Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[C:10]([O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[C:11]2[N:12]=[N:24][NH:1][C:2]2=[CH:3][CH:4]=3)=[CH:21][CH:20]=1
Reactant: O=N[O-]
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1oc2c(ccc3[nH]nnc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 7,8-diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (115 mg, 0.35 mmol) and 5% aqueous acetic acid (5 ml) is cooled to 0° C., and sodium nitrite (26 mg, 0.38 mmol) is added portionwise. The mixture is stirred for 18 h as it is allowed to warm to room temperature. The reaction is quenched with saturated aqueous sodium bicarbonate (50 ml), and the mixture is extracted with ethyl acetate (3×50 ml). The organic phases are combined, washed with saturated aqueous sodium bicarbonate (50 ml) and then with saturated brine (50 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel using n-hexane/ethyl acetate (0-100% ethyl acetate) as eluant to give the product as a colourless solid.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Na]>CN(C)C=O>[N:17]1([CH2:2][CH:3]=[CH:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CC=CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCn1ccnc1

Procedure:
A mixture of 23.5 g. of N-(4-chloro-2-butenyl)-isoindole-1,3(2H)-dione, 11.0 g. of sodium imidazole and 200 ml. of dimethyl formamide was heated on the steam bath for 18 hours and concentrated to remove the solvent; the residue was taken up in methylene chloride, washed with water, dried with magnesium sulfate and again concentrated. The residue was dissolved in hot ethylacetate and allowed to cool and N-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, m.p. 106°-108° C., was obtained.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25]CC[Si](C)(C)C)=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:25][C:13]1[C:12]([CH2:11][CH:10]=[C:9]([CH3:32])[CH2:8][CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[C:6]([OH:42])=[O:5])=[C:20]([O:21][CH3:22])[C:19]([CH3:23])=[C:18]2[C:14]=1[C:15](=[O:24])[O:16][CH2:17]2
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)O)C(=O)OC2
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) was added TBAF (50 μL, 1M solution in THF) at room temperature. The solution was stirred for 16 hours and concentrated. The solution was dried under reduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL). The solution was filtered through Acrodisc (13 mm syringe filter with a 0.45 μm Nylon membrane) and purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H2O, 0.1% TFA-CH3CN, 0.1% TFA. The product from the column was subjected to ion exchange chromatography (Sodium salt form of Dowex 50WX8-400) using a 2×4.5 cm column eluting with H2O-MeOH (1:1) to provide 7.5 mg of the desired product as an oil. 1H NMR (300 MHz, CDCl3) δ 1.80 (s, 3H), 2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6 Hz), 5.43-5.54 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 23.5 ppm; MS (m/z) 469.2 [M+H]+, 491.3 [M+Na]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=O)[O:12][C:13]2=[O:18])([O-:8])=[O:7].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]C(O)=O)=[CH:23][C:22]=1[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:39][CH3:40])[CH2:35][CH2:34]1)=[O:32]>>[F:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[C:11]2\[O:12][C:13](=[O:18])[C:14]3[C:10]\2=[C:9]([N+:6]([O-:8])=[O:7])[CH:17]=[CH:16][CH:15]=3)=[CH:23][C:22]=1[C:31]([N:33]1[CH2:34][CH2:35][CH:36]([O:39][CH3:40])[CH2:37][CH2:38]1)=[O:32]
Reactant: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cccc([N+](=O)[O-])c43)ccc2F)CC1
Temperature: 240 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
Sodium acetate (6.97 mg, 0.08 mmol) was added to 4-nitroisobenzofuran-1,3-dione (558 mg, 2.89 mmol) and 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (43) (502 mg, 1.70 mmol) under air. The resulting mixture was stirred at 240° C. for 30 minutes. The cooled mixture was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a yellow gum (50 mg, 6.90% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.59-2.00 (4H, m), 3.10-3.26 (1H, m), 3.37 (3H, s), 3.43-3.57 (2H, m), 3.61-3.71 (1H, m), 3.88-4.05 (1H, m), 7.16-7.20 (1H, m), 7.30 (1H, s), 7.70-7.76 (1H, m), 7.86-7.88 (1H, m), 7.97-8.01 (1H, m), 8.27 (1H, d), 8.39 (1H, d); m/z (LC-MS, ESI+), RT=2.29 (M+H 427.3).
Reaction SMILES: [CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16](O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)([Cl:35])=O>C1C=CC=CC=1>[CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]([Cl:35])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)Cl
Yield: 72.1 %

