []
for i, compats in enumerate(reactionDefs):
  tmp = []
  for i1, i2, bType in compats:
    e1 = environs['L%s' % i1]
    e2 = environs['L%s' % i2]
    patt = '[$(%s)]%s;!@[$(%s)]' % (e1, bType, e2)
    patt = Chem.MolFromSmarts(patt)
    tmp.append((i1, i2, bType, patt))
  bondMatchers.append(tmp)

reactions = tuple([[Reactions.ReactionFromSmarts(y) for y in x] for x in smartsGps])
reverseReactions = []
for i, rxnSet in enumerate(smartsGps):
  for j, sma in enumerate(rxnSet):
    rs, ps = sma.split('>>')
    sma = '%s>>%s' % (ps, rs)
    rxn = Reactions.ReactionFromSmarts(sma)
    labels = re.findall(r'\[([0-9]+?)\*\]', ps)
    rxn._matchers = [Chem.MolFromSmiles('[%s*]' % x) for x in labels]
    reverseReactions.append(rxn)


def FindBRICSBonds(mol, randomizeOrder=False, silent=True):
  """ returns the bonds in a molecule that BRICS would cleave

  >>> from rdkit import Chem
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> res = list(FindBRICSBonds(m))
  >>> res
  [((3, 2), ('3', '4')), ((3, 4), ('3', '4'))]

  a more complicated case:
  >>> m = Chem.MolFromSmiles('CCCOCCC(=O)c1ccccc1')
  >>> res = list(FindBRICSBonds(m))
  >>> res
  [((3, 2), ('3', '4')), ((3, 4), ('3', '4')), ((6, 8), ('6', '16'))]

  we can also randomize the order of the results:
  >>> random.seed(23)
  >>> res = list(FindBRICSBonds(m,randomizeOrder=True))
  >>> sorted(res)
  [((3, 2), ('3', '4')), ((3, 4), ('3', '4')), ((6, 8), ('6', '16'))]

  Note that this is a generator function :
  >>> res = FindBRICSBonds(m)
  >>> res
  <generator object ...>
  >>> next(res)
  ((3, 2), ('3', '4'))

  >>> m = Chem.MolFromSmiles('CC=CC')
  >>> res = list(FindBRICSBonds(m))
  >>> sorted(res)
  [((1, 2), ('7', '7'))]
  
  make sure we don't match ring bonds:
  >>> m = Chem.MolFromSmiles('O=C1NCCC1')
  >>> list(FindBRICSBonds(m))
  []
  
  another nice one, make sure environment 8 doesn't match something connected
  to a ring atom:
  >>> m = Chem.MolFromSmiles('CC1(C)CCCCC1')
  >>> list(FindBRICSBonds(m))
  []
  
  """
  letter = re.compile('[a-z,A-Z]')
  indices = list(range(len(bondMatchers)))
  bondsDone = set()
  if randomizeOrder:
    random.shuffle(indices, random=random.random)

  envMatches = {}
  for env, patt in iteritems(environMatchers):
    envMatches[env] = mol.HasSubstructMatch(patt)
  for gpIdx in indices:
    if randomizeOrder:
      compats = bondMatchers[gpIdx][:]
      random.shuffle(compats, random=random.random)
    else:
      compats = bondMatchers[gpIdx]
    for i1, i2, bType, patt in compats:
      if not envMatches['L' + i1] or not envMatches['L' + i2]:
        continue
      matches = mol.GetSubstructMatches(patt)
      i1 = letter.sub('', i1)
      i2 = letter.sub('', i2)
      for match in matches:
        if match not in bondsDone and (match[1], match[0]) not in bondsDone:
          bondsDone.add(match)
          yield (((match[0], match[1]), (i1, i2)))


def BreakBRICSBonds(mol, bonds=None, sanitize=True, silent=True):
  """ breaks the BRICS bonds in a molecule and returns the results

