Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][CH:13]2[CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])=[CH:8][CH:7]=1)([OH:5])[CH3:4].I([O-])(=O)(=O)=[O:37].[Na+]>CCOC(C)=O.O.O.O=[Ru]=O>[CH3:33][C@@H:28]1[N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[C:32](=[O:37])[CH2:31][O:30][CH2:29]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H]1COCCN1CC1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1COCC(=O)N1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A solution of (2S)-1,1,1-trifluoro-2-(4-(2-(((R)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (50 mg, 0.094 mmol, Example 45, peak 2) in EtOAc (1 mL) was added to a mixture of dioxoruthenium hydrate (1.42 mg, 9.37 μmol, Sigma Aldrich, St. Louis, Mo.) and 10% aqueous sodium periodate (30.1 mg, 0.141 mmol, Sigma Aldrich, St. Louis, Mo.) in water (1.5 mL). The solution was stirred vigorously for 48 hours at room temperature. The reaction mixture was then concentrated in a GeneVac HT-12 (GeneVac Technologies, IPS Technologies, UK), re-dissolved in MeOH (1.5 mL), filtered through syringe filters (Pall Life Sciences, Acrodic®, 25 mm Syringe Filter w/0.45 μm HT Tuffryn® Membrane) and purified on Prep HPLC (Method: 10 min, 10 to 90% ACN, Water, 0.1% TFA, 254 nm; Column: Phenomenex, Gemini-NX, 5μ, C18, 150×30.00 mm) to afford (S)-5-methyl-4-(((S)-4-(thiophen-2-ylsulfonyl)-1-(4-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)morpholin-3-one (12.6 mg).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:22]([Cl:25])(=O)C>CO>[ClH:25].[CH3:22][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1
Reactant: CC(=O)Cl
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: CO
Product: COC(=O)CC(N)c1ccc(OC(F)F)c(OCC2CC2)c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
To a stirred suspension of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (500 mg, 1.7 mmol) in methanol (10 ml) was added dropwise acetyl chloride (0.3 ml, 4.3 mmol) under nitrogen atmosphere at 0° C. After the addition, the mixture was stirred at 0° C. for 15 min and the ice bath was removed. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The resulted solid was stirred with ether (30 ml) for 2 hours. The suspension was filtered to give 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester HCl salt as a white solid (540 mg, 90%). 1H NMR (DMSO-d6): δ 0.30-0.36 (m, 2H), 0.54-0.61 (m, 2H), 1.22-1.32 (m, 1H), 3.01-3.10 (m, 1H), 3.56 (s, 3H), 3.89 (d, J=7.5 Hz, 2H), 4.53-4.63 (m, 1H), 7.04 (d, J=7.5 Hz, 1H), 7.09 (t, JH-F=75 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.39 (s, 1H), 8.55 (broad, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13][CH2:11][CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(C)c1ccc(Cl)nc1
Reaction time: 8 h
Yield: 80 %

Procedure:
6-chloro-3-acetylpyridine (1.03 g, 0.3 mmol) and a 30% ethylamine-methanol solution (1.0 mL) were mixed with 8 mL of chloroform, and the mixture was subjected to refluxing. After 8 hours, 1 mL of 30% ethylamine-methanol solution was added and stirring was continued for 12 hours at the same temperature. The chloroform was distilled off and the residue was dissolved in 10 mL of methanol, then ice-cooled. Sodium borohydride (1 g) was added a little at a time, and the system was stirred overnight. The methanol was distilled off, and the residue was extracted with acetonitrile. The extract was then concentrated under reduced pressure. Acetonitrile extraction and concentration under reduced pressure were each repeated another two times, following which the residue was dissolved in chloroform, washed with 1% aqueous NaOH, and the chloroform phase was dried over solid KOH. The chloroform was distilled off under reduced pressure, giving 790 mg of crude N-[1-(6-chloro-3-pyridyl)ethyl]-N-ethylamine product (purity, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@H:10]([CH2:19][OH:20])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([CH3:26])=[CH2:25].C([O-])([O-])=O.[K+].[K+].[I:33]I>CC#N.CCOC(C)=O.CCCCCC>[CH2:1]([O:8][C:9]([CH:10]1[CH2:19][O:20][C:24]([CH2:23][I:33])([CH3:25])[CH2:26][N:11]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H](CO)NCc1ccccc1
Reactant: C=C(C)CBr