Procedure:
A solution of 1.0 g of 2-tetradecylhexadecanoic acid and 0.79 g of thionyl chloride in 5 ml of benzene was refluxed for 7 hours. After removal of benzene and thionyl chloride, anhydrous benzene was added to the residue and then benzene was removed by distillation. This procedure was repeated 3 times to remove thionyl chloride completely. The residue was recrystallized from anhydrous hexane to obtain 0.75 g of 2-tetradecylhexadecanoyl chloride having a melting point of 51°-53° C. To the solution of 0.85 g of 1-α-O-benzyl-N-acetylmuramyl-L-alanyl-D-isoglutamine benzyl ester in 35 ml of anhydrous pyridine, was added 4.9 g of 2-tetradecylhexadecanoyl chloride dissolved in 35 ml of anhydrous tetrahydrofuran at 17°-18° C. After 45 minutes, 20 ml of water was added and the solution was stirred for 35 minutes at room temperature. The solution was adjusted to pH 3 with 1 M hydrochloric acid and extracted with chloroform. The chloroform solution was washed with saturated brine, and dried. After removal of solvent, the residue was subjected to silica gel column chromatography. Eluate with a mixture of chloroform and methanol (20:1) was concentrated and the residue was recrystallized from methanol to obtain 0.75 g of 6-O-(2-tetradecylhexadecanoyl)-1-α-O-benzyl-N-acetylmuramyl-L-alanyl-D-isoglutamine benzyl ester having a melting point of 173°-174° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][N:4]([CH2:9][CH:8]([OH:10])[CH2:7][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: C1CNCCN1
Solvent: CO
Product: OC(COc1ccc(Cl)cc1)CN1CCN(CC(O)COc2ccc(Cl)cc2)CC1

Procedure:
While 9.3 g of piperazine is refluxed in 50 ml of methanol with stirring, 10 g of p-chlorophenyl glycidyl ether are added dropwise over a period of 1.5 hours. After the addition has been completed, the mixture is refluxed with stirring for a further 1.5 hours, and then concentrated to dryness under reduced pressure. The residue is dissolved in dilute hydrochloric acid and extracted with ethyl acetate. The water layer is rendered basic with sodium hydroxide, extracted first with benzene from which there can be obtained N,N'-bis[3-(4-chlorophenoxy)-2-hydroxypropyl]piperazine, and then with n-butanol. The butanol extracts are washed with water and the solvent then removed by distillation under reduced pressure to yield 10.0 g of N-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperazine as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][NH:27]1>CN(C=O)C>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][N:27]1[C:16]1[C:17]([F:19])=[C:18]2[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]=1[F:21]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 33.4 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 76 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC1C=C([N+]([O-])=O)C=C(F)C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cc(F)cc([N+](=O)[O-])c2)C1
Agent: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(3-Fluoro-5-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. A 3 L 3-neck round bottom flask was charged with sodium hydride (60% in oil, 54.24 g, 1.356 mol) and DMF (1 L). The flask was cooled in an ice bath, a solution of (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester alcohol (210 g, 1.043 mol) in DMF (500 mL) was added dropwise over 30 minutes to the flask, maintaining an internal temperature below 5° C. The solution was stirred for 1 hour, then was added via a canula into a 5 L 3-neck round bottom flask charged with a solution of 3,5-difluoronitrobenzene (169.25 g, 1.064 mol) that was cooled in an ice bath. The addition lasted for 1 hour, maintaining an internal temperature below 5° C. The reaction mixture was warmed to room temperature and stirred for 4 hours and diluted with 6 L ethyl acetate. The organic layer was washed with saturated ammonium chloride (4 L), sodium bicarbonate (2 L) and brine (2 L), dried (Na2SO4) and concentrated to afford the desired product (S)-3-(3-fluoro-5-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as an syrup (360 g, purity ˜95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:6]=2[N:7]=1.S(=O)(=O)([OH:15])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCCC1.C(O)(C)(C)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:15])=[O:12])[C:6]=2[N:7]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1csc2cnc(Cl)nc12
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1csc2cnc(Cl)nc12
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a suspension of 0.640 g (3.22 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde in 20 mL of tetrahydrofuran, 10 mL of tert-butanol and 10 mL of water was added 1.25 g (12.9 mmole) of sulfamic acid. A solution of 0.729 g (8.06 mmole) sodium chlorite and 3.33 g (24.5 mmole) of potassium dihydrogen phosphate in 24 mL of water was slowly added via additional funnel. The reaction mixture was stirred at room temperature for over night. Water and ethyl acetate were added, separated. Aqueous layer was washed with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was dried in high vacuum for over night to give 0.660 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid as a yellow solid. MH+/Z=215
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[CH:27][C:19]([C:18]([F:30])([F:29])[F:17])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(C(F)(F)F)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-trifluoromethyl-2-oxindole to give 0.35 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-trifluoromethyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH:29]([CH3:31])[CH3:30])[NH:17][CH:16]2[C:32](O)=[O:33])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:40][C@@H:39]([CH2:41][CH2:42][NH2:43])[CH2:38][O:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:40][C@H:39]([CH2:38][OH:37])[CH2:41][CH2:42][NH:43][C:32]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH:29]([CH3:30])[CH3:31])[NH:17]1)=[O:33]
Reactant: CC(C)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 52.6 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 49c (0.5 g, 0.97 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.25 g, 52%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1ccccc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccccc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (62 mg, 82%), MS (ISP) m/z=302.6 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [C:1](C(N)CN)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C([N:24](CC)CC)C>CN(C=O)C>[C:1]([NH2:24])([O:3][CH2:4][CH:5]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: NCC(N)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-1,2-diaminoethane (0.06 mmol) in 0.4 mL DMF at 0° C., is added triethylamine (0.12 mmol) followed by dropwise addition of DOTA(OtBu)3 NHS ester (0.05 mmol) in 0.5 mL DMF for 10 min with stirring. After 10 min, the ice bath is removed and stirring is continued at room temperature (RT) for 6 h. The reaction mixture is poured over 2 mL ice-cold water and purified by preparative HPLC. After concentration and lyophilization, Fmoc amine monomer 23 is obtained which is further treated with 1 mL 20% piperidine in DMF, and the solution is stirred at RT for 30 min. The reaction mixture is poured over 2 mL ice-cold water and purified by preparative HPLC. After lyophilization, DOTA(OtBu)3-aminoethane 24 is obtained.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][SiH:22]([O:25][CH3:26])[O:23][CH3:24]>[Pt].C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][Si:22]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:20])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOc1cccc(OC(=O)c2ccccc2)c1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1cccc(OC(=O)c2ccccc2)c1)(OC)OC
Temperature: 20 °C

