Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:26])[CH3:27])[CH:20]=4)[CH:16]=3)[CH:32]=[CH:33][C:6]=2[N:5]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
Potassium thiocyanate (4.80 g, 49.2 mmol) was suspended in acetic acid (80 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a is solution of N-[5-(4-aminophenoxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (5.00 g, 12.3 mmol) in acetic acid (80 mL), and the mixture was further stirred at room temperature for 20 min. To the obtained solution was added dropwise slowly a solution of bromine (2.46 g, 15.4 mmol) in acetic acid (50 mL) and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (300 mL) and saturated brine (300 mL), successively, and dried over anhydrous sodium sulfate. Activated carbon was added, and the mixture was stood for a while. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.57 g, 66%) as a pale-yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][CH2:26][O:27][CH3:28].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:25][CH2:26][O:27][CH3:28])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)ccc(OC)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 563.9 %

Procedure:
To a stirred solution of 500 mg (1.45 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole in 11 ml DMF, NaH (38 mg, 1.6 mmol) is added and stirring is continued for 1 h at RT, and then the reaction mixture is heated to 60° C. 0.152 ml (0.175 mmol) (2-bromoethyl)-methyl ether is added and stirring is continued at this temperature for another 6 h. The reaction mixture is cooled to room temperature, poured into water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 398 mg of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.ClCCl.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Yield: 67.4 %

Procedure:
tert-Butyl (3S)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidine-1-carboxylate (1 g), trifluoroacetic acid (10 ml) and dichloromethane (20 ml) were stirred at room temperature for one hour. The solvent was removed in vacuo to yield a dark brown oil. Water (20 ml) was added to this giving a milky solution and this was then basified to ˜pH 6 by addition of solid NaHCO3. This left a milky solution which was diluted with water (˜50 ml) before extracting with ethyl acetate (3×75 ml). The combined organics were washed with brine (˜100 ml) and separated then dried (MgSO4) before removing solvent in vacuo to yield the title compound (531 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of 3.4 g of ethyl 2-p-chlorophenyl-5-phenylthio-4-thiazoleacetate in 100 ml of methanol was added 15 ml of 3 N aqueous potassium hydroxide. The mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and water was added to the residue. The solution was acidified with hydrochloric acid. The white precipitated solid was filtered off, washed with water, dried and recrystallized from ethanol to give 2.3 g of the title compound, melting at 191°-193° C.
Reaction SMILES: I.[C:2](=[S:5])(S)[NH2:3].[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH2:16].[Na]>C(O)C>[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH:16][C:2]([NH:3][CH2:15][CH2:14][S:13][CH2:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:6])=[S:5]
Reactant: NC(=S)S
Reactant: Cc1nc[nH]c1CSCCN
Agent: I
Agent: [Na]
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C

Procedure:
A solution prepared from S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamate hydriodide (15.6 g.), 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (6.8 g.) in ethanol (200 ml.) containing sodium (0.9 g.) was heated under reflux for 8 hours. Concentration followed by chromatographic purification of the product on a column of silica gel with ethyl acetate-isopropyl alcohol (5:1) as eluant gave the title compound which was converted to the dihydrochloride (2.5g., m.p. 115°- 120° ) with ethanolic hydrogen chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].II.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[F:9][C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:18]1([CH2:21][OH:22])[CH:17]=[CH:16][N:15]=[CH:20][CH2:19]1)([F:11])[F:10]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccncc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OCC1(c2ccccc2C(F)(F)F)C=CN=CC1
Temperature: 0 °C

Procedure:
A solution of 4-bromobenzotrifluoride in 62 mL of THF was carefully added to a mixture of 1.9 grams (0.079 mole) of magnesium turnings and an iodine crystal (catalyst), during a period of 60 minutes while maintaining the reaction mixture at a temperature of no higher than 40° C. After this time, the reaction mixture was stirred and a solution of 5.0 grams (0.047 mole) of 4-pyridinecarboxaldehyde in 45 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was then cooled to 0° C. and a sufficient amount of an aqueous solution saturated with ammonium chloride was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium chloride. The extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding about 15.2 grams of crude product.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[CH3:36][OH:37].O>C(Cl)Cl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([O:37][CH3:36])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Reactant: CO
Solvent: O
Solvent: ClCCl
Product: COc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 12 h
Yield: 73.5 %

