Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:11]3([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Through a solution of N-((1-benzyl-4-(4-cyclopropylpiperazin-1-yl)-piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide (5.4 mmol) in methanol (30 ml) was passed argon gas for 10 min. Then acetic acid (855 μl) and Pd(OH)2 (40% by weight) were added to the reaction mixture and it was stirred at room temperature for 16 h under an atmosphere of H2 by using a hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to yield the desired product which was used in the next step without further purification. Yield: 90%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:26]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: c1ccoc1
Reactant: CCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1ccco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A dry 50 ml round bottom flask charged with furan (1.40 g, 20.6 mmol) and THF (10 ml), was cooled to -78° C. and n-butyllithium (13.6 ml, 1.50 M in hexanes, 20.6 mmol) was added dropwise. The solution was stirred for 30 mm at -78° C., then warmed to 0° C. and placed in an ice bath for 1 h. The mixture was then cooled to -78° C. and 1-bromopentadecane 9 (5 g, 17.2 mmol) in THF (10 ml) were added dropwise. The resulting solution was stirred for 1 h, then warmed to room temp and stirred 12 h. The reaction was quenched with a saturated solution of NH4Cl (5 ml). The organic layer was separated and the aqueous layer extracted with ether (3×20 ml). The combined organic layers were washed with saturated NaHCO3 (1×20 ml), brine (1×20 ml), dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography on silica, eluting with hexanes to afford a oily liquid that was recrystallized from methanol (~ 50 ml/g, cooling to 5° C.) to afford 4.8 g (64%) of 2-(pentadecyl)furan (1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:16]1NC(=O)C=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[O:34]P(CC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1)(=O)OC.[N+](C1C=CC(C=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16](=[O:34])/[CH:21]=[CH:20]/[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{1-[4-(4-Nitro-phenyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester: A suspension of ((S)-3-tert-butoxycarbonylamino-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester (1.114 g, 3 mmol, Resmini, M. et al., Tetrahedron Asymmetry, 2004, 15, 1847.), 4-nitrobenzaldehyde (0.453 g, 3 mmol) and potassium carbonate (0.415 g, 3 mmol) in ethanol (60 mL) was stirred at rt for 5 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4, filtered and concentrated to give 1.276 g of [(E)-(S)-1-benzyl-4-(4-nitro-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow solid. This yellow solid was suspended in ethanol (30 mL), then 1-ethoxycarbonylmethyl-pyridinium chloride (0.605 g, 3 mmol) and ammonium acetate (4.63 g, 60 mmol) were added. The reaction mixture was stirred at rt for 10 min, then heated at 80° C. for 5 h to yield a white suspension. The reaction was cooled to rt and the solid was collected by filtration, washed with methanol, and dried in vacuo (50° C.) to give 0.85 g (62%) of 64A as a white solid. LCMS m/z 436.3 (M+H)+. 1HNMR (400 MHz, DMSO-D6) δ: 1.26 (s, 9H), 2.76-2.82 (m, 1H), 3.01-3.06 (m, 1H), 4.68-4.74 (m, 1H), 6.54-6.60 (m, 2H), 7.18-7.29 (m, 5H), 7.40 (d, J=9.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 8.34 (d, J=8.8 Hz, 2H), 11.96 (s, 1H).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6]1[C:7]([CH:20]=[N:21][OH:22])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)#[CH:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([C:23]2[O:22][N:21]=[C:20]([C:7]3[C:6]([O:5][CH3:4])=[CH:15][C:14]4[C:13]([CH3:16])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:19])[C:9]=4[CH:8]=3)[CH:24]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: C#Cc1ccc(C#N)cc1
Reactant: COc1cc2c(cc1C=NO)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [O-]Cl
Product: COc1cc2c(cc1-c1cc(-c3ccc(C#N)cc3)on1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
17.2 g of a 10% strength aqueous sodium hypochlorite solution were added dropwise at 10°-15° C. to a solution of 5.0 g (19 millimoles) of 5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthaldoxime and 2.4 g (19 millimoles) of 4-ethynylbenzonitrile. The mixture was stirred for 1.5 hours at room temperature. Thereafter, the reaction mixture was poured onto water, the phases were separated and the aqueous phase was extracted again with methylene chloride. The combined organic extracts were washed with sodium bisulfite solution, dried over sodium sulfate and evaporated down. The residue was digested in hot methanol, the mixture was allowed to cool and the crystals were filtered off under suction and dried to give 5.4 g of the title compound of melting point 202°-203° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[O-:35][Mn](=O)(=O)=O.[K+]>O>[CH2:13]([N:8]([C:9](=[O:12])[CH2:10][CH3:11])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C=O)s1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C(=O)O)s1

Procedure:
57.8 g of N-(5-formyl-thien-2-yl)-N-hexadecyl-propionic acid amide are dissolved in 300 cc. of pyridine. A solution of 14.6 g of KMnO4 in 198 cc. of pyridine and 85 cc. of water is added with stirring and cooling such that the temperature of the reaction does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvent is distilled off, the residue is triturated with dillued acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].[CH3:12]I>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:12]
Reactant: CI
Reactant: OCc1ccncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-methanol (300 mg, 1.6 mmol) in THF (50 mL) at 0° C. is added 60% NaH (96 mg, 2.4 mmol). Then the mixture is stirred at room temperature for 30 min. MeI (270 mg, 1.9 mmol) is added to the mixture at 0° C. and again the mixture is stirred at room temperature for 4 hrs. Then the reaction is quenched with saturated NH4Cl aqueous solution and the mixture is extracted with EtOAc. The organic layer is separated, dried and concentrated to give the crude product. Purification by prep-TLC affords 274 mg of 3-bromo-4-methoxymethyl-pyridine.
