rBRICS_public.py

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# Created by Greg Landrum, Nov 2008
# Updated by Leili Zhang, Vasu Rao, Jul 2022

""" Implementation of the BRICS algorithm from Degen et al. ChemMedChem *3* 1503-7 (2008)
*** Unpublished manuscript by Zhang et al. *** (to be updated)

"""
from rdkit import Chem
from rdkit.Chem import rdChemReactions as Reactions
import sys,re,random

# 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]);!$([N;R]@[C;R]=O)]',
  'L51':'[N;!R;!D1;$(N(!@[N,O]))]', #Leili N-N, N-O, only breaks with carbon
  'L6':'[C;D3;!R](=O)-;!@[#0,#6,#7,#8]',
  'L7a':'[C;D2,D3]-[#6]',
  'L7b':'[C;D2,D3]-[#6]',
  '#L8':'[C;!R;!D1]-;!@[#6]', #Original L8
  '##L8':'[C;!R;!D1;!$(C!-*)]',
  'L8':'[C;!R;!D1;!$(C!-*);!$(C([H])([H])([H]))]',  #Leili fixed a problem when Hs are explicit
  'L81':'[C;!R;!D1;$(C(-[C,N,O,S])(=[N,S]))]', #Leili amidine group
  #'L82':'[C;!R;!D1;$(C(-NH2)(=[O]))]', #Leili terminal COCH2, only for long chains
  'L9':'[RN,n;+0;$([RN,n](@[RC,RN,RO,RS,c,n,o,s])@[RC,RN,RO,RS,c,n,o,s])]', #Leili generalized ring
  '#L9':'[n;+0;$(n(:[c,n,o,s]):[c,n,o,s])]', #Original L9
  'L10':'[N;R;$(N(@C(=O))@[C,N,O,S])]',
  'L11':'[S;D2](-;!@[#0,#6])',
  'L12':'[S;D4]([#6,#0])(=O)(=O)',
  'L12b':'[S;D4;!R](!@O)(!@O)', #Leili, PDB-SMI conversion issue
  'L13':'[C;$(C(-;@[C,N,O,S])-;@[N,O,S])]',
  'L14':'[c;$(c(:[c,n,o,s]):[n,o,s])]',
  'L14b':'[RC;$([RC](@[RC,RN,RO,RS])@[RN,RO,RS])]', #Leili generalized ring
  'L15':'[C;$(C(-;@C)-;@C)]',
  'L16':'[c;$(c(:c):c)]',
  'L16b':'[RC;$([RC](@[RC])@[RC])]', #Leili generalized ring

  # Our Proposed Environments, by Zhang and Rao

  'L17':'[C](-C)(-C)(-C)', #Aliphatic 1 - isobutyl/isopropyl
  'L18':'[R!#1;x3]', #Ring 1
  'L19':'[R!#1;x2]', #Ring 2
  'L182':'[R!#1;x3]', #Ring 1b double bond - for assembly
  'L192':'[R!#1;x2]', #Ring 2b double bond - for assembly
  'L20':'[CH2][CH2][CH2][CH3,RC,c,$(C(~[!#6]))]', #Aliphatic 2 - butyl, v2
  'L21':'[CH2][CH2][CH2][CH2][CH3,RC,c,$(C(~[!#6]))]', #Aliphatic 3 - butyl-CH3 or butyl-ring C or butyl-C-X, v2
  'L22':'[CH2][CH2][CH2][CH2][CH2][CH2][CH2][CH3,RC,c,$(C(~[!#6]))]', #Aliphatic 4 - octanyl, v2
  'L23':'[CH2][CH2][CH2][CH2][CH2][CH2][CH2][CH2][CH3,RC,c,$(C(~[!#6]))]', #Aliphatic 5 - octanyl-CH3 or octanyl-ring C or octonyl-C-X, v2
  'L30':'[C;D2]([#0,#6,#7,#8,#16])(#[N,C])' #C#N C#C
  #'L51':'[N;!R;!D1;$(N(!@[N,O]))]', #duplication for record
  #'L81':'[C;!R;!D1;$(C(-[C,N,O,S])(=[N,S]))]', #duplication for record
    