  >>> from rdkit import Chem
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> m2=BreakBRICSBonds(m)
  >>> Chem.MolToSmiles(m2,True)
  '[3*]O[3*].[4*]CC.[4*]CCC'

  a more complicated case:
  >>> m = Chem.MolFromSmiles('CCCOCCC(=O)c1ccccc1')
  >>> m2=BreakBRICSBonds(m)
  >>> Chem.MolToSmiles(m2,True)
  '[16*]c1ccccc1.[3*]O[3*].[4*]CCC.[4*]CCC([6*])=O'


  can also specify a limited set of bonds to work with:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> m2 = BreakBRICSBonds(m,[((3, 2), ('3', '4'))])
  >>> Chem.MolToSmiles(m2,True)
  '[3*]OCC.[4*]CCC'
  
  this can be used as an alternate approach for doing a BRICS decomposition by
  following BreakBRICSBonds with a call to Chem.GetMolFrags:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> m2=BreakBRICSBonds(m)
  >>> frags = Chem.GetMolFrags(m2,asMols=True)
  >>> [Chem.MolToSmiles(x,True) for x in frags]
  ['[4*]CCC', '[3*]O[3*]', '[4*]CC']

  """
  if not bonds:
    #bonds = FindBRICSBonds(mol)
    res = Chem.FragmentOnBRICSBonds(mol)
    if sanitize:
      Chem.SanitizeMol(res)
    return res
  eMol = Chem.EditableMol(mol)
  nAts = mol.GetNumAtoms()

  dummyPositions = []
  for indices, dummyTypes in bonds:
    ia, ib = indices
    obond = mol.GetBondBetweenAtoms(ia, ib)
    bondType = obond.GetBondType()
    eMol.RemoveBond(ia, ib)

    da, db = dummyTypes
    atoma = Chem.Atom(0)
    atoma.SetIsotope(int(da))
    atoma.SetNoImplicit(True)
    idxa = nAts
    nAts += 1
    eMol.AddAtom(atoma)
    eMol.AddBond(ia, idxa, bondType)

    atomb = Chem.Atom(0)
    atomb.SetIsotope(int(db))
    atomb.SetNoImplicit(True)
    idxb = nAts
    nAts += 1
    eMol.AddAtom(atomb)
    eMol.AddBond(ib, idxb, bondType)
    if mol.GetNumConformers():
      dummyPositions.append((idxa, ib))
      dummyPositions.append((idxb, ia))
  res = eMol.GetMol()
  if sanitize:
    Chem.SanitizeMol(res)
  if mol.GetNumConformers():
    for conf in mol.GetConformers():
      resConf = res.GetConformer(conf.GetId())
      for ia, pa in dummyPositions:
        resConf.SetAtomPosition(ia, conf.GetAtomPosition(pa))
  return res


def BRICSDecompose(mol, allNodes=None, minFragmentSize=1, onlyUseReactions=None, silent=True,
                   keepNonLeafNodes=False, singlePass=False, returnMols=False):
  """ returns the BRICS decomposition for a molecule

  >>> from rdkit import Chem
  >>> m = Chem.MolFromSmiles('CCCOCc1cc(c2ncccc2)ccc1')
  >>> res = list(BRICSDecompose(m))
  >>> sorted(res)
  ['[14*]c1ccccn1', '[16*]c1cccc([16*])c1', '[3*]O[3*]', '[4*]CCC', '[4*]C[8*]']

  >>> res = list(BRICSDecompose(m,returnMols=True))
  >>> res[0]
  <rdkit.Chem.rdchem.Mol object ...>
  >>> smis = [Chem.MolToSmiles(x,True) for x in res]
  >>> sorted(smis)
  ['[14*]c1ccccn1', '[16*]c1cccc([16*])c1', '[3*]O[3*]', '[4*]CCC', '[4*]C[8*]']

