Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]([C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].Br[C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([NH:45][C:46]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:53]=2)=[O:47])[CH:33]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC.O>[C:11]([O:10][C:9]([N:8]([CH3:7])[C:16]1[CH:17]=[CH:18][C:19]([C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])=[C:34]([NH:45][C:46]([C:48]3[CH:49]=[N:50][CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH:53]=3)=[O:47])[CH:33]=2)=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)cc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Water (0.60 mL), sodium carbonate (88 mg), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.13 g), and bis(triphenylphosphine)palladium(II) dichloride (5.0 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.16 g of tert-butyl 4-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [Li+].[OH-].[C:3]([NH:10][C@H:11]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:20]1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH4+].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:39]>COCCOC.CCOCC>[C:3]([NH:10][C@@H:11]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[C@@H:19]([OH:39])[CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:22]([OH:23])=[O:24])([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)OC2=O)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1000 ml of 1M aqueous LiOH solution are added, under a protective gas, to a solution of 103 g (239 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-[(p-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 800 ml 1,2-dimethoxyethane. After 3 h at RT, the reaction solution is poured onto an ice-cold mixture of 1.5 l of sat. NH4Cl solution, 1 l of 10% citric acid solution and 2 l of ether. The aqueous phase is separated off and extracted 2× with 1 l of ether on each occasion. The organic phases are washed 4× with ice-water and finally with saline. Drying with sodium sulfate and evaporating yields the title compound from the organic phases: tRet (II)=16.0 min; FAB-MS (M+H)+ =450.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1>C(O)C>[F:23][C:22]([S:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][C:7]3=[O:12])=[CH:16][CH:17]=1)([F:25])[F:24]
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: O=C1NCCc2c(O)cccc21
Solvent: CCO
Product: O=C1NCCc2c(OCc3ccc(SC(F)(F)F)cc3)cccc21

Procedure:
166 mg (1.017 mmol) of 5-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, 289 mg (1.068 mmol) of 1-(bromomethyl)-4-[(trifluoromethyl)sulphanyl]benzene and 365 mg (2.645 mmol) were suspended in 3 ml of ethanol and stirred under reflux for 6 h. After cooling, the insoluble constituents were filtered off and the solvent was removed under reduced pressure. The residue was dissolved in chloroform and water. The phases were separated, the organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by chromatography (ethyl acetate:n-heptane 2:1). This gave 200 mg (54% of theory) of the desired 5-({4-[(trifluoromethyl)sulphanyl]benzyl}oxy)-3,4-dihydroisoquinolin-1(2H)-one. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 7.89 (br. s, 1H), 7.52-7.44 (m, 4H), 7.28 (t, 1H), 7.22 (d, 1H), 5.16 (s, 2H), 3.33 (dt, 2H), 2.84 (t, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=2.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[O:43])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:35][CH2:36][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:2][C:3]4[CH:4]=[N:5][C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=5)[CH2:46][CH2:45]3)=[O:43])[CH2:38][CH2:39]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Reactant: FC(F)(F)c1ccc2cc(CCl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2cnc3cc(C(F)(F)F)ccc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg, 0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345 mg, 2.5 mmol, 5 eq.) then 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution was stirred overnight at 70° C. and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with methanol in dichloromethane. The semi-purified material was further purified by HPLC to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone as a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]+ 640; 1H NMR (400 MHz, CDCl3): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H), 2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H) 7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:21]=3[C:14]([C:15]3[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11]4.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[C:29]1([N:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:21]=4[C:14]([C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[CH:11]5)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc2c3cccc4cccc(c5cccc1c52)c43