  }
reactionDefs = (
  # L1
  [
    ('1','3','-'),
    ('1','5','-'),
    ('1','10','-'),
  ],

  # L30
  [
    ('30','30','-'),
    ('30','4','-'),
    ('30','5','-'),
    ('30','51','-'),
    ('30','6','-'),
    ('30','81','-'),
    ('30','9','-'),
    ('30','10','-'),
    ('30','11','-'),
    ('30','12','-'),
    ('30','12b','-'),
    ('30','13','-'),
    ('30','14','-'),
    ('30','14b','-'),
    ('30','15','-'),
    ('30','16','-'),
    ('30','16b','-'),
  ],
   # 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','-'),
   ],

   # L51 Leili
   [
    ('51','1','-'),
    ('51','4','-'),
    ('51','12','-'),
    ('51','12b','-'),
    ('51','14','-'),
    ('51','16','-'),
    ('51','13','-'),
    ('51','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','-'),
    ],
    
    # L81 Leili
    [
    ('81','8','-'),
    ('81','9','-'),
    ('81','10','-'),
    ('81','13','-'),
    ('81','14','-'),
    ('81','15','-'),
    ('81','16','-'),
    ],
  
    # L9
    [
    ('9','13','-'),# not in Degen paper
    ('9','14','-'),# not in Degen 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
    # L12b Leili
    [
    ('12b','12b','-'),
    ('12b','5','-'),
    ('12b','4','-'),
    ('12b','13','-'),
    ('12b','14','-'),
    ('12b','15','-'),
    ('12b','16','-'),
    ],
    # L13
    [
    ('13','14','-;@,!@'),
    ('13','15','-;!@'),
    ('13','16','-;@,!@'),
    ],
  
    # L14
    [
    ('14','14','-;@,!@'),
    ('14','15','-;@,!@'),
    ('14','16','-;@,!@'),
    ],
  
    # L14b
    [
    ('3','14b','-'),
    ('5','14b','-'),
    ('51','14b','-'),
    ('6','14b','-'),
    ('8','14b','-'),
    ('81','14b','-'),
    ('9','14b','-'),
    ('10','14b','-'),
    ('11','14b','-'),
    ('12b','14b','-'),
    ('13','14b','-'),
    ('14','14b','-'),
    ('14b','14b','-'),
    ('14b','16','-'),
    ('14b','16b','-'),   
    ('14b','15','-'),
    ('14b','17','-'),
    ],

    # L15
    [
    ('15','16','-;@,!@'),
    ],

    # L16
    [
    ('16','16','-;@,!@'), # not in Degen paper
    ],
    
    # L16b
    
    [
    ('3','16b','-'),
    ('5','16b','-'),
    ('51','16b','-'),
    ('6','16b','-'),
    ('8','16b','-'),
    ('81','16b','-'),
    ('9','16b','-'),
    ('10','16b','-'),
    ('11','16b','-'),
    ('12b','16b','-'),
    ('13','16b','-'),
    ('15','16b','-'),
    ('16','16b','-'),
    ('16b','16b','-'),
    ('17','16b','-'),
    ],

    # L17 Vasu and Leili (17-21)
    [
      ('17','17','-'),
      ('17','16','-'),
      ('17','15','-'),
      ('17','14','-'),
      ('17','13','-'),
      ('17','12b','-'),
      ('17','12','-'),
      ('17','11','-'),
      ('17','10','-'),
      ('17','9','-'),
      ('17','8','-'),
      ('17','81','-'),
      ('17','51','-'),
      ('17','5','-'),
    ],
    #L18
    [
        ('18','19','-;@'),
        ('182','192','=;@'),
    ],

    #L20
    [
      ('20','21','-')
    ],
    #L22
    [
      ('22','23','-')
    ]
  )

reactionDefs_r = (
     [
       ('20','21','-')
     ],
  )

import copy
def init_reactions(environs,reactionDefs):
  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)
      if "@" not in bnd: #Leili
        #if 1 == 1:
        sma = '[$(%s):1]%s;!@[$(%s):2]>>[%s*]-[*:1].[%s*]-[*:2]' % (r1, bnd, r2, g1, g2)
      else:
        sma = '[$(%s):1]%s[$(%s):2]>>[%s*]-[*:1].[%s*]-[*:2]' % (r1, bnd, r2, g1, g2)
      gp[j] = sma
      #sma='[$(%s):1]%s;!@[$(%s):2]>>[%s*]-[*:1].[%s*]-[*:2]'%(r1,bnd,r2,g1,g2) #original
      #gp[j] =sma
    