Reaction SMILES: II.[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:7]1[CH2:6][CH2:5]2)[CH2:21][CH2:20][C:18](=[O:19])[CH:17]=3.S([O-])([O-])(=[O:25])=S.[Na+].[Na+].[CH3:30][OH:31]>>[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][C:15]([C:16]3[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=3[C@H:7]1[CH2:6][CH2:5]2)=[O:25].[CH3:30][O:31][CH3:3]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S([O-])([O-])=S
Reactant: CO
Agent: II
Agent: [Na+]
Product: COC
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C(=O)C[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Iodine (560 mg, 2.2 mmol) and 19-nor-4-androstene-3,17-dione (200 mg, 0.735 mmol) were dissolved in methanol (10 mL), and the resultant mixture was stirred for two hours under cooling in an ice-bath. The mixture was maintained at room temperature, and the mixture was further stirred for 1.5 hours, and subsequently refluxed for one hour. The reaction mixture was cooled to room temperature, and an aqueous solution of sodium thiosulfate was added to the mixture. The mixture was extracted with chloroform, and the organic phase was washed sequentially with an aqueous solution of sodium bicarbonate and saturated brine. The washed matter was dried over magnesium sulfate anhydrate, filtered, and evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform), to thereby yield 177 mg of the title compound (yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.CS(Cl)(=O)=O.CS(OC(C1C(C2C=CC=C(F)C=2)=C2C(C=CN=C2)=C(Cl)C=1)C)(=O)=O.[N-:59]=[N+:60]=[N-:61].[Na+]>C(Cl)Cl.CN(C)C=O>[N:59]([CH:12]([C:10]1[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]([CH:4]=[CH:5][N:6]=[CH:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13])=[N+:60]=[N-:61]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Agent: CC(OS(C)(=O)=O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a mixture of 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethanol (0.100 g, 0.331 mmol) in methylene chloride (0.6 mL) was added triethylamine (0.092 mL, 0.66 mmol) followed by methanesulfonyl chloride (0.038 mL, 0.50 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes, then diluted with dichloromethane and washed with water. The organic layers were dried over magnesium sulfate and concentrated to dryness under reduced pressure. The resulting sulfonate was used in the next step. LCMS (M+H)+380.1. To the this crude 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethyl methanesulfonate in N,N-dimethylformamide (0.6 mL) was added sodium azide (0.11 g, 1.6 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness to provide crude desired azide (0.105 mg, 97%). LCMS calculated for C17H13ClFN4 (M+H)+: m/z=327.1; Found: 327.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C1COc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2N1

Procedure:
The title compound is prepared from 6-amino-4H-benzo[1,4]oxazin-3-one and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 186-187° C. (diethylether)
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:20].C(OCC)C>C1(C)C=CC=CC=1>[Br-:20].[C:14]1([PH+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [Br-]
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of 26.23 g (0.10 mole) triphenylphosphine in 100 ml toluene at 0°-5° C. was perfused with HBr gas for 20 minutes, 250 ml ethyl ether was added and the mixture stirred for 20 minutes. The mixture was filtered, the white solid cake slurried in ether (500 ml), filtered again and air-dried to obtain 33.2 g (97%) of triphenylphosphonium bromide, m.p. 203°-205° C. (decomp.). In a separate flask 33 g (0.096 mole) of this salt, 11.9 g (0.096 mole) o-hydroxybenzyl alcohol and 100 ml dry acetonitrile were combined and heated at reflux for two hours. The resulting solution was cooled, filtered, the cake washed with 100 ml acetonitrile and dried in vacuo at 120° C. to obtain 26.2 g (61%) of the desired product, m.p. 223°-225° C. Mass spectrum (m/e): 368, 291, 262, 107.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a stirred solution of dimethyl 2-(4-nitrophenyl)malonate (10 g, 39.52 mmol, 1.0 eq) and K2CO3 (10.9 g 79.05 mmol 2.0 eq) in DMF (40 mL), was added methyl iodide (4.94 mL, 79.05 mmol 2.0 eq) at 0° C. and the mixture stirred at RT for 18 h. K2CO3 was filtered out and the filtrate concentrated under vacuum. The residue was diluted with water (80 mL) and extracted with EtOAc (2×80 mL). The organic layer was separated washed with brine solution, dried over anhydrous Na2SO4 and the solvent evaporated to get dimethyl 2-methyl-2-(4-nitrophenyl)malonate (7 g, 66%; TLC system: EtOAc/PE (3:7), Rf: 0.5.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][C:14]=2[N+:28]([O-])=O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:31](O)(=O)[CH3:32]>[Fe]>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH2:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[C:31]([CH3:32])=[N:28][C:14]=2[CH:15]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1cccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])c1
