Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:34]=[O:35])C>>[CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:34]=[O:35])=[C:13]2[N:12]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Nc2cc(SCc3ccccc3)n3nccc3n2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(SCc3ccccc3)cc(Nc3cccc(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 7-(benzylthio)-N-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine (4.1 g, 11.3 mmol) in DMF (42 mL), POCl3 (6.3 mL, 67.6 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 3 hours at room temperature. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as a solid in 83% yield. LCMS (M+1=395)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[OH-:11].[Na+].CO.O.Cl>C(OCC)(=O)C>[Br:10][C:8]1[C:9]([OH:11])=[C:5]([C:3]([OH:2])=[O:4])[S:6][CH:7]=1
Reactant: [OH-]
Reactant: COC(=O)c1cc(Br)cs1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1scc(Br)c1O
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 4-bromothiophene-2-carboxylic acid methyl ester (500 mg, 2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed solvent of methanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (326 mg, 69.4%) as a red brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(C(Cn2cncn2)OCc2ccccc2)cc1

Procedure:
Following the procedure of Example 9, Step 2, 1-p-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (4.48 g), benzyl chloride (2.54 g) and sodium hydride (1 g; 50%) were reacted to give the title compound as a crystalline solid. Analysis:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:15][OH:16]>CO.C(OCC)(=O)C.[Pt]>[CH2:1]([N:15]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC=O
Reactant: NO
Agent: [Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 50.9 %

Procedure:
A solution of dodecanal (9.2 g, 50 mmol) and hydroxylamine hydrochloride (3.8 g, 54 mmol) in 75 ml of methanol and 10 ml of ethyl acetate is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for five hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (450 mg). The reaction mixture is then filtered through CELITE filter agent. The filtrate is concentrated and the residue is treated with a saturated aqueous potassium carbonate solution till the pH is over 10. A white solid is isolated by filtration and is recrystallized from methanol to provide 4.7 g (51% yield) of the title compound as a white solid melting at 88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9](I)[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]=2[O:16][CH3:15])[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c(I)n(C)c1C
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)c(-c2cccc([N+](=O)[O-])c2OC)n(C)c1C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
5-Iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane followed by addition of 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (3.6 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature followed by addition of 30 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (1.25 g, yield 40.4%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CC(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a mixture of 3-fluoro-4-nitrobenzaldehyde (4.85 g, 28.7 mmol), piperidine (3.12 mL, 31.5 mmol) and 20 drops of AcOH in DCM was added sodium triacetoxyborohydride (6.69 g, 31.5 mmol), and the resulting suspension was stirred at RT for 30 minutes. The reaction was made basic with 2N aqueous NaOH, and extracted with DCM. The organic layer was washed with brine and was dried over sodium sulfate, filtered and concentrated in vacuo to yield a red oil. The residual oil was purified via MPLC, eluting with a gradient of 0-100% EtOAc in hexane to yield 1-(3-fluoro-4-nitrobenzyl)piperidine (3.98 g, 16.70 mmol, 58.2% yield) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH:13](O)=O.Cl.[OH-].[NH4+]>O>[CH3:12][C:3]1[C:2]2[NH:1][CH:13]=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (11.81 g), formic acid (88%, 390 mL) and 12N HCl (38 mL) is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (200 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×200 mL). The combined extracts are dried over magnesium sulfate (MgSO4) and evaporated to afford 4-methyl-5-nitrobenzimidazole as an orange solid.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1.[Li+].[Cl-:24].O>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([CH2:6][Cl:24])=[CH:8][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Cl-]
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution of thionyl chloride (10.0 g, 84.0 mmol) in DMF (10 mL) was added dropwise to a solution of 4-hydroxymethyl-2-phenylbenzoic acid, methyl ester (12.1 g, 50 mmol), prepared as in Example 158C, and LiCl (2.33 g, 55.0 mmol) in DMF (40 mL). After 1 hour, the reaction mixture was poured into H2O and the resulting mixture was extracted with ether (3×). The combined organic extracts were rinsed with H2O (2×), saturated aqueous NaHCO3 (3×) and brine, dried (MgSO4) and concentrated under reduced pressure to provide the desired compound (10.8 g, 83%) as a clear, colorless oil.
Reaction SMILES: C(C1(C([O-])=O)C(O)=C(C(C)(C)C)C=C(C)C1)(C)(C)C.[K+].[C:21](=[O:23])=[O:22].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([CH2:25][C:21]([OH:23])=[O:22])(=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=C=O
Agent: CC1=CC(C(C)(C)C)=C(O)C(C(=O)[O-])(C(C)(C)C)C1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
6.7 g of potassium 2,6-di-t-butyl-p-cresolate in 30 cc of toluene were introduced into a 4-neck flask, having a capacity of 100 cc, provided with stirrer, thermometer and gas inlet pipe. In a carbon dioxide atmosphere 3.1 g of acetophenone (phenate: substrate molar ratio = 1 : 1) were added; the whole was stirred at 20°C for 4 hours and then acidified with cold sulphuric acid at 10% concentration. The organic phase separated, and was then extracted with a 10% sodium carbonate aqueous solution. 0.9 g of benzoylacetic acid were isolated by acidification and extraction with ether. 2.3 g of acetophenone were recovered from the organic phase.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC)c(O)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-hydroxy4-methoxybenzaldehyde gave the title compound as a yellow solid m.p.: 140-148° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(OCC)C>[O:17]=[C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.5 %