  for gp in smartsGps:
    for defn in gp:
      try:
        t=Reactions.ReactionFromSmarts(defn)
        t.Initialize()
      except:
        print(defn)
        raise

  environMatchers={}
  for env,sma in environs.items():
    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]
      if "@" in bType: #Leili
        patt = '[$(%s)]%s[$(%s)]' % (e1, bType, e2)
      else:
        patt = '[$(%s)]%s;!@[$(%s)]' % (e1, bType, e2)
      #patt = '[$(%s)]%s;!@[$(%s)]'%(e1,bType,e2) #original
      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)
        
  return gp, environMatchers, bondMatchers, reactions, reverseReactions

gp, environMatchers, bondMatchers, reactions, reverseReactions = init_reactions(environs,reactionDefs)
gp_r, environMatchers_r, bondMatchers_r, reactions_r, reverseReactions_r = init_reactions(environs,reactionDefs_r)

def FindrBRICSBonds(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(FindrBRICSBonds(m))
  >>> res
  [((3, 2), ('3', '4')), ((3, 4), ('3', '4'))]

  a more complicated case:
  >>> m = Chem.MolFromSmiles('CCCOCCC(=O)c1ccccc1')
  >>> res = list(FindrBRICSBonds(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(FindrBRICSBonds(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 = FindrBRICSBonds(m)
  >>> res
  <generator object ...>
  >>> res.next()
  ((3, 2), ('3', '4'))

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

  envMatches={}
  for env,patt in environMatchers.items(): #Leili
    envMatches[env]=mol.HasSubstructMatch(patt)
  for gpIdx in indices:
    if randomizeOrder:
      compats =bondMatchers[gpIdx][:]
      random.shuffle(compats)
    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)))

#Leili
def FindreBRICSBonds(mol,randomizeOrder=False,silent=True):
  letter = re.compile('[a-z,A-Z]')
  indices = range(len(bondMatchers_r))
  bondsDone=set()
  if randomizeOrder: random.shuffle(indices)

  envMatches={}
  for env,patt in environMatchers_r.items(): #Leili
    envMatches[env]=mol.HasSubstructMatch(patt)
  for gpIdx in indices:
    if randomizeOrder:
      compats =bondMatchers_r[gpIdx][:]
      random.shuffle(compats)
    else:
      compats = bondMatchers_r[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 BreakrBRICSBonds(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=BreakrBRICSBonds(m)
  >>> Chem.MolToSmiles(m2,True)
  '[3*]O[3*].[4*]CC.[4*]CCC'

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


  can also specify a limited set of bonds to work with:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> m2 = BreakrBRICSBonds(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 BreakrBRICSBonds with a call to Chem.GetMolFrags:
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> m2=BreakrBRICSBonds(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 = FindrBRICSBonds(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 rBRICSDecompose(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(rBRICSDecompose(m))
  >>> sorted(res)
  ['[14*]c1ccccn1', '[16*]c1cccc([16*])c1', '[3*]O[3*]', '[4*]CCC', '[4*]C[8*]']

  >>> res = rBRICSDecompose(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(rBRICSDecompose(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(rBRICSDecompose(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(rBRICSDecompose(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(rBRICSDecompose(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(rBRICSDecompose(m,keepNonLeafNodes=True,minFragmentSize=2))
  >>> sorted(res)
  ['CCCOCC', '[3*]OCC', '[3*]OCCC', '[4*]CC', '[4*]CCC']
  >>> m = Chem.MolFromSmiles('CCCOCC')
  >>> res = list(rBRICSDecompose(m,keepNonLeafNodes=True,minFragmentSize=3))
  >>> sorted(res)
  ['CCCOCC', '[3*]OCC', '[4*]CCC']
  >>> res = list(rBRICSDecompose(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 = list(activePool.keys())[0]
      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
            prodSeq = [(prod.GetNumAtoms(onlyExplicit=True),prod) for prod in prodSeq]
            #print(prodSeq)
            prodSeq.sort(key=lambda y: y[0])
            for nats,prod in prodSeq:
              try:
                Chem.SanitizeMol(prod)
              except:
                seqOk=False #Issue 1
                continue
              pSmi = Chem.MolToSmiles(prod,1)
              if minFragmentSize>0:
                nDummies = pSmi.count('*')
                if nats-nDummies<minFragmentSize:
                  seqOk=False
                  break
              prod.pSmi = pSmi
            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)
  if scrambleReagents:
    tempReactions = list(reverseReactions)
    random.shuffle(tempReactions)
  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
  