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(CI)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of N-benzyl-serine benzyl ester (Intermediate 16, 6.35 g) in 90 ml of MeCN at ambient temperature was added 3-bromo-2-methyl-propene (5.6 ml), KI (740 mg) and K2CO3 (7.7 g). The reaction mixture was stirred at ambient temperature for 72 hrs. 1 ml of 3-bromo-2-methyl-propene was added and the reaction mixture was stirred for another 15 hrs. Only a small amount of starting material remained based on TLC (1:1; EtOAc-hexane). To the resulting mixture was added 11.2 g of iodine. After 4 hrs of stirring, TLC (10% EtOAc/hexane) showed complete conversion. The reaction mixture was partitioned into ether (300 ml) and 0.5 M Na2S2O3 (100 ml). The separated organic phase was washed successively with water, saturated NaHCO3 and brine, dried over MgSO4, and concentrated to dryness. The residue was purified on silica (5% EtOAc/Hexane) to give 6.65 g (yellowish oil, 64% yield, about 4:1 mixture) of compound 4-benzyl-6-iodomethyl-6-methyl-morpholine-3-carboxylic acid benzyl ester. Major Component: 1H-NMR (300 MHz, CDCl3): δ 1.22 (s, 3H), 2.50 (d, 1H), 3.16-3.36 (m, 3H), 3.75-3.95 (m, 4H), 4.06 (dd, 1H), 5.16 (d, 1H), 5.21 (d, 1H), 7.28-7.36 (m, 10H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH2:31][NH:33][C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Reactant: Nc1cccnc1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(CNc6cccnc6)o5)cc34)cc2)cc1

Procedure:
In an analogous manner to Example 1, 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde and 3-aminopyridine were converted into the title compound; δH [2H6]-DMSO 10.42 (1H, b), 9.08 (1H, s), 8.69 (1H, s), 8.55 (1H, s), 8.09 (1H, d), 7.79 (1H, d), 7.70 (2H, d), 7.52−7.27 (5H, m), 7.16−6.99 (5H, m), 6.52 (2H, m), 5.11 (2H, s), 4.42 (2H, d); m/z 501 (M+1)+.
Reaction SMILES: C([C@@:9]1([OH:34])[C@@H:13]([CH:14](C(=O)C2C=CC=CC=2)[OH:15])[O:12][C@@H:11]([N:24]2[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]2=[O:26])[C@@:10]1([F:33])[CH3:32])(=O)C1C=CC=CC=1.N>CO>[F:33][C@:10]1([CH3:32])[C@H:9]([OH:34])[C@@H:13]([CH2:14][OH:15])[O:12][C@H:11]1[N:24]1[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Agent: N
Solvent: CO
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][OH:14])=[CH:5][NH:6]2.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][NH:6]2
Reactant: Cc1ccc(Br)c2c(CCO)c[nH]c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of 2-(4-bromo-7-methyl-1H-indol-3-yl)-ethanol (2.51 g, 9.89 mmol), imidazole (1.68 g, 24.7 mmol) and tert-butyldimethylsilyl chloride (1.79 g, 11.9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL). The organic solution was washed with H2O (5×200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to give 3.49 g (96%) of title compound as yellow oil. 1H NMR (CDCl3): 300 MHz δ 8.14 (bs, 1H), 7.11 (d, J=7.59 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J=7.59 Hz, 1H), 3.90 (t, J=7.17 Hz, 2H), 3.19 (t, J=7.17 Hz, 2H), 2.31 (s, 3H), 0.87 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=O)N.C(O)C.[C:17](#[N:20])[CH:18]=C>O.C(O)(=O)C>[C:17]([CH2:18][CH2:3][S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)#[N:20]
Reactant: NC(=O)SCc1csc(=O)[nH]1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: N#CCCSCc1csc(=O)[nH]1
Reaction time: 0.08 h
Yield: 76.2 %

Procedure:
60 ml (0.60 mol) of 10N sodium hydroxide solution are added dropwise to a suspension containing 57 g (0.30 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone [compound of the formula (Ib)] in 150 ml of water and 90 ml of ethanol under stirring while bubbling an inert gas through the mixture. After 5 minutes, 17.5 g (0.33 mol) of acrylnitrile are added dropwise to the resulting solution at 25° to 30° C. The mixture is stirred for an additional 4 hours, then filtered to obtain a sharply clear solution which is then acidified by adding 27 ml of glacial acetic acid. The crystalline precipitate is filtered off at 15° to 20° C., washed with water and then with isopropanol and dried to give 45.8 g (76.5%) of the named compound, m.p.: 108°-111° C. The active ingredient content of the substance is 99.6%.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCCC1>[C:18]([O:17][C:15]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC2O. The mixture was stirred for about 16 h at 22° C. and 100 mL of water was added. The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was further converted to 2d in a manner analogous to Method B.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C)C=O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([O:9][CH2:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: OCC1CC2CCC1C2
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC2CC3CCC2C3)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 2-norbornane methanol (1.3 g, 10.3 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (450 mg, 11.33 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warned to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.58 g, 11.33 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) yielded 986 mg of 2-fluoro-5-(bicyclo[2.2.1]hept-2-ylmethoxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:28]=1[CH:29]([OH:32])[CH2:30]Cl>C(#N)C1C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:30][CH:29]([OH:32])[C:28]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:27]=2[Cl:26])[CH:7]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: OC(CCl)c1ccc(Cl)cc1Cl
Solvent: N#Cc1ccccc1
Product: OC(Cn1cc[n+](CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1)c1ccc(Cl)cc1Cl
Product: [Cl-]

Procedure:
4.2 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)-phenethyl]imidazole and 3 parts of 2,4-dichloro-α-(chloromethyl)-benzyl alcohol are mixed together in 40 parts of benzonitrile and the resulting mixture is stirred at reflux temperature for 3 days. At the end of this period the reaction solvent is evaporated off under reduced pressure to obtain a 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-3-(2,4-dichloro-β-hydroxyphenethyl)imidazolium chloride product as residue.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39]I)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:34][CH:35]=1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Temperature: 65 °C
Yield: 10 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500 mg, 1.2 mmol, 1 equiv), 1-(4-fluorophenyl)-4-iodobutan-1-one (351.1 mg, 1.2 mmol, 1 equiv), and potassium carbonate (497.6 mg, 3.6 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude was purified using preparatory thin layer chromatography in 10% methanol in dichloromethane followed by a purification using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a yellow powder (65 mg, ˜10%); 1H NMR (400 MHz, DMSO-d6): δ 1.58 (d, 2H, J=14 Hz), 1.81-1.88 (m, 2H); 2.39-2.47 (m, 4H); 2.67-2.75 (m, 4H); 3.04 (t, 2H, J=6.4 and 7.2 Hz); 3.84 (s, 3H); 4.57 (s, 2H); 4.61 (s, 2H); 6.74-6.77 (m, 3H); 7.14-7.18 (m, 2H); 7.32-7.37 (m, 2H); 7.52-7.58 (m, 2H); 7.88-7.90 (m, 2H); 8.05-8.08 (m, 2H); 10.82 (s, 1H); MS for C32H34FN3O4 m/z 544.02 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 42.6 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 38 parts of 1-(diphenylmethyl)piperazine, 48 parts of sodium carbonate and 400 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>>[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][NH:11]2
Reactant: CN(C)C=O
Reactant: Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N,N-dimethylformamide (6 ml) and phosphorus oxychloride (1.78 g) was stirred at room temperature for 30 minutes. 4-Methylindole (1.0 g) was added to the reaction solution, followed by stirring at room temperature for one hour. A 5N aqueous solution of sodium hydroxide (15 ml) was added thereto, followed by stirring at 100° C. for further 30 minutes. The reaction solution was cooled, and the precipitated crystals were collected by filtration to give 4-methylindole-3-carboxaldehyde (Compound III-1, 1.14 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[N+:33]([C:36]([CH3:41])([CH2:39]O)[CH2:37][OH:38])([O-:35])=[O:34]>C(Cl)Cl.C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:39][C:36]([CH3:41])([N+:33]([O-:35])=[O:34])[CH2:37][OH:38])=[O:30])[CH:22]=[CH:21]2
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)[N+](=O)[O-])ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9 mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) in CH2Cl2 (50 mL) and THF (50 mL) was stirred at ambient temperature overnight. The solvent was evaporated and EtOAc (100 mL) was added to the resulting crude material, cooled in a dry-ice bath and the byproduct, dicyclohexyl urea was removed by filtration. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture of diasteromers) as an oil (2.77 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 7.69-7.60 (m, 3H), 7.34-7.3 (m, 1H), 7.14-7.08 (m, 2H), 4.44 (d, J=4.2 Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d, J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.14, 174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87, 125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04, 18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[N:28]([CH3:30])[CH:27]=[CH:26]3)=[CH:6]1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:58]>CCOC(C)=O.O>[Br:58][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[N:28]([CH3:30])[CH:27]=[CH:26]3)=[CH:6]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCCBr)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-[1-(3-hydroxypropyl)-6-methoxy-1H-indol-3-yl]-4-(1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione (3.0 g, 7.0 mmol) in solution of DMF (300 mL) was added PPh3 (2.6 g, 10.5 mmol) and CBr4 (3.3 g, 10.5 mmol). The reaction mixture was stirred at room temperature and under nitrogen for 1 h. The reaction was monitored by TLC and was completed after 2 h. The reaction mixture was diluted with EtOAc (300 mL) and water (800 mL). The aqueous phase was extracted with EtOAc (3×300 ml). The combined organic phases were washed with saturated aq NaHCO3 (300 mL), brine (500 mL) dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (2.4 g, 71%) as a red solid. 1H NMR (300 MHz, DMSO-d6) 11.04 (s, 1H), 7.88 (s, 1H), 7.62 (d, J=6.1 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.00–6.91 (m, 2H), 6.84 (d, J=6.0 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 6.10 (m, 2H), 4.27 (t, J=5.8 Hz, 2H), 3.71 (s, 3H), 3.62 (s, 3H), 3.32 (t, J=5.8 Hz, 2H), 2.11 (m, 2H). MS (electrospray, m/z) 492.1/494.1 (M++1), 490.2/492.2 (M−−1).