  nexavar, an example from the paper (corrected):
  >>> m = Chem.MolFromSmiles('CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1')
  >>> res = list(BRICSDecompose(m))
  >>> sorted(res)
  ['[1*]C([1*])=O', '[1*]C([6*])=O', '[14*]c1cc([16*])ccn1', '[16*]c1ccc(Cl)c([16*])c1', '[16*]c1ccc([16*])cc1', '[3*]O[3*]', '[5*]NC', '[5*]N[5*]', '[8*]C(F)(F)F']

  it's also possible to keep pieces that haven't been fully decomposed:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> res = list(BRICSDecompose(m,keepNonLeafNodes=True))
  >>> sorted(res)
  ['CCCOCC', '[3*]OCC', '[3*]OCCC', '[3*]O[3*]', '[4*]CC', '[4*]CCC']

  >>> m = Chem.MolFromSmiles('CCCOCc1cc(c2ncccc2)ccc1')
  >>> res = list(BRICSDecompose(m,keepNonLeafNodes=True))
  >>> sorted(res)
  ['CCCOCc1cccc(-c2ccccn2)c1', '[14*]c1ccccn1', '[16*]c1cccc(-c2ccccn2)c1', '[16*]c1cccc(COCCC)c1', '[16*]c1cccc([16*])c1', '[3*]OCCC', '[3*]OC[8*]', '[3*]OCc1cccc(-c2ccccn2)c1', '[3*]OCc1cccc([16*])c1', '[3*]O[3*]', '[4*]CCC', '[4*]C[8*]', '[4*]Cc1cccc(-c2ccccn2)c1', '[4*]Cc1cccc([16*])c1', '[8*]COCCC']

  or to only do a single pass of decomposition:
  >>> m = Chem.MolFromSmiles('CCCOCc1cc(c2ncccc2)ccc1')
  >>> res = list(BRICSDecompose(m,singlePass=True))
  >>> sorted(res)
  ['CCCOCc1cccc(-c2ccccn2)c1', '[14*]c1ccccn1', '[16*]c1cccc(-c2ccccn2)c1', '[16*]c1cccc(COCCC)c1', '[3*]OCCC', '[3*]OCc1cccc(-c2ccccn2)c1', '[4*]CCC', '[4*]Cc1cccc(-c2ccccn2)c1', '[8*]COCCC']

  setting a minimum size for the fragments:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> res = list(BRICSDecompose(m,keepNonLeafNodes=True,minFragmentSize=2))
  >>> sorted(res)
  ['CCCOCC', '[3*]OCC', '[3*]OCCC', '[4*]CC', '[4*]CCC']
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> res = list(BRICSDecompose(m,keepNonLeafNodes=True,minFragmentSize=3))
  >>> sorted(res)
  ['CCCOCC', '[3*]OCC', '[4*]CCC']
  >>> res = list(BRICSDecompose(m,minFragmentSize=2))
  >>> sorted(res)
  ['[3*]OCC', '[3*]OCCC', '[4*]CC', '[4*]CCC']


  """
  global reactions
  mSmi = Chem.MolToSmiles(mol, 1)

  if allNodes is None:
    allNodes = set()

  if mSmi in allNodes:
    return set()

