Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH3:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2c(N)cccc2c1C
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2c(NS(=O)(=O)c3cccs3)cccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a mixture of ethyl 7-amino-3-methyl-1H-indole-2-carboxylate (0.95 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (0.95 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (1.13 g, yield 70%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 198-199° C.
Reaction SMILES: C1COCC1.[CH3:6][C:7]1[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1.[CH3:16][C:17]([S@:20]([NH-:22])=[O:21])([CH3:19])[CH3:18].[BH4-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCO.O>[CH3:6][C:7]1[N:12]=[CH:11][C:10]([C@H:13]([NH:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(C)nc1
Reactant: CC(C)(C)[S@]([NH-])=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1ccc([C@@H](C)NS(=O)C(C)(C)C)cn1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a THF (25 ml) solution of 1-(6-methylpyridin-3-yl)ethanone (2.1 g, 15.5 mmol), (R)-(+)-2-methyl-2-propanesulfinylamide (2.26 g, 18.6 mmol) and titanium(IV) ethoxide (25 ml) were added and the mixture was stirred for 24 hours at 70° C. Then, the mixture was cooled to 0° C. and sodium borohydride (2060 mg, 54 mmol) was added. After stirring for 2 hours, water and EtOH were added to the mixture with stirring for 1 hour at room temperature. Filtration, evaporation gave N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide which was treated with hydrochloric acid-MeOH (2.0 M, 15.0 ml) and 1,4-dioxane (15.0 ml) for 1.5 hours at room temperature. Then, the reaction mixture was evaporated and diethyl ether was added to form a precipitate, which was collected, washed with diethyl ether to give (1R)-1-(6-methylpyridin-3-yl)ethanamine hydrochloride (2.12 g, 28%). MS (ESI) m/z 161 (M−H)−.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.O1CCCC1>CN(C)C1C=CN=CC=1.CCCCCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:26]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCCCCCBr)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of benzoin (26.15 g), 8-bromooctanoic acid (25.0 g), 4-dimethylaminopyridine (1.35 g), 1,3-dicyclo-hexylcarbodiimide (25.4 g) and dry tetrahydrofuran (350 ml) was stirred under nitrogen at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (350 ml), washed with 5% aqueous hydrochloric acid (3×175 ml), saturated sodium hydrogen carbonate solution (2×200 ml), saturated sodium chloride solution (220 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chro-matography on silica gel eluted with a hexane: dichloromethane gradient gave a yellow oil. This oil was stirred in hexane to give 2-oxo-1,2- diphenyl-ethyl 8-bromooctanoate (27.1 g, 52.7%) as a pale yellow solid m.p. 60°-61° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:3]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:3]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](N)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 83.6 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-[(3R)-3-aminopyrrolidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (238a) (116 mg, 0.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (79 mg, 0.45 mmol), WSC hydrochloride (260 mg, 1.36 mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol) and N-methylmorpholine (0.10 mL, 0.90 mmol), to obtain 155 mg of the title compound as a white solid (83%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH:17]=[C:16]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:15]=[N:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:16]1[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cn1cc(C(CN)c2ccc(C(F)(F)F)nc2)cn1
Product: Cn1cc(C(CNC(=O)c2cccc(Cl)c2Cl)c2ccc(C(F)(F)F)nc2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=443.2, tR (minutes, Method D)=0.67
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O.O.C(OCC)(=O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][N:11]([C:57](=[O:58])/[CH:56]=[CH:55]/[C:50]2[CH:49]=[C:48]3[C:53](=[N:52][CH:51]=2)[NH:54][C:45](=[O:44])[CH2:46][CH2:47]3)[CH2:10]1
Reactant: c1coc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4ccco4)C3)cnc2N1
Reaction time: 48 h

Procedure:
3-(Furan-2-ylmethoxy)-azetidine hydrochloride (558 mg, 2.94 mmol), EDCI (563 mg, 2.94 mmol), HOBt (410 mg, 2.94 mmol) and diisopropylethylamine (853 μL, 4.9 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (500 mg, 1.96 mmol) in dimethylformamide (50 mL) at room temperature. The reaction mixture was stirred for 2 days and then diluted by addition of ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×50 mL) and dichloromethane (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×60 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (10:0 to 95:5) as eluent. After trituration of the isolated solid in diethylether, the title product was obtained as a white solid (236 mg, 34%).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[O:27][C@H:26]([CH2:28][O:29]C(C4C=CC(C)=CC=4)=O)[C@@H:15]([O:16]C(C4C=CC(C)=CC=4)=O)[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.CO.C(Cl)Cl.CO>O1CCOCC1>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:15]([OH:16])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: N