Procedure:
A solution of morpholine (8.7 g, 0.1 mole) and triethylamine (15.3 ml, 0.1 mole) in ethyl ether (100 ml) was cooled to +5° C. A solution of acryloyl chloride (9.0 g, 0.10 mole) in 25 ml of ethyl ether was added dropwise over a 30 minute period, resulting in the formation of a white solid. An additional 100 ml of ethyl ether was added and the reaction stirred for 72 hours at room temperature. The white solid was filtered and washed well with ethyl ether. The ethyl ether wash and filtrate were combined and solvent removed, leaving an orange oil which was transferred to a 50 ml Erlenmeyer flask and dried overnight under nitrogen to yield 11.5 g of product. The structure was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1.CN(C)CCN(C)C.[F:31][C:32]([F:35])([F:34])I.O>C(#N)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[C:5]([C:32]([F:35])([F:34])[F:31])[C:4]=2[CH:3]=1
Reactant: FC(F)(F)I
Reactant: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1NCCn2c1c(C(F)(F)F)c1cc(F)cc(-c3ccc(F)cc3)c12
Temperature: -78 °C
Reaction time: 40 h
Yield: 34 %

Procedure:
To a solution of 8-fluoro-6-(4-fluoro-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 18) (0.1 g, 0.335 mmol) in acetonitrile (1 ml) and DMF (1 ml), N,N,N′,N′-tetra-methylethylenediamine (77.9 mg, 101 μl, 670 μmol) and tris(2,2′-biryridyl)ruthenium(II)-chloride hexahydrate (5.02 mg, 6.7 μmol) were added at room temperature. The vial was sealed, cooled to −78° C., and with the help of a needle trifluoroiodomethane (˜0.5 ml) was condensed into the reaction tube. A high lumen (6500K) cool daylight lamp was positioned in front of the reaction vial and the reaction was allowed to stir for 40 h at room temperature. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate 20-80%) and trituration (diethyl ether/heptane) to yield the title compound as a white solid (42 mg, 34%), MS (ISP) m/z=367.4 [(M+H)+], mp 193° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].O>CC(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[S:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCc1ccccn1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)CCc2ccccn2)cc1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Methyl-(2-pyridin-2-ylethyl)amine (8.9 ml, 0.0643 mol) was dissolved in acetone (13 ml) and cooled to 0° C., 4-acetylaminobenzenesulfonyl chloride (5 g, 0.0214 mol) was added over 10 min. Additional acetone (5 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water and extracted with EtOAc. The extracts were dried (MgSO4). The mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, EtOAc-MeOH/EtOAc 1:19) to give 5.6 g of N-{4-[methyl-(2-pyridin-2-yl-ethyl)sulfamoyl]phenyl}acetamide. Step B: The compound from step A (5.6 g) was suspended in water (22.4 ml), treated with concentrated HCl (13.4 ml), and the mixture heated at reflux for 1 h. After cooling to rt, NH4OH (13.7 ml) was added with stirring. The resulting mixture was extracted with CH2Cl2; the extracts were washed with water, dried (MgSO4), and concentrated under reduced pressure to give 4.8 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. LCMS: MH+=292.0.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][O-:12].[Na+].O>CN(C=O)C.[Cu](I)I>[CH3:11][O:12][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccsc12
Reactant: C[O-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2ccsc12
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a solution of 7-bromobenzo[b]thiophene (10.0 g, 46.9 mmol) in dry DMF (234 mL) is added copper iodide (8.90 g, 46.9 mmol), followed by the addition of sodium methoxide (30% in MeOH, 176 mL, 938 mmol) at room temperature under nitrogen atmosphere. The mixture is heated at 100° C. for 2 hours and cooled to room temperature. Water (400 mL) is added and the mixture is extracted with diethyl ether (4×200 mL). Organic layers are washed with cooled water (3×75 mL), saturated aqueous sodium chloride (100 mL), dried (MgSO4), and concentrated to give the title compound as yellow oil (7.58 g, 98% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:8]2.[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36](=[O:54])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:34][C:23]=2[CH:22]=1>>[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36]([N:17]3[CH2:18][CH2:19][CH:14]([C:9]4[C:10](=[O:13])[NH:11][C:12]5[C:7]([CH:8]=4)=[CH:6][CH:5]=[CH:4][C:3]=5[F:2])[CH2:15][CH2:16]3)=[O:54])[CH2:34][C:23]=2[CH:22]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 36 %