  activePool = {mSmi: mol}
  allNodes.add(mSmi)
  foundMols = {mSmi: mol}
  for gpIdx, reactionGp in enumerate(reactions):
    newPool = {}
    while activePool:
      matched = False
      nSmi = next(iterkeys(activePool))
      mol = activePool.pop(nSmi)
      for rxnIdx, reaction in enumerate(reactionGp):
        if onlyUseReactions and (gpIdx, rxnIdx) not in onlyUseReactions:
          continue
        if not silent:
          print('--------')
          print(smartsGps[gpIdx][rxnIdx])
        ps = reaction.RunReactants((mol, ))
        if ps:
          if not silent:
            print(nSmi, '->', len(ps), 'products')
          for prodSeq in ps:
            seqOk = True
            # we want to disqualify small fragments, so sort the product sequence by size
            tSeq = [(prod.GetNumAtoms(onlyExplicit=True), idx) for idx, prod in enumerate(prodSeq)]
            tSeq.sort()
            for nats, idx in tSeq:
              prod = prodSeq[idx]
              try:
                Chem.SanitizeMol(prod)
              except Exception:
                continue
              pSmi = Chem.MolToSmiles(prod, 1)
              if minFragmentSize > 0:
                nDummies = pSmi.count('*')
                if nats - nDummies < minFragmentSize:
                  seqOk = False
                  break
              prod.pSmi = pSmi
            ts = [(x, prodSeq[y]) for x, y in tSeq]
            prodSeq = ts
            if seqOk:
              matched = True
              for nats, prod in prodSeq:
                pSmi = prod.pSmi
                #print('\t',nats,pSmi)
                if pSmi not in allNodes:
                  if not singlePass:
                    activePool[pSmi] = prod
                  allNodes.add(pSmi)
                  foundMols[pSmi] = prod
      if singlePass or keepNonLeafNodes or not matched:
        newPool[nSmi] = mol
    activePool = newPool
  if not (singlePass or keepNonLeafNodes):
    if not returnMols:
      res = set(activePool.keys())
    else:
      res = activePool.values()
  else:
    if not returnMols:
      res = allNodes
    else:
      res = foundMols.values()
  return res


import random
dummyPattern = Chem.MolFromSmiles('[*]')


def BRICSBuild(fragments, onlyCompleteMols=True, seeds=None, uniquify=True, scrambleReagents=True,
               maxDepth=3):
  seen = set()
  if not seeds:
    seeds = list(fragments)
  if scrambleReagents:
    seeds = list(seeds)
    random.shuffle(seeds, random=random.random)
  if scrambleReagents:
    tempReactions = list(reverseReactions)
    random.shuffle(tempReactions, random=random.random)
  else:
    tempReactions = reverseReactions
  for seed in seeds:
    seedIsR1 = False
    seedIsR2 = False
    nextSteps = []
    for rxn in tempReactions:
      if seed.HasSubstructMatch(rxn._matchers[0]):
        seedIsR1 = True
      if seed.HasSubstructMatch(rxn._matchers[1]):
        seedIsR2 = True
      for fragment in fragments:
        ps = None
        if fragment.HasSubstructMatch(rxn._matchers[0]):
          if seedIsR2:
            ps = rxn.RunReactants((fragment, seed))
        if fragment.HasSubstructMatch(rxn._matchers[1]):
          if seedIsR1:
            ps = rxn.RunReactants((seed, fragment))
        if ps:
          for p in ps:
            if uniquify:
              pSmi = Chem.MolToSmiles(p[0], True)
              if pSmi in seen:
                continue
              else:
                seen.add(pSmi)
            if p[0].HasSubstructMatch(dummyPattern):
              nextSteps.append(p[0])
              if not onlyCompleteMols:
                yield p[0]
            else:
              yield p[0]
    if nextSteps and maxDepth > 0:
      for p in BRICSBuild(fragments, onlyCompleteMols=onlyCompleteMols, seeds=nextSteps,
                          uniquify=uniquify, maxDepth=maxDepth - 1):
        if uniquify:
          pSmi = Chem.MolToSmiles(p, True)
          if pSmi in seen:
            continue
          else:
            seen.add(pSmi)
        yield p

  # ------- ------- ------- ------- ------- ------- ------- -------
  # Begin testing code


  #------------------------------------
  #
  #  doctest boilerplate
  #
def _test():
  import doctest, sys
  return doctest.testmod(sys.modules["__main__"],
                         optionflags=doctest.ELLIPSIS + doctest.NORMALIZE_WHITESPACE)


if __name__ == '__main__':
  import unittest

  class TestCase(unittest.TestCase):

    def test1(self):
      m = Chem.MolFromSmiles('CC(=O)OC')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2)

      m = Chem.MolFromSmiles('CC(=O)N1CCC1=O')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2, res)

      m = Chem.MolFromSmiles('c1ccccc1N(C)C')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2, res)

