Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.C(O)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of ethanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.5 parts of 1,4-diaminoanthraquinone-2-carboxylic acid. Recrystallisation from alcohol yields an analytically pure sample with a melting point of about 352° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.O[Li].O.OO>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Cc1cccc(N)c1O
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-methylphenol (0.74 g, 6.0 mmol) and 4-bromophenyl isothiocyanate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 303 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21

Procedure:
A mixture of 4.00 g (14.9 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate (Via), 3.19 g (16.4 mmol) of tert-butyl bromoacetate and 7.28 g (22.3 mmol) of cesium carbonate in acetonitrile (80 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, the residue was mixed with water, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% ethyl acetate in dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH:21]=[O:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(C=O)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (2.90 g) and triethylamine (13.3 mL) in DMSO (45 mL) was added sulfur trioxide pyridine complex (6.08 g), and the mixture was stirred at room temperature for 10 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (2.69 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:11]1C(CCl)=CC=C(Cl)[N:12]=1>>[Cl:1][C:2]1[C:7]([CH2:8][NH:12][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: ClCc1cccnc1Cl
Product: CNCc1cccnc1Cl

Procedure:
The reaction according to Reference Example 11 was carried out using (2-chloro-3-pyridyl)methyl chloride in lieu of 2,6-dichloro-3-pyridylmethyl chloride to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][NH:77]1)([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][N:77]1[C:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:15][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[N:19]=3)[CH3:17])=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[Cl:1])=[O:13])([C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3C(c3ccccc3)c3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-benzhydryl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:5]2[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=[C:9]([CH:12]=O)[C:10]=2[CH:11]=1.OCC1N(S(C2C=CC=CC=2)(=O)=O)C2C(C=1)=C(C(F)(F)F)C=C(C=O)C=2.C([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)(OC(C)(C)C)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[C:21]1([S:18]([N:4]2[C:5]3[C:10](=[C:9]([CH2:12][N:60]4[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]4)[CH:8]=[C:7]([C:14]([F:17])([F:15])[F:16])[CH:6]=3)[CH:11]=[C:3]2[CH2:2][OH:1])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(C(F)(F)F)cc2c1cc(CO)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=Cc1cc(C(F)(F)F)c2cc(CO)n(S(=O)(=O)c3ccccc3)c2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(CO)cc2c(CN3CCNCC3)cc(C(F)(F)F)cc21

Procedure:
2-(Hydroxymethyl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-4-carbaldehyde and 2-(Hydroxymethyl)-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole-6-carbaldehyde (Intermediates 71) in dry THF (8 mL), was distributed into two micro wave vials (47 mg, 0.12 mmol, in each), where after 1-BOC-piperazine (46 mg, 0.25 mmol), acetic acid (70 μL, 1.23 mmol) and NaB(OAc)3H (78 mg, 0.37 mmol) were added to each vial. The mixtures were irradiated with microwaves for 720 s at 130° C., filtered and concentrated. The residues were dissolved in MeOH (1.5 mL) and conc. HCl (0.5 mL) and irradiated using microwaves at 100° C. for 300 s, filtered and purified using preparative HPLC/UV (System A, 20-50% MeCN, 0.1% TFA). Concentration of fractions from the compound with shortest retention time gave 38 mg of [1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-indol-2-yl]methanol. Purification was performed by preparative HPLC/UV (System A, 20-50% MeCN, 0.1% NH4OAc). Concentration was followed by extraction using DCM (×2) and aq. Na2CO3/brine. The organic layers were combined, dried, filtered and concentrated to give 7 mg, 6% of a light yellow solid. HPLC purity 98% RT=1.59 min (System A, 10-97% MeCN over 3 minutes), 98% RT=1.35 min (System B, 10-97% MeCN over 3 minutes). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.37 (s, 4 H) 2.88 (t, J=4.71 Hz, 4 H) 3.60 (s, 2 H) 4.95 (s, 2 H) 6.82 (s, 1 H) 7.45 (t, J=7.85 Hz, 2 H) 7.49 (s, 1 H) 7.56 (t, J=7.54 Hz, 1 H) 7.85 (d, J=8.48 Hz, 2 H) 8.19 (s, 1H). 13C NMR (126 MHz, CHLOROFORM-D) δ ppm 45.97 (s, 2 C) 54.23 (s, 2 C) 58.43 (s, 1 C) 63.31 (s, 1 C) 109.04 (s, 1 C) 117.93 (s, 1 C) 121.88-127.09 (m, 1 C) 122.09 (s, 1 C) 124.91 (s, 2 C) 126.55 (s, 2 C) 129.49 (s, 2 C) 134.32 (s, 1 C) 135.61 (s, 1 C) 137.53 (s, 1 C) 138.15 (s, 1 C) 141.98 (s, 1 C). COSY, HSQC and HMBC were also run to confirm the structure. MS (ESI+) for C21H22F3N3O3S m/z 454 (M+H)+
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CO.N1C=CC=CC=1>[Br:1][C:10]1[CH:11]=[C:6]2[CH2:5][CH2:4][NH:3][C:7]2=[N:8][CH:9]=1
Reactant: c1cnc2c(c1)CCN2
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Brc1cnc2c(c1)CCN2
Yield: 84.7 %

