Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[I:28]I.Cl>C1COCC1>[F:16][C:17]1[C:25]([I:28])=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: II
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(I)c(F)c(C(=O)O)c1
Temperature: -60 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (42 g, 298 mmol, 2.5 eq) in THF at −60° C. under N2 was added n-BuLi (2.2 M, 141 mL, 309.3 mmol, 2.6 eq) dropwise over a period of 30 min. The reaction mixture was stirred at −60° C. for 2 h, then a solution of 2-fluoro-5-methoxy-benzoic acid (15 g, 119 mmol, 1.0 eq) in THF (300 mL) was added dropwise with stirring. The reaction was stirred for a further 2 h at −60° C., then iodine (45 g, 179 mmol, 1.5 eq) was added in portions. The reaction was warmed to room temperature slowly and the resulting mixture acidified by addition of 1M HCl and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (5.6 g, 16%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[C:22]([Br:27])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[C:22]([Br:27])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 5) (480 mg, 0.913 mmol) in DCM (8 mL) at 0° C. was added TFA (1.9 mL) dropwise. The mixture was stirred for 2 h at RT and evaporated. The residue was triturated with hexane to afford (S)-3-amino-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (260 mg) as brown solid. LC-MS: 428 (M+H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([N:6](S(C(F)(F)F)(=O)=O)[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])(=[O:5])=[O:4].[OH-].[Na+].CO.O>Cl>[F:24][C:2]([F:1])([F:25])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:5]
Reactant: COC(=O)c1cccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(NS(=O)(=O)C(F)(F)F)c1

Procedure:
A solution of methyl 3-{bis[(trifluoromethyl)sulfonyl]amino}benzoate (5.4 g, 13.0 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to 3-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (2.3 g, 66%). 1H-NMR (400 MHz, DMSO-d6): ): δ 7.83-7.78 (m, 2H), 7.55-7.50 (m, 1H), 7.50-7.46 (m, 1H). ES-LCMS m/z 269 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=O)=[CH:10][CH:9]=1)([CH3:5])[CH3:4].Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:1][CH2:2][C:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15]/[C:16](=[N:35]\[OH:36])/[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:10][CH:9]=1)([CH3:5])[CH3:4]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1

Procedure:
In analogy to example 151, step 3, N-(1-hydroxy-2-methylpropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=462.3 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[CH:37]=[N:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[N:34][C:33]=2[C:32]([CH3:52])=[N:31]1>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[N:36]=[CH:37][C:38]4[N:30]([CH3:29])[N:31]=[C:32]([CH3:52])[C:33]=4[N:34]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc2c(n1)c(C)nn2C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ncc4c(n3)c(C)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (0.055 g, 0.107 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[4,3-d]pyrimidine (0.058 mg, 0.133 mmol), copper(I) iodide (6 mg, 0.032 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.012 mmol) in dioxane (1 mL) was heated at 90° C. for 16 hr. Reaction mixture was cooled to rt, filtered through a syringe filter and purified by CombiFlash (0 to 70% EtOAc/Hex) to give title product. LCMS-ESI+: calc'd for C28H29ClN5O3S: 550.2 (M+H+); Found: 550.3 (M+H+); 1H NMR (400 MHz, Methanol-d4) δ 9.32 (s, 1H), 7.88 (s, 1H), 7.70-7.53 (m, 4H), 5.30 (s, 1H), 4.13 (s, 3H), 3.75 (s, 3H), 2.57 (s, 3H), 2.54 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: Cc1ccc(C)c(CN)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: Cc1ccc(C)c(CNC(=O)C(C)c2cccc3cnccc23)c1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,5-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 319 (M+H)+; MS (ESI−) m/z 317 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 6.79 (s, 1H), 6.91 (d, J 7.8, 1H), 6.98 (d, J 7.8, 1H), 7.83 (t, J 7.8, 1H), 8.00 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.37 (d, J 6.4, 1H), 8.46 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=3)=[O:18])[C:6]1=[O:7])(O)=[O:2].Cl.C(OCC)(=O)C>B.O1CCCC1>[OH:2][CH2:1][CH2:4][N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=3)=[O:18])[C:6]1=[O:7]
Reactant: O=C(O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 35 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A mixture of (S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 10) (6 mg) in 1.0 M borane in tetrahydrofuran solution (2 mL) under argon was stirred at 35° C. for 3 h. After cooling to room temperature, 1.0 M aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL) were added. This mixture was stirred for 3 h before the layers were separated. The organic phase was washed with water (10 mL three times) and evaporated under vacuum. The residue was chromatographed on reverse phase preparative HPLC to isolate the title compound (1.1 mg) and the over-reduction product (S)-1-(2-hydroxyethyl)-3-(5-chloroindole-2-carbonylamino)-1,2,3,4-tetrahydroquinoline (0.9 mg). Title compound HPLC/MS [M+H]+, 384.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH3:17])[CH3:2].[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:7]=1[CH3:17])[CH3:2]
Reactant: CCCCCCCCI
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCn1c(C)c(CC(=O)OCC)c2cc(OC)ccc21
Yield: 51.5 %