      m = Chem.MolFromSmiles('c1cccnc1N(C)C')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2, res)

      m = Chem.MolFromSmiles('o1ccnc1N(C)C')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2)

      m = Chem.MolFromSmiles('c1ccccc1OC')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2)

      m = Chem.MolFromSmiles('o1ccnc1OC')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2)

      m = Chem.MolFromSmiles('O1CCNC1OC')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 2)

      m = Chem.MolFromSmiles('CCCSCC')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 3, res)
      self.assertTrue('[11*]S[11*]' in res, res)

      m = Chem.MolFromSmiles('CCNC(=O)C1CC1')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 4, res)
      self.assertTrue('[5*]N[5*]' in res, res)

    def test2(self):
      # example from the paper, nexavar:
      m = Chem.MolFromSmiles('CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 9, res)

    def test3(self):
      m = Chem.MolFromSmiles('FC(F)(F)C1=C(Cl)C=CC(NC(=O)NC2=CC=CC=C2)=C1')
      res = BRICSDecompose(m)
      self.assertTrue(res)
      self.assertTrue(len(res) == 5, res)
      self.assertTrue('[5*]N[5*]' in res, res)
      self.assertTrue('[16*]c1ccccc1' in res, res)
      self.assertTrue('[8*]C(F)(F)F' in res, res)

    def test4(self):
      allNodes = set()
      m = Chem.MolFromSmiles('c1ccccc1OCCC')
      res = BRICSDecompose(m, allNodes=allNodes)
      self.assertTrue(res)
      leaves = res
      self.assertTrue(len(leaves) == 3, leaves)
      self.assertTrue(len(allNodes) == 6, allNodes)
      res = BRICSDecompose(m, allNodes=allNodes)
      self.assertFalse(res)
      self.assertTrue(len(allNodes) == 6, allNodes)

      m = Chem.MolFromSmiles('c1ccccc1OCCCC')
      res = BRICSDecompose(m, allNodes=allNodes)
      self.assertTrue(res)
      leaves.update(res)
      self.assertTrue(len(allNodes) == 9, allNodes)
      self.assertTrue(len(leaves) == 4, leaves)

      m = Chem.MolFromSmiles('c1cc(C(=O)NCC)ccc1OCCC')
      res = BRICSDecompose(m, allNodes=allNodes)
      self.assertTrue(res)
      leaves.update(res)
      self.assertTrue(len(leaves) == 8, leaves)
      self.assertTrue(len(allNodes) == 18, allNodes)

    def test5(self):
      allNodes = set()
      frags = [
        '[14*]c1ncncn1',
        '[16*]c1ccccc1',
        '[14*]c1ncccc1',
      ]
      frags = [Chem.MolFromSmiles(x) for x in frags]
      res = BRICSBuild(frags)
      self.assertTrue(res)
      res = list(res)
      self.assertTrue(len(res) == 6)
      smis = [Chem.MolToSmiles(x, True) for x in res]
      self.assertTrue('c1ccc(-c2ccccc2)cc1' in smis)
      self.assertTrue('c1ccc(-c2ccccn2)cc1' in smis)

    def test5a(self):
      allNodes = set()
      frags = [
        '[3*]O[3*]',
        '[16*]c1ccccc1',
      ]
      frags = [Chem.MolFromSmiles(x) for x in frags]
      res = BRICSBuild(frags)
      self.assertTrue(res)
      res = list(res)
      smis = [Chem.MolToSmiles(x, True) for x in res]
      self.assertTrue(len(smis) == 2, smis)
      self.assertTrue('c1ccc(Oc2ccccc2)cc1' in smis)
      self.assertTrue('c1ccc(-c2ccccc2)cc1' in smis)