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c4c(Cl)ncnc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
25% aqueous ammonia is added to 1.0 g (2.5 mmol) of 4-chloro-7-[2-deoxy-3,5-di-O-(4-toluoyl)-β-D-erythropentofuranosyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine which is dissolved in 80 ml of dioxane (80 ml). The mixture is stirred in a steel cylinder at 110° C. for 48 h. After the solvent has been evaporated off, the concentrated residue is chromatographed on silica gel (20×5 cm column, solvent B). Colorless crystals from MeOH (0.75 g, 2.0 mmol, 45%). M.p. 194° C. TLC: Rf 0.4 (CH2Cl2/MeOH, 9:1). UV (MeOH) 283 nm (5 800).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CCC(=O)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CO
Product: CCC(=O)c1ccc(OC)nc1
Yield: 77 %

Procedure:
Sodium methoxide (2.8 g, 50 mmol) was added to a solution of 1-(6-chloro-pyridin-3-yl)-propan-1-one (2.8 g, 16.5 mmol) in methanol (70 mL) and the reaction mixture was heated under reflux for eighteen hours. The solution was concentrated to fifty percent, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give product as a colorless oil (2.1 g, 77 percent yield), which was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.C1C=CC(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=CC=1>C1COCC1>[F:35][C:34]([F:37])([F:36])[S:31]([O:22][C:19]1[CH2:18][CH2:17][C:16]2([O:15][CH2:14][CH2:13][O:23]2)[CH2:21][CH:20]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine, (6.24 mL, 44.2 mmol) in THF (60 mL) at −78° C. under argon was slowly added n-butyllithium (17.7 mL, 44.2 mmol, 2.5 M in hexanes). The mixture was stirred for 30 min at that temperature before 1,4-cyclohexanedione mono-ethylene ketal (6.00 g, 38.4 mmol) was added slowly as a solution in THF (20 mL). The mixture was stirred for an additional 30 min at −78° C. and then n-phenyltriflamide (13.7 g, 38.4 mmol) was slowly added as a suspension in THF (50 mL). This mixture was stirred overnight with gradual warming to room temperature. The solvent was removed in vacuo and the remaining oil was partitioned between 3:1 ethyl acetate/hexane and water. The layers were separated and the organic layer was washed with water (3×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[CH:5]=1)(=O)[CH3:2].N1C=CC=CC=1.Cl.[NH2:35][OH:36]>CCO>[Cl:25][C:24]1[C:23]([Cl:26])=[C:22]([CH3:27])[NH:21][C:20]=1[C:18]([NH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:5]=[C:4](/[C:1](=[N:35]/[OH:36])/[CH3:2])[CH:9]=[C:8]([Cl:10])[N:7]=2)[CH2:12][CH2:13]1)=[O:19]
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C/C(=N\O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[1-(4-Acetyl-6-chloropyridin-2-yl)piperidin-4-yl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (Example 115) (49 mg, 0.114 mmol) was dissolved in EtOH (2 ml). Pyridine (74 μl, 0.913 mmol) was added followed by hydroxylamine hydrochloride (63.4 mg, 0.913 mmol). The mixture was stirred at room temperature overnight. The product was purified by semi-prep reverse phase HPLC eluting with CH3CN/H2O (0.1% TFA). (28 mg).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[CH2:16]([OH:19])[CH2:17][OH:18]>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:18][CH2:17][CH2:16][OH:19])=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: OCCO
Product: CCCc1c(COCCO)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 48, 6.8 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 150 ml. of ethylene glycol were reacted to provide 4.6 g. of the title alcohol. NMR.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([NH2:27])=[O:26].C(OC(C)C)(C)C>COC(OC)N(C)C>[CH3:3][N:4](/[CH:12]=[N:27]/[C:25]([C:5]1[N:4]([CH2:3][O:2][CH3:1])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15])=[O:26])[CH3:5]
Reactant: COCN(c1cccc2cc(C(N)=O)n(COC)c12)S(=O)(=O)c1cccs1
Agent: COC(OC)N(C)C
Solvent: CC(C)OC(C)C
Product: COCN(c1cccc2cc(C(=O)/N=C/N(C)C)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 8 h
Yield: 186.9 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g) and N,N-dimethylformamide dimethyl acetal (10 mL) was stirred at 50° C. overnight. To the reaction mixture was added diisopropyl ether, and the resulting crystals were filtrated and dried to give the title compound (1.06 g, yield 93%) as colorless crystals. melting point 146-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][C:18]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][O:22][CH2:21]5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:30]=1.C=O.[C:33]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:16][CH2:17][C:18]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][O:22][CH2:21]5)[CH2:19][CH2:20]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([CH3:33])[CH2:7][C:6]=2[CH:30]=1
Reactant: [BH3-]C#N