Procedure:
Using the procedure described in Example 50, Part A, 2.47 g (0.01 mol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 0.48 g (0.012 mol) of 60% NaH/mineral oil and then 2.17 mL (0.012 mol of iodooctane. The product was chromatographed on silica gel and eluted with 5% EtOAc/toluene to give 1.85 g (51% yield) of 5-methoxy-2-methyl-1-octyl-1H-indole-3-acetic acid ethyl ester as an oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18]>CS(C)=O>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:17]=[CH2:18]
Reactant: C=CCNCC=C
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCN(CC=C)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
Under an Ar atmosphere, 2.16 ml p-fluorobenzaldehyde and 3 ml DMSO were added sequentially to 3.5 g (30 mmol) of anhydrous K2CO3, 3.70 ml (20 mmol) diallylamine. With constant stirring, the mixture was heated to about 155°-160° C. After refluxing for 20 hours, the solution became intense red. The mixture was cooled to room temperature and 10 ml distilled water was added to dissolve any inorganic salts and the product was extracted with ether. The water layer was washed with ether several times and the combined organic layers were dried over MgSO4. The ether solution was then filtered and the ether, unreacted starting materials and solvent DMSO were removed by vacuum distillation at 100° C. A very viscous orange red product was left in the flask. Yield=2.05 g (51%). Mass spectrum: M+ /e=201. Calcd. M+ /e=201.27 Anal. calcd. for C13H15NO, C, 77.58; H, 7.51; N, 6.96. Found: C, 77.33; H, 7.33; N, 6.66. 1H NMR(CDCl3), δ 9.71 (1H,s), 7.70 (2H, d, J=9Hz), 6.70 (2H, d, J=9Hz), 5.82 (2H, m), 5.19 (4H, m), 4.00 (4H,t). 13C NMR (CDCl3) δ 189.4, 152.8, 131.8, 116.8, 110.9, 52.22 ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C:10]2=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+].[BH4-]>CO.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([CH2:14][N:15]3[CH2:31][CH2:30][C:18]4([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][NH:20][C:19]4=[O:29])[CH2:17][CH2:16]3)[C@@H:10]2[OH:13])=[CH:5][CH:4]=1
Reactant: O=C1c2cc(Cl)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(C[C@@H]1CCc3ccc(Cl)cc3[C@H]1O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A slurry of 8-[(7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (9.0 g, see example 189) in 200 ml of methanol is treated with a solution of 3.7 g of sodium borohydride in 25 ml of water. The soldium borohydride solution is added dropwise with ice cooling. The resulting mixture is stirred for 16 hours under nitrogen at room temperature. The reaction mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution affords a crude semi-solid. Trituration with absolute ehtanol gives 6.4g of the title compound, melting point 248°-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:19][CH:20]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:19][CH:20]=2)[C:9]1=[O:13]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(N2CCN(c3cnccc3C)C2=O)cn1
Yield: 39.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with N-(5-bromo-pyridin-2-yl)-acetamide (217.4 mg, 1.016 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 105 mg of the product (40% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a solution of iodobenzene (102 mg), 4-chlorophenylboronic acid (117 mg), and potassium carbonate (138 mg) in ethanol (3 ml) was added the mesh catalyst precursor (12 mm by 14 mm) prepared in Example 3 and heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol and taken off from the mixture. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane) to give an intended product, 4-chlorobiphenyl quantitatively. The mesh catalyst precursor taken off from the mixture was again used in the same reaction to again give the intended product, 4-chlorobiphenyl quantitatively. The mesh catalyst precursor could be recycled at least thirty times.
Reaction SMILES: [CH:1]1([C:4]2[N:9]([CH2:10][C:11](O)=[O:12])[C:8](=[O:14])[C:7]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][NH:20][C:19]=4[N:18]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C@H:32]([NH2:35])[C:33]#[CH:34])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:36])[CH2:31][C@H:32]([NH:35][C:11](=[O:12])[CH2:10][N:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:8]1=[O:14])[C:33]#[CH:34])[CH3:28]
Reactant: O=C(O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O
Reactant: C#C[C@@H](N)CC(=O)OCC
Product: C#C[C@H](CC(=O)OCC)NC(=O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O

Procedure:
Following the procedures described for Scheme 16, the acid 17-7 was coupled with 3-amino