    def test6(self):
      allNodes = set()
      frags = [
        '[16*]c1ccccc1',
        '[3*]OC',
        '[9*]n1cccc1',
      ]
      frags = [Chem.MolFromSmiles(x) for x in frags]
      res = BRICSBuild(frags)
      self.assertTrue(res)
      res = list(res)
      self.assertTrue(len(res) == 3)
      smis = [Chem.MolToSmiles(x, True) for x in res]
      self.assertTrue('c1ccc(-c2ccccc2)cc1' in smis)
      self.assertTrue('COc1ccccc1' in smis)
      self.assertTrue('c1ccc(-n2cccc2)cc1' in smis, smis)

    def test7(self):
      allNodes = set()
      frags = [
        '[16*]c1ccccc1',
        '[3*]OC',
        '[3*]OCC(=O)[6*]',
      ]
      frags = [Chem.MolFromSmiles(x) for x in frags]
      res = BRICSBuild(frags)
      self.assertTrue(res)
      res = list(res)
      smis = [Chem.MolToSmiles(x, True) for x in res]
      self.assertTrue(len(res) == 3)
      self.assertTrue('c1ccc(-c2ccccc2)cc1' in smis)
      self.assertTrue('COc1ccccc1' in smis)
      self.assertTrue('O=C(COc1ccccc1)c1ccccc1' in smis)

    def test8(self):
      random.seed(23)
      base = Chem.MolFromSmiles("n1cncnc1OCC(C1CC1)OC1CNC1")
      catalog = BRICSDecompose(base)
      self.assertTrue(len(catalog) == 5, catalog)
      catalog = [Chem.MolFromSmiles(x) for x in catalog]
      ms = list(BRICSBuild(catalog, maxDepth=4))
      for m in ms:
        Chem.SanitizeMol(m)
      ms = [Chem.MolToSmiles(x) for x in ms]
      self.assertEqual(len(ms), 36)

      ts = ['n1cnc(C2CNC2)nc1', 'n1cnc(-c2ncncn2)nc1', 'C(OC1CNC1)C(C1CC1)OC1CNC1',
            'n1cnc(OC(COC2CNC2)C2CC2)nc1', 'n1cnc(OCC(OC2CNC2)C2CNC2)nc1']
      ts = [Chem.MolToSmiles(Chem.MolFromSmiles(x), True) for x in ts]
      for t in ts:
        self.assertTrue(t in ms, (t, ms))

    def test9(self):
      m = Chem.MolFromSmiles('CCOc1ccccc1c1ncc(c2nc(NCCCC)ncn2)cc1')
      res = BRICSDecompose(m)
      self.assertEqual(len(res), 7)
      self.assertTrue('[3*]O[3*]' in res)
      self.assertFalse('[14*]c1ncnc(NCCCC)n1' in res)
      res = BRICSDecompose(m, singlePass=True)
      self.assertEqual(len(res), 13)
      self.assertTrue('[3*]OCC' in res)
      self.assertTrue('[14*]c1ncnc(NCCCC)n1' in res)

    def test10(self):
      m = Chem.MolFromSmiles('C1CCCCN1c1ccccc1')
      res = BRICSDecompose(m)
      self.assertEqual(len(res), 2, res)

    def test11(self):
      # test coordinate preservation:
      molblock = """
     RDKit          3D

 13 14  0  0  0  0  0  0  0  0999 V2000
   -1.2004    0.5900    0.6110 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2328    1.3173    0.0343 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.4299    0.6533   -0.1500 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3633   -0.7217   -0.3299 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.1552   -1.3791   -0.2207 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.1425   -0.7969    0.5335 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1458   -1.4244    0.4108 O   0  0  0  0  0  0  0  0  0  0  0  0
    1.2976   -0.7398   -0.1026 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.4889   -0.7939    0.5501 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.4615    0.1460    0.3535 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.0116    1.4034   -0.0296 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.9786    1.4264   -0.9435 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.1399    0.3193   -0.9885 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  2  0
  2  3  1  0
  3  4  2  0
  4  5  1  0
  5  6  2  0
  6  7  1  0
  7  8  1  0
  8  9  2  0
  9 10  1  0
 10 11  2  0
 11 12  1  0
 12 13  2  0
  6  1  1  0
 13  8  1  0
M  END
"""
      m = Chem.MolFromMolBlock(molblock)
      pieces = BreakBRICSBonds(m)