Agent: [Fe]
Product: COC(=O)c1cccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Yield: 64 %

Procedure:
To 2-(2-(3-methoxycarbonylphenylmethyl)aminonitrobenzen-5-yl)benzoxazole (see Working Example 117-1) (220 mg, 0.545 mmol) was added iron powder (91.4 mg, 1.64 mmol) and acetic acid (5 mL), and this was heated to reflux for 12 hours. After the reaction solution was cooled, it was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (139 mg, 64% yield) as white crystals.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.C(N(CC)CC)C.[CH3:20][NH:21][CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:25]1>CCO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[N:21]([CH3:20])[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:25]1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(N(C)CCC2CN(C(=O)OCc3cc(Cl)cc(Cl)c3)CCO2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising of 3,4-diethoxycyclobut-3-ene-1,2-dione (29.0 μl, 0.196 mmol) and triethylamine (1093 μl, 7.84 mmol) in EtOH (654 μl) was stirred at 40° C. for 20 minutes. The reaction was allowed to cool back to room temperature and 3,5-dichlorobenzyl 2-(2-(methylamino)ethyl)morpholine-4-carboxylate (Example 13, step 2) (68.1 mg, 0.196 mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure and purification was carried our using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[F:10].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]2)=[C:12]=[O:13].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:11][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]3)=[O:13])=[CH:4][C:3]=1[F:10]
Reactant: NCc1ccc(Br)c(F)c1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-bromo-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.51 (m, 2H), 8.01 (d, 1H, J=7.8 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.36 (dd, 1H, J=9, 1.5 Hz), 7.18 (dd, 1H, J=9, 1 Hz), 4.39 (d, 2H, J=6 Hz), 2.77 (s, 3H); MS (ESI) 388/390 (M+H)+; Anal. Calcd for C18H15BrFN3O.HCl: C, 50.91; H, 3.80; N, 9.89. Found: C, 50.81; H, 3.74; N, 9.87
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])[CH:17]=1)[NH:14][C:13]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:12]2)(=[O:4])=[O:3].[C:33](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:33][N:18]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:21])=[O:20])[C:16]1[CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:12]2
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a mixture of ethyl 5-[3-(methylsulfonyl)propoxy]-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (3.50 g), potassium carbonate (1.01 g) and N,N-dimethylformamide (50 mL) was added methyl iodide (1.14 g) at 0° C., and the reaction mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:4, volume ratio) to give the title compound (2.70 g, yield 75%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 176-177° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)=[S:29])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.01g, 0.028 mol), 4nitrophenyl isothiocyanate (5.31g, 0.03 mol) and toluene (50 ml) was heated under reflux for 2 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 11.07 g (86%), m.p. 214° 215 ° C.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH2:37][CH3:38]>CN(C=O)C.CO>[ClH:1].[CH2:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:38]
Reactant: CCI
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCN1CCN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg) in DMF (1 mL) was added sodium hydride (60%, 10 mg). The mixture was stirred for 15 minutes, then iodoethane (11 □L) was added. The mixture was stirred for 90 minutes then diluted with methanol (5 mL) and purified by ion exchange chromatography [SCX-2; MeOH-(1M NH3/MeOH): (100:0)→(0:100)]. The basic washings were concentrated in vacuo and purified by column chromatography [SiO2; cyclohexane-EtOAc-MeOH: (1:1:0)→(0:10:1)] and converted to the hydrochloride salt according to the description given in the general procedure (D6) to give the title compound (49 mg).