#
#Leili
#Iteratively breaks all aliphatic chains using linkage L20-L21, just in case chain is too long and L20-L23 aren't enough
#Not the most efficient code yet
def reBRICS(fragments):
    oldfragments=fragments
    breakable=[1]*len(oldfragments)
    breakout=sum(breakable)
    iteri=0
    while breakout>0:
        iii=0
        newfrags=()
        newbreakable=[]
        for frag in oldfragments:
            heavy=frag.GetNumHeavyAtoms()
            if heavy > 5:
                if len(frag.GetSubstructMatch(Chem.MolFromSmiles("CCCCCC"))) > 0:
                    secondbonds=FindreBRICSBonds(frag)  #only breaks aliphatic chains
                    secondpieces=BreakrBRICSBonds(frag,secondbonds)
                    secondfrags=Chem.GetMolFrags(secondpieces,asMols=True)
                    if len(secondfrags) > 1:
                        newfrags=newfrags+secondfrags
                        newbreakable=newbreakable+[1]*len(secondfrags)
                    else:
                        newfrags=newfrags+secondfrags
                        newbreakable=newbreakable.append(0)  #1 frag->1 frag, no longer breakable, criteria #1
                else:
                    newfrags=newfrags+(frag,)
                    newbreakable.append(0)  #frag doesn't contain CCCCCC chain, no longer breakable, criteria #2
            else:
                newfrags=newfrags+(frag,)
                newbreakable.append(0)  #frag contains less than 5 heavy atoms, no longer breakable, criteria #3
            iii+=1
        oldfragments=newfrags
        breakable=newbreakable
        breakout=sum(newbreakable)
        iteri+=1
        if iteri > 100:  #more than 100 iterations, criteria #4
            print("Too many iterations. Not trying to break a polymer, are we? :)")
            breakout = 0
    return newfrags

# ------- ------- ------- ------- ------- ------- ------- -------
# 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 = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2)

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

      m = Chem.MolFromSmiles('c1ccccc1N(C)C')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2,res)

      m = Chem.MolFromSmiles('c1cccnc1N(C)C')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2,res)

      m = Chem.MolFromSmiles('o1ccnc1N(C)C')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2)

      m = Chem.MolFromSmiles('c1ccccc1OC')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2)

      m = Chem.MolFromSmiles('o1ccnc1OC')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2)

      m = Chem.MolFromSmiles('O1CCNC1OC')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==2)

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

      m = Chem.MolFromSmiles('CCNC(=O)C1CC1')
      res = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==4,res)
      self.failUnless('[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 = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(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 = rBRICSDecompose(m)
      self.failUnless(res)
      self.failUnless(len(res)==5,res)
      self.failUnless('[5*]N[5*]' in res,res)
      self.failUnless('[16*]c1ccccc1' in res,res)
      self.failUnless('[8*]C(F)(F)F' in res,res)


    def test4(self):
      allNodes = set()
      m = Chem.MolFromSmiles('c1ccccc1OCCC')
      res = rBRICSDecompose(m,allNodes=allNodes)
      self.failUnless(res)
      leaves=res
      self.failUnless(len(leaves)==3,leaves)
      self.failUnless(len(allNodes)==6,allNodes)
      res = rBRICSDecompose(m,allNodes=allNodes)
      self.failIf(res)
      self.failUnless(len(allNodes)==6,allNodes)

      m = Chem.MolFromSmiles('c1ccccc1OCCCC')
      res = rBRICSDecompose(m,allNodes=allNodes)
      self.failUnless(res)
      leaves.update(res)
      self.failUnless(len(allNodes)==9,allNodes)
      self.failUnless(len(leaves)==4,leaves)
      