      frags = Chem.GetMolFrags(pieces, asMols=True)
      self.assertEqual(len(frags), 3)
      self.assertEqual(frags[0].GetNumAtoms(), 7)
      self.assertEqual(frags[1].GetNumAtoms(), 3)
      self.assertEqual(frags[2].GetNumAtoms(), 7)

      c1 = m.GetConformer()
      c2 = frags[0].GetConformer()
      for i in range(6):
        p1 = c1.GetAtomPosition(i)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[2].GetConformer()
      for i in range(6):
        p1 = c1.GetAtomPosition(i + 7)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[1].GetConformer()
      for i in range(1):
        p1 = c1.GetAtomPosition(i + 6)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.assertEqual((p1 - p2).Length(), 0.0)

      # make sure multiple conformations (include 2D) also work:
      molblock = """
     RDKit          2D

 13 14  0  0  0  0  0  0  0  0999 V2000
   -1.2990   -0.8654    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.5981   -1.6154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.8971   -0.8654    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.8971    0.6346    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.5981    1.3846    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2990    0.6346    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.0000    1.3846    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990    0.6346    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990   -0.8654    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.5981   -1.6154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8971   -0.8654    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8971    0.6346    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.5981    1.3846    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  2  0
  2  3  1  0
  3  4  2  0
  4  5  1  0
  5  6  2  0
  6  7  1  0
  7  8  1  0
  8  9  2  0
  9 10  1  0
 10 11  2  0
 11 12  1  0
 12 13  2  0
  6  1  1  0
 13  8  1  0
M  END
"""
      m2 = Chem.MolFromMolBlock(molblock)
      m.AddConformer(m2.GetConformer(), assignId=True)
      self.assertEqual(m.GetNumConformers(), 2)

      pieces = BreakBRICSBonds(m)
      frags = Chem.GetMolFrags(pieces, asMols=True)
      self.assertEqual(len(frags), 3)
      self.assertEqual(frags[0].GetNumAtoms(), 7)
      self.assertEqual(frags[1].GetNumAtoms(), 3)
      self.assertEqual(frags[2].GetNumAtoms(), 7)
      self.assertEqual(frags[0].GetNumConformers(), 2)
      self.assertEqual(frags[1].GetNumConformers(), 2)
      self.assertEqual(frags[2].GetNumConformers(), 2)

      c1 = m.GetConformer(0)
      c2 = frags[0].GetConformer(0)
      for i in range(6):
        p1 = c1.GetAtomPosition(i)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[2].GetConformer(0)
      for i in range(6):
        p1 = c1.GetAtomPosition(i + 7)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[1].GetConformer(0)
      for i in range(1):
        p1 = c1.GetAtomPosition(i + 6)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c1 = m.GetConformer(1)
      c2 = frags[0].GetConformer(1)
      for i in range(6):
        p1 = c1.GetAtomPosition(i)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[2].GetConformer(1)
      for i in range(6):
        p1 = c1.GetAtomPosition(i + 7)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.assertEqual((p1 - p2).Length(), 0.0)

      c2 = frags[1].GetConformer(1)
      for i in range(1):
        p1 = c1.GetAtomPosition(i + 6)
        p2 = c2.GetAtomPosition(i)
        self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.assertEqual((p1 - p2).Length(), 0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.assertEqual((p1 - p2).Length(), 0.0)

    def test12(self):
      m = Chem.MolFromSmiles('CCS(=O)(=O)NCC')
      res = list(FindBRICSBonds(m))
      self.assertEqual(len(res), 2, res)
      atIds = [x[0] for x in res]
      atIds.sort()
      self.assertEqual(atIds, [(5, 2), (6, 5)])

  failed, tried = _test()
  if failed:
    sys.exit(failed)

  unittest.main()