Procedure:
A mixture of 25.4 g. (0.1 mole) of 3-allyloxyphenyl benzoate, 50 ml. of dry toluene, 20 g. (0.15 mole) of trimethoxysilane and 2 drops of platinum hydrosilation catalyst is heated at 90° C. for 17 hours under nitrogen. After the reaction mixture is cooled to about 20° C., it is concentrated under reduced pressure to produce the uv precursor product. For purification, the product is passed through a short silica column using dichloromethane as an eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCC(C)CBr
Solvent: CO
Product: CCCC(C)COc1ccc(OC)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
Sodium metal (6.99 g, 304 mmol) was dissolved in dry methanol (120 ml) under Ar to give a 2.5M solution of sodium methoxide. A solution of 4-methoxyphenol (31.4 g, 253 mmol) in dry methanol (150 ml) was added and this mixture was heated to reflux for 30 min. After cooling to room temperature, a solution of 1-bromo-2-methylpentane (46.0 g, 279 mmol) in dry methanol (100 ml) was added. The mixture was then heated to reflux for 16 hours. The solvent was removed in vacuo, the residue dissolved in ether (200 ml), washed with dilute aqueous sodium hydroxide (250 ml) and water (500 ml), dried over MgSO4 and concentrated in vacuo again. Distillation at 80° C./0.5 mm Hg afforded 14.0 g (27%) 1-methoxy-4-(2'-methylpentyloxy)benzene, 1H NMR (250.1 MHz, CDCl3): δ=0.94(t,3H), 1.02 (d, 3H), 1.16-1.56 (m, 4H), 1.93 (m, 1H), 3.64-3.82 (m, 2H), 3.77 (s, 3H), 6.81-6.89 (m, 4H), 13C NMR (100.6 MHz, CDCl3): δ=14.3, 17.0 (both CH3), 20.1, 35.8 (both CH2), 33.0 (CH), 55.7 (OCH3), 73.9 (OCH2), 114.6, 115.4 (arom. CH), 153.5, 153.6 (ipso C). IR(film): 2956(m), 1509(s), 1232(s), 1045(m), 824(m) cm-1, MS(EI): m/z (%)=208 (100), 124 (32), Calcd. for C13H20O2 : C 74.96, H 9.68 found: C 75.03, H 9.70.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Br:28]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a solid mixture of 7-(4-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (305 mg, 0.83 mmol) and N-bromosuccinimide (162 mg, 0.91 mmol) cooled with an ice bath was added acetonitrile (6 mL). Resulting mixture was stirred at 0° C. for 1.5 h and was concentrated. The residue was purified by silica gel chromatography (eluting with 10%-40% ethyl acetate in hexanes) to provide the title compound (217 mg). 1H NMR (200 MHz, CDCl3) δ 11.88 (s, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.46 (dd, J=9.0, 2.4 Hz, 1H), 7.08 (d, J=9.4 Hz, 2H), 6.95 (d, J=9.8 Hz, 2H), 4.46 (t, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.85 (m, 2H), 1.47 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:27]1([O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCC1
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC)CCCCC1
Yield: 34.4 %

Procedure:
The compound 19 (345 mg, 1.00 mmol) was converted to the acetal with 1,1-dibutoxycyclohexane (2.28 g, 10.0 mmol) in the same manner as the example 18 to give the compound 21 (172 mg, 35%) as oil. Rf 0.41 (Al2O3 60, Type E, toluene).