Procedure:
A solution of Br2 (18.1 mL, 56.2 g, 0.351 mol) in dry CH2Cl2 (250 mL) was added dropwise over a period of 1 h 45 min to a stirred and cooled (−5° C.) solution of 2 (42.22 g, 0.351 mol) in dry CH2Cl2 (410 mL)-pyridine (40 mL). The yellow suspension was stirred at 0° C. for 45 min and poured into a mixture of saturated aqueous NaHCO3 (800 mL) and saturated aqueous Na2S2O3 (100 mL). Methanol (10 mL) was added and the lower organic layer was separated and dried over MgSO4. The aqueous layer was extracted with AcOEt:MeOH=99:1 (7×1000 mL). These extracts were also dried with MgSO4. The organic solutions were combined and concentrated to afford 5 (59.17 g, 85%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.07 (tt, J=8.4, 1.1 Hz, 2H), 3.64 (t, J=8.4 Hz, 2H), 4.47 (bs, 1H), 7.31 (m, 1H), 7.85 (dt, J=2.1, 0.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:42])[NH:25][C@H:26]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:49]1([CH3:72])[CH:54]=[CH:53][C:52]([S:55]([O:58][CH2:59][CH2:60]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C=O>[C:31]([O:30][C:28](=[O:29])[CH2:27][C@H:26]([NH:25][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:60][CH2:59][O:58][S:55]([C:52]2[CH:53]=[CH:54][C:49]([CH3:72])=[CH:50][CH:51]=2)(=[O:57])=[O:56])=[CH:37][CH:36]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]3CCCN(C(=O)CCC4CCN(C(=O)OC(C)(C)C)CC4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
270.0 mg (0.46 mmol) 4-(3-{(R)-3-[(S)-2-tert-butoxycarbonyl-1-(4-hydroxy-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 17.7 ml N,N-dimethylformamide. 449 mg (1.38 mmol) cesium carbonate and 255.3 mg (0.69 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 20 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 227 mg (63%) tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate which were purified by HPLC:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:58]=[CH:57][C:52]([O:53][CH2:54][CH2:55][OH:56])=[CH:51][C:50]=1[O:59][CH3:60]>CN(C=O)C>[OH:56][CH2:55][CH2:54][O:53][C:52]1[CH:57]=[CH:58][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:59][CH3:60])[CH:51]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: COc1cc(OCCO)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OCCO)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.8 mg, 0.035 mmol), TBTU (11.2 mg, 0.035 mmol) and ethyl-diisopropylamine (18.0 μL, 0.105 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to 2-(4-aminomethyl-3-methoxy-phenoxy)-ethanol (6.4 mg, 0.035 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless lyophilisate. LC-MS: tR=0.98 min, [M+1]+=402.16.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 34% yield: LCMS (ESI) m/z 450 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][C:12]#[C:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1>C(N(CC)CC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: CC#CN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 cm3 of 1-bromo-2,3,5-trifluorobenzene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 17.28 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 173 cm3 of triethylamine. After heating for 2 hours at a temperature in the region of 80° C., the reaction mixture is cooled to approximately 20° C., diluted with 100 cm3 of water and then extracted with 4 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 5 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution being carried out with ethyl acetate. Fractions 3 to 11 are combined and then concentrated under the above conditions. 18.4 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:6][CH:7]=2.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl.O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[C:3]1=[N:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:6][CH:7]=2
Reactant: CCOC(=O)CCl
Reactant: Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one (22.6 g), ethyl chloroacetate (13.5 g), potassium carbonate (15.2 g) and dimethylformamide (250 ml) is stirred at room temperature for one hour. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetate (26 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:21][CH3:22].[Cl-].[NH4+]>CN(C)C=O>[CH2:21]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[O:15])[CH3:22]
Reactant: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (1.3 g) obtained in Step F in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 340 mg) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added dropwise iodoethane (0.90 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[N:15]([CH2:38][CH3:39])[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)c3ncn(C)c32)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc2n1CC
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (example 1F, 5.046 g, 9.90 mmol) in DMF (49.5 mL) was added ethyl iodide (1.601 mL, 19.81 mmol) and cesium carbonate (6.45 g, 19.81 mmol). The reaction mixture was heated at 60° C. 60 min and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and vacuum filtered to remove cesium carbonate. Saturated aqueous sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with 10% lithium chloride (3×), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Crude product was carried forward.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:6][C:3]=1[CH2:4][OH:5].[C:23](=O)([O-])[O-:24].[K+].[K+].C(Cl)(Cl)=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:17]1([S:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:2]3[NH:1][C:23](=[O:24])[O:5][CH2:4][C:3]=3[CH:6]=2)=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(OCCCCS(=O)c2ccccc2)cc1CO
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
An amount of 4.2 gm (0.0133 mol) of 2-amino-5-(4-phenylsulfinylbutoxy)-benzyl alcohol [prepared from 2-nitro-5-(4-phenylsulfinyl-butoxy)-benzyl alcohol by catalytic hydrogenation] is dissolved in 150 ml of chloroform and mixed with 6.9 gm (0.05 mol) of potassium carbonate. Ten milliliters of a 20% solution of phosgene in toluene is slowly added dropwise to this mixture under stirring. After further stirring for two hours, the solution is washed with water and dried with sodium sulfate, and the solvents are distilled off in vacuo. The residue is recrystallized from ethyl acetate/cyclohexane.