Procedure:
To a solution of 0.45 g (0.87 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 15 ml methanol 0.123 g (2.17 mmol) sodiummethanolate (95%) were added at RT and the reaction solution stirred for 12 hrs. The reaction mixture was distibuted between 100 ml H2O and 100 ml CH2Cl2. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/methanol 40:1) to give 0.30 g (73%) 2-methoxy-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 97.5-98.5°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:13][CH2:12]2)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:28]1([N:25]2[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=4)[CH2:15]3)[CH2:27][CH2:26]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CN1CCc2cc(OCc3ccccc3)ccc2C1)N1CCN(C2CCC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(CN1CCc2cc(O)ccc2C1)N1CCN(C2CCC2)CC1
Reaction time: 2 h

Procedure:
To a mixture of 6-(benzyloxy)-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline (2.5 g, 5.96 mmol) in EtOH (30 ml) is added 10% Pd(OH)2/C (0.5 g). The mixture is hydrogenated at 45 psi for 2 hr. The mixture is filtered through celite and washed with EtOH. The solvent is removed under reduced pressure to give the title compound. MS (+VE) m/z 330.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][C:11]([NH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15])=[O:12]>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)([CH3:16])[CH3:15])=[CH:22][CH:21]=1
Reactant: CC(C)(NC(=O)CCCl)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)CCn1ccnc1)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52c a mixture of imidazole (1.05 g) and sodium hydride (0.63 g, 60% dispersion) in THF (35 ml) was treated with 3-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]propionamide (4.0 g) in THF (15 ml) to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propionamide which was used directly in part (c).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=[C:6]([NH:17][C@H:18]([CH2:20][CH3:21])[CH3:19])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1>[C@@H:18]([NH:17][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=1)[C:3]([OH:22])=[O:2])([CH2:20][CH3:21])[CH3:19]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2ccccc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(-c2ccccc2F)n1
Yield: 80 %

Procedure:
Chill a solution of (S)-2-sec-butylamino-6-(2-fluorophenyl)-isonicotinic acid methyl ester (1.31 g, 4.32 mmol) in methanol (5 mL) and THF (5 mL). Ada 2 N NaOH (6.50 mL, 13.0 mmol) stir at room temperature for 3 h, and acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (2×30 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (80%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([Cl:26])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:18]1[N:17]=[C:16]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Oc2nc(Cl)cc3ccccc23)cc1
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of ethyl 4-hydroxyphenoxyacetate (1.0 g), 1,3-dichloroisoquinoline (1.0 g), anhydrous potassium carbonate (0.7 g) and dry dimethylformamide (10 ml) was heated, with stirring, at a temperature of 120°-130° C. for a period of 3 hours. The solvent was removed by distillation under reduced pressure and the residue was treated with water. The aqueous mixture was extracted with a mixture of acetone and chloroform and the solvents were removed from the organic extract by distillation under reduced pressure. The residue was chromatographed over silica gel with chloroform elution to give ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate (1.2 g), mp 97° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy, mass spectrometry and elemental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:16][C@H:17]1[O:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:19]1[CH2:18][C@H:17]1[CH2:16][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1Cc2c(O)cccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1Cc2c(cccc2OC[C@@H]2CO2)N1
Yield: 21.8 %

Procedure:
Prepared from 4-hydroxy-2-oxindole (1.1 g, 7.38 mmol), (S)-glycidyl nosylate (1.91 g, 7.38 mmol) and potassium carbonate (1.1 g, 8 mmol) according to the procedure used for Intermediate 1 to give 0.33 g product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Product: CC1(C)COC(=O)C1=O
Reaction time: 1 h
Yield: 98.6 %

Procedure:
5 g (38.4 mmol) of pantolactone were reacted with 3.6 g (15.5 mmol) of trichloroisocyanuric acid as described in Example 13. In contrast to Example 13, 63 mg (0.24 mmol) of Tempo derivative D were used as the catalyst. The reaction had finished after 1 hour. After recrystallization of the crude product there were obtained 4.85 g (98%) of ketopantolactone, m.p. 68°-69° C., GC content: 100% (area percent).
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[O:7][C:6]1=[O:14].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14]
Reactant: [I-]
Reactant: O=c1oc2ccccc2n1CCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1oc2ccccc2n1CCCI
Yield: 82.7 %