      
      m = Chem.MolFromSmiles('c1cc(C(=O)NCC)ccc1OCCC')
      res = rBRICSDecompose(m,allNodes=allNodes)
      self.failUnless(res)
      leaves.update(res)
      self.failUnless(len(leaves)==8,leaves)
      self.failUnless(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.failUnless(res)
      res= list(res)
      self.failUnless(len(res)==6)
      smis = [Chem.MolToSmiles(x,True) for x in res]
      self.failUnless('c1ccc(-c2ccccc2)cc1' in smis)
      self.failUnless('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.failUnless(res)
      res=list(res)
      smis = [Chem.MolToSmiles(x,True) for x in res]
      self.failUnless(len(smis)==2,smis)
      self.failUnless('c1ccc(Oc2ccccc2)cc1' in smis)
      self.failUnless('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.failUnless(res)
      res= list(res)
      self.failUnless(len(res)==3)
      smis = [Chem.MolToSmiles(x,True) for x in res]
      self.failUnless('c1ccc(-c2ccccc2)cc1' in smis)
      self.failUnless('COc1ccccc1' in smis)
      self.failUnless('c1ccn(-c2ccccc2)c1' in 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.failUnless(res)
      res= list(res)
      smis = [Chem.MolToSmiles(x,True) for x in res]
      self.failUnless(len(res)==3)
      self.failUnless('c1ccc(-c2ccccc2)cc1' in smis)
      self.failUnless('COc1ccccc1' in smis)
      self.failUnless('O=C(COc1ccccc1)c1ccccc1' in smis)

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

      
      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.failUnless(t in ms,(t,ms))
        
    def test9(self):
      m = Chem.MolFromSmiles('CCOc1ccccc1c1ncc(c2nc(NCCCC)ncn2)cc1')
      res=rBRICSDecompose(m)
      self.failUnlessEqual(len(res),7)
      self.failUnless('[3*]O[3*]' in res)
      self.failIf('[14*]c1ncnc(NCCCC)n1' in res)
      res = rBRICSDecompose(m,singlePass=True)
      self.failUnlessEqual(len(res),13)
      self.failUnless('[3*]OCC' in res)
      self.failUnless('[14*]c1ncnc(NCCCC)n1' in res)

    def test10(self):
      m = Chem.MolFromSmiles('C1CCCCN1c1ccccc1')
      res=rBRICSDecompose(m)
      self.failUnlessEqual(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 = BreakrBRICSBonds(m)

      frags = Chem.GetMolFrags(pieces,asMols=True)
      self.failUnlessEqual(len(frags),3)
      self.failUnlessEqual(frags[0].GetNumAtoms(),7)
      self.failUnlessEqual(frags[1].GetNumAtoms(),3)
      self.failUnlessEqual(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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.failUnlessEqual((p1-p2).Length(),0.0)

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

      c2 = frags[1].GetConformer()
      for i in range(1):
        p1 = c1.GetAtomPosition(i+6)
        p2 = c2.GetAtomPosition(i)
        self.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.failUnlessEqual((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.failUnlessEqual(m.GetNumConformers(),2)

      pieces = BreakrBRICSBonds(m)
      frags = Chem.GetMolFrags(pieces,asMols=True)
      self.failUnlessEqual(len(frags),3)
      self.failUnlessEqual(frags[0].GetNumAtoms(),7)
      self.failUnlessEqual(frags[1].GetNumAtoms(),3)
      self.failUnlessEqual(frags[2].GetNumAtoms(),7)
      self.failUnlessEqual(frags[0].GetNumConformers(),2)
      self.failUnlessEqual(frags[1].GetNumConformers(),2)
      self.failUnlessEqual(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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.failUnlessEqual((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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.failUnlessEqual((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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.failUnlessEqual((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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.failUnlessEqual((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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(6)
      self.failUnlessEqual((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.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(5)
      p2 = c2.GetAtomPosition(1)
      self.failUnlessEqual((p1-p2).Length(),0.0)
      p1 = c1.GetAtomPosition(6)
      p2 = c2.GetAtomPosition(0)
      self.failUnlessEqual((p1-p2).Length(),0.0)

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


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

  unittest.main()