Procedure:
Title compound was prepared from 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 36% yield. MS m/e (M+H)+=592.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 11.78 (s, 1H), 8.36 (s, 1H), 7.76 (d, J=5.19, 1H), 7.46 (d, J=7.93, 1H), 7.34 (dd, J1=10.53, J2=8.70, 1H), 7.24 (s, 1H), 7.14 (m, 1H), 5.36 (d, J=16.48, 1H), 4.63 (d, J=17.40, 1H), 4.55 (d, J=11.29, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.17 (m, 1H), 3.05 (m, 4H), 2.88 (m, 1H), 2.65 (m, 1H), 2.34 (d, J=15.87 1H), 1.92 (d, J=12.51, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: C([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:7][CH2:6][C:5]1=[O:23])C=C.[Mn]([O-])(=O)(=O)=[O:25].[K+].[CH3:30][C:31]([CH3:33])=[O:32]>>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([CH2:30][CH:31]([OH:32])[CH2:33][OH:25])[C:5](=[O:23])[CH2:6][N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:14]=1
Reactant: C=CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)=O
Agent: [K+]
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO

Procedure:
33.0 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved in 300 ml of acetone. 16 g of potassium permanganate are dissolved in 300 ml of a buffer solution (sodium acetate/acetic acid buffer) and added dropwise at 10°C within 20 minutes and with stirring to the foregoing solution. After complete decolouration of the potassium permanganate solution, the mixture is filtered off under vacuum from the manganese dioxide, the manganese dioxide is washed with acetone and the residue is extensively freed from acetone on a rotary evaporator. The remaining aqueous solution is treated with equal portions of methanol, toluene and cyclohexane and partitioned by stirring well. The aqueous/ methanolic phase is then extensively freed from methanol on a rotary evaporator and the remaining aqueous phase is extracted with ethyl acetate. The ethyl acetate solution is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is brought to crystallization by seeding from a small amount of ethyl acetate. By recrystallization of the first crystalline product from ethyl acetate there is obtained pure 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 117°-118°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH:15]1([CH2:21][N:22]2[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[C:23]2=[O:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([CH2:21][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:23]1=[O:30])=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(CC2CCCCC2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(CC2CCCCC2)C1=O
Yield: 38.4 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxylic acid (0.097; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in dichloromethane (2 mL) and DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0668 g (38%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:11]2[CH:12]=[CH:13][CH:2]=[C:3]([CH:10]=2)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1N
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CON(C)C(=O)c1cccc(-c2cccc(Cl)c2)c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and heated at 85° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone as a yellow solid (2 g, 47%): mp 89-90° C.; 1H-NMR (CDCl3) d 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268 ([M+Na]+, 60%); Anal. Calcd. For C14H12ClNO: C, 68.44; H, 4.92; N, 5.70. Found: C, 68.40; H, 4.89; N, 5.61.