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc3c4cccc5cccc(c6cccc2c63)c54)cc1
Reaction time: 40 h

Procedure:
The following compounds were introduced into a vessel: (a) 3-bromoperylene; (b) diphenylamine; (c) potassium carbonate; (d) copper power; and (e) nitrobenzene. Then, the mixture was stirred at 200 degrees centigrade for 40 hours. After reaction has finished, nitrobenzene was removed under a reduced pressure. Then, chloroform was added to the mixture, and filtered for removing inorganic materials. A filtrate was condensed, and then, impurities were removed by silica gel column chromatography employing ligroin. As a result, there was obtained a target material, 3-diphenylaminoperylene.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]([N:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:11])[CH:7]=[CH2:8].C(OC([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.Cl>O1CCCC1.[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.O.C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[CH2:6]([O:9][C:10]([N:12]([CH2:13][C:14]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])=[O:16])[CH3:17])=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)N(C)CC(=O)O
Reactant: C=CCOC(=O)N1CCC[C@H]1C=C(C)C(C)=O
Agent: [Pd]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)CC(=O)N1CCC[C@H]1C=C(C)C(C)=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a mixture of dimethylformamide (4.2 ml) and tetrahydrofuran (10 ml) was added phosphorus oxychloride (4.2 ml) at 5° C. After stirring at 5° C. for 30 minutes, to the mixture were added successively tetrahydrofuran (60 ml) and N-allyloxycarbonyl-N-methylglycine (8.7 g). The mixture was stirred for 30 minutes at 5° C. (solution A). To a solution of (2S)-1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (10.0 g) in tetrahydrofuran (160 ml) were added successively triphenylphosphine (5.5 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (5.8 g), acetic acid (4.8 ml) and tetrakis(triphenylphosphine)-palladium(0) (2.4 g). After stirring at ambient temperature for 30 minutes, the mixture was taken up into a mixture of ethyl acetate (100 ml) and water (100 ml). After adjusting to around pH 2 with 1N hydrochloric acid, the aqueous layer was separated, washed with e&hyl acetate and tetrahydrofuran (200 ml) was added thereto. After adjusting to around pH 8.5 with 20% aqueous sodium hydroxide, to the mixture was added dropwise the solution A. After stirring at 5° C. for 1 hour, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:5-3:7 V/V) to give (2S)-1-(N-allyloxycarbonyl-N-methylaminoacetyl)-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (3.4 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14](C(OCC)=O)[C:15]3[C:20]([C:21]=2[NH:22][C:23](=[O:30])[C@@H:24]([O:26]C(=O)C)[CH3:25])=[CH:19][CH:18]=[C:17]([Cl:31])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=O)C.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:31][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([NH:22][C:23](=[O:30])[C@@H:24]([OH:26])[CH3:25])=[C:13]([C:11]([C:8]3[O:9][CH:10]=[C:6]([CH2:5][OH:4])[CH:7]=3)=[O:12])[NH:14]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)[C@H](C)OC(C)=O)c2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](O)C(=O)Nc1c(C(=O)c2cc(CO)co2)[nH]c2cc(Cl)ccc12
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 2-(4-acetoxymethyl-2-furoyl)-6-chloro-1-ethoxycarbonyl-3-[(S)-2-acetoxypropionylamino]indole (step 1, 267 mg, 0.494 mmol) in ethanol (2 ml) was added 2N aqueous sodium hydroxide (2 ml). After stirrig for 3 h, the mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (50/1) and recrystallized from 2-propanol/isopropyl ether to give 43 mg (24%) of the titled compound as yellow solids. m.p.: 213-214° C. 1H-NMR (CDCl3) δ: 11.4 (1H, br s), 10.8 (1H, br s), 8.35 (1H, d, J=8.90 Hz), 7.76 (1H, s), 7.53 (1H, d, J=1.81 Hz), 7.45 (1H, s), 7.01 (1H, dd, J=8.90 Hz, 1.81 Hz), 4.58 (2H, d, J=5.11 Hz), 4.36 (1H, q, J=6.92 Hz), 1.52 (3H, d, J=6.92 Hz).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:16][CH:11]=1
Reactant: Clc1ccccc1Br
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(Oc2ccc(Cl)cc2)cn1
Reaction time: 18 h

Procedure:
7.35 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 20 ml of dimethylformamide, and 9.6 g of bromochlorobenzene and 800 mg of a copper powder were added to the suspension. The reaction was effected at a temperature of 120° C. for a period of 18 hours in a nitrogen stream while stirring. After allowing the reaction mixture to cool, the reaction mixture was diluted with 50 ml of methanol and then filtered. The filtrate was immediately concentrated to dryness, and 200 ml of chloroform and 100 ml of water were added to the dried material, and the mixture adjusted to a pH of 9 with 5 N sodium hydroxide. The insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-methylpyridine. Gas chromatography revealed that the thus-obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.[N:19]([C:22]1[C:31]([CH2:32]Cl)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1)=[N+:20]=[N-:21].[Li+].[OH-]>C1COCC1>[N:19]([C:22]1[C:31]([CH2:32][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1)=[N+:20]=[N-:21]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(N=[N+]=[N-])c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2N=[N+]=[N-])c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (161 mg, 0.69 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2-azido-3-(chloromethyl)-6-methoxyquinoline hydrochloride SLA 41152 (197 mg, 0.69 mmol) followed by a 2 N aq. LiOH solution (0.69 mL, 1.38 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 4-((2-azido-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol (10 mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-((2-azido-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 68 as a yellow solid (11 mg, 3% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:40])[CH2:31][N:32]([C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-leucine (1.31 g) and N-(benzyl)glycine ethyl ester (738 mg) were reacted in the same manner as in Preparation Example 52 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5].Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)c(F)cc3F)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A suspension of 2-chloro-3-(1-cyanocyclopropyl)-N-(2,4-difluoro-5-hydroxyphenyl)benzamide (4.20 g, 12 mmol), 2-chloro-5-nitropyridine (1.9 g, 12 mmol) and potassium carbonate (1.66 g, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (5.20 g, 92%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl[C:12]1[CH:21]=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[N:13]=1.O>CS(C)=O.O1CCOCC1>[Cl:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH:21]=[N:20]2
Reactant: Nc1cccc(O)c1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2cnc3cc(Cl)ccc3n2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
6.6 g (0.06 mol) of m-aminophenol in 4.0 g (0.06 mol) of 85% potassium hydroxide and 80 ml of dimethylsulfoxide was heated under stirring. The water generated was distilled away under reduced pressure to make the potassium m-aminophenolate. To the solution which was allowed to cool to room temperature was added a solution of 11.9 g (0.06 mol) of 2,6-dichloroquinoxaline dissolved in 80 ml of dioxane. The mixture was reacted at 50°-60° C. for 5 hours. After the reaction was over, the reaction mixture was poured into ice and cold water. The formed solid was filtered off and washed with 5% aqueous solution of sodium hydroxide and then washed with water. The crude crystals thus obtained were recrystallized from ethanol, to produce 8.8 g (yield 54%) of white crystals, m.p. 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11]
Reactant: C#Cc1cccc(Cl)c1Cl
Reactant: Fc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2cccc(Cl)c2Cl)SC(/C=C\c2cccc(Cl)c2Cl)c2ccc(F)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,3-dichlorophenylacetylene (0.02 mol), 2-chloro-4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dichlorostyryl-2-chloro-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:47]([NH2:57])[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.C(Cl)Cl>[C:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:57][CH2:47][C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
Boc-D-Pro-OH (209 mg, 0.970 mmol) was dissolved in DMF (4 mL), followed by addition of the HBTU (552 mg, 1.46 mmol) and Triethylamine (270 μL). The solution was stirred at room temperature for 30 minutes prior to the addition of piperonylamine (121 μL, 0.970 mmol). The reaction mixture stirred at rt for 16 h then the solution was transferred to a separatory funnel containing DCM (50 mL). The organic layer was washed with NaHCO3 (2×50 mL, sat. aq.) and dried over Na2SO4. The solution was concentrated and purified by prep LCMS to afford 278.0 mg (82.5%) of 2-[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. [M+H]+ 349.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]CC3C=CC=CC=3)[CH:21]=2)=[CH:5][CH:4]=1.O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1

Procedure:
A slurry was prepared consisting of 2-(4-methoxyphenyl)-3-(3-benzyloxyphenyl)-6-methoxybenzo[b]thiophene in 1 L of EtOH, 250 mL of EtOAc, and 40 mL of water. Palladium(0) black 4.04 g (38 mmol) and ammonium formate 12.6 g (200 mmol) was added. The reaction mixture was heated to reflux for one hour, then filtered hot through celite and evaporated to dryness. The solid was partioned between EtOAc and a saturated solution of Na2HCO3. The organic layer was washed with brine, dried with Na2SO4, and evaporated to dryness. This yielded 12.8 g of the title compound as a white solid.