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC4(CC3)COCc3ccccc34)n1-2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC3(CC2)COCc2ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the crude 1′-(8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)-1H-spiro[isochromene-4,4′-piperidine] (0.10 g, 0.24 mmol) and paraformaldehyde (0.057 g, 1.9 mmol) in methanol (2 ml) was heated at reflux for 4 h. After cooling to room temperature sodium cyanoborohydride (0.03 g, 0.47 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. Quenching with 1 M aqueous sodium hydroxide solution (30 ml) was followed by extraction with ethyl acetate.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:7][CH:6]=1>C1COCC1.CSC>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([CH3:1])[CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1C(=O)OC[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II) bromide dimethylsulfide complex (8.78 g, 42.7 mmol) in THF (60 mL) and dimethylsulfide (30 mL) was added methylmagnesium bromide (12.7 mL, 3.0M in diethyl ether, 38.1 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −20° C. The product from Step A (3.53 g, 9.48 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −20° C. The resultant mixture was stirred at −20° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)NCCCCC1.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([Cl:40])=[CH:34][CH:35]=3)[C:30](=[O:41])[C:29]=2[C:28]([OH:42])=[CH:27][C:26]=1[O:43]C1C=CC=CC=1>CO>[NH2:24][C:25]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([Cl:40])=[CH:34][CH:35]=3)[C:30](=[O:41])[C:29]=2[C:28]([OH:42])=[CH:27][C:26]=1[O:43][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Nc1c(Oc2ccccc2)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Agent: O=C([O-])[O-]
Agent: O=C1CCCCCN1
Agent: [K+]
Solvent: CO
Product: Nc1c(OCCc2ccccc2)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Temperature: 140 °C

Procedure:
A mixture of 48.8 g of β-phenylethanol, 45.2 g of ε-caprolactam, 5.2 g of dry potassium carbonate and 18.3 g of 1-amino-2-phenoxy-4-hydroxy-6-chloroanthraquinone (preparation see Example 467c) is heated at 140° C. until, after about 4 hours, the reaction is complete. The mixture at 70° C. is diluted with 100 ccm of methanol, allowed to cool down, filtered with suction, washed with methanol and hot water and dried at 60° C. 14 g, corresponding to 71% of theory, of 1-amino-2-(2-phenylethoxy)-4-hydroxy-6-chloroanthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue between Indicator Numbers 50 and 51 (Colour Index Hue Indication Chart).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([NH2:57])[CH:52]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([NH:57][C:22](=[O:24])[CH2:21][O:20][C:19]2[CH:25]=[CH:26][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)[CH:54]=[CH:55][CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc(NC(=O)COc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 89 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. m-Anisidine (63 mg) was then added to the solution, and the mixture was heated under reflux for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (173 mg, yield 89%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].Cl.[OH2:13]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:13])=[CH:5][C:4]=1[Cl:11]
Reactant: O
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise DIBA1-H (1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: [CH:1]1([N:5]([CH3:47])[CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[CH:39][CH:38]=3)[C:28](=[O:36])[C:29]3[CH:35]=[CH:34][CH:33]=[N:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([N:5]([CH3:47])[CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=3)[C:28](=[O:36])[C:29]3[CH2:35][CH2:34][CH2:33][NH:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)N(C)C3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Solvent: CO
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)N(C)C3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3c(c2=O)CCCN3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
E5 (33 mg, 0.048 mmol) was dissolved in methanol and degassed with nitrogen for 5 min. Palladium (10% wt. on C, 33 mg) was added, then the reaction was placed under hydrogen atmosphere with a balloon. It was stirred for 2 h at room temperature, then filtered through Celite, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 16 mg, a colorless solid, 4. MS (MH+): 658.3. 1H NMR (400 MHz; CDCl3; T=298 K): δ 7.40 (m, 1H), 7.14 (m, 4H), 6.89 (dd, 2H, J=8.7, 22.9 Hz), 5.21 (m, 1H), 4.81 (m, 1H), 4.02 (dd, 2H, J=15.9, 9.9 Hz), 3.57 (d, 1H, J=9.6 Hz), 3.39 (m, 2H), 3.21 (m, 2H), 3.03 (m, 1H), 2.76 (d, 1H, J=14.8 Hz), 2.56 (m, 2H), 2.20 (dd, 1H, J=25.0, 15.8 Hz), 1.97 (d, 3H, J=11.2 Hz), 1.88 (s, 3H), 1.74 (m, 3H), 1.64 (m, 3H), 1.40 (d, 4H, J=10.8 Hz), 1.30 (d, 6H, J=18.8 Hz) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 45 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 4-methoxybenzenesulfonyl chloride (0.0420 g, 0.205 mmol) to obtain 4-(4-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0194 g, yield 45%).