Procedure:
To a solution of 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.04 g, 14.36 mmol) in acetone (60 mL), was added sodium iodide (4.3 g, 28.73 mmol). After refluxing for 60 hours, the reaction mixture was filtered. The filtrate was washed with water and dried to obtain the title compound (3.6 g, 83%); 1H NMR (DMSO-d6): δ 2.19-2.24 (m, 2H), 3.28 (t, 2H, J=6.8 Hz), 3.87 (t, 2H, J=6.8 Hz), 7.11 (t, 1H, J=8 Hz), 7.22 (t, 1H, J=8 Hz), 7.32 (t, 2H, J=8.4 Hz). MS for C10H10INO2 m/z 304.33 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=1)[CH:2]=C.CO.C[N+]1([O-])CC[O:19]CC1.I([O-])(=O)(=O)=O.[Na+]>O.C1COCC1>[N:8]1[O:9][N:10]=[C:6]2[CH:5]=[C:4]([CH2:1][CH:2]=[O:19])[CH:12]=[CH:11][C:7]=12
Reactant: C=CCc1ccc2nonc2c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=CCc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Allyl-2,1,3-benzoxadiazole (4.1 g, 26 mmol) in a solution of MeOH (30 mL), THF (50 mL), and water (20 mL) was added Osium Tetraoxide (6.0 mL 4% aq. solution, 0.77 mmol) and NMO (4.5 g, 38 mmol). The mixture was allowed to stir at 25° C. for 16 hours. TLC showed complete reaction. The reaction was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The extractions were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting product was redissolved in water and methanol (50 mL each), and cooled to 0° C. To that solution was added an aqueous solution of sodium periodate (7.2 g, 33 mmol). TLC showed complete reaction within 15 minutes. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The extractions were combined, washed with brine, dried over sodium sulfate, and concentrated to obtain the product which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:1][C:30](=[O:31])[C:29]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:11]=1
Reactant: CSc1ccc(C(=O)C2(O)CCCC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC23CCCC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the alcohol from Step 2 (924 mg, 3.91 mmol) in 10 mL CH2Cl2 at 0° C. was added pyridine (928 mg, 11.7 mmol) followed by phenylacetyl chloride (1.51 g, 9.77 mmol). The ice bath was removed and the mixture was stirred at room temperature for 15 h. Aq. NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 16 mL CH2Cl2, DBU (595 mg, 3.91 mmol) was added and the brown solution was stirred at room temperature for 0.5 h. 5% aq. HCl (100 mL) was added and the mixture was extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 1.40 g (quantitative) of the title compound as a yellow solid, used directly in the next step. An analytical sample had mp. 147-148° C. after stirring with Et2O/hexane (2:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[CH:48]=[CH:49][C:50]2[N:54]=[C:53]([C@@H:55]3[CH2:59][CH2:58][CH2:57][N:56]3[C:60](=[O:70])[C@@H:61]([NH:65][C:66](=[O:69])[O:67][CH3:68])[CH:62]([CH3:64])[CH3:63])[NH:52][C:51]=2[CH:71]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:47]1[CH:48]=[CH:49][C:50]3[N:54]=[C:53]([C@@H:55]4[CH2:59][CH2:58][CH2:57][N:56]4[C:60](=[O:70])[C@@H:61]([NH:65][C:66]([O:67][CH3:68])=[O:69])[CH:62]([CH3:63])[CH3:64])[NH:52][C:51]=3[CH:71]=1)=[CH:31][CH:30]=2)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3ccc4nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c4c3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C

Procedure:
To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.85 mmol), methyl(S)-1-((S)-2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (360 mg, 0.85 mmol), tetrakis(triphenylphosphine) palladium(0) (38 mg, 0.03 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(11) (48 mg, 0.07 mmol) in a mixture of 1,2-dimethoxyethane (8.0 mL) and dimethylformamide (1.4 mL) was added a solution of potassium carbonate (2M in water, 0.98 mL, 1.96 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (156 mg, 29%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH3:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)=[O:9])[N:3]=[CH:2]1.I[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:20][CH:19]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][CH2:6][C:4]2[N:3]=[CH:2][N:1]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][CH:19]=3)[CH:5]=2)=[O:9])[N:11]([CH3:16])[CH:12]=1
Reactant: O=c1ccccn1-c1ccc(I)cc1
Reactant: Cn1cc(Cl)cc1C(=O)NCc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1cc(Cl)cc1C(=O)NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Temperature: 130 °C
Yield: 26.7 %

Procedure:
A mixture of N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide (81 mg, 0.23 mmol), 1-(4-iodophenyl)pyridin-2(1H)-one (100 mg, 0.33 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K2CO3 (193 mg, 1.40 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (21 mg, 0.11 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (25 mg). MS 408.1 and 410.1 (M+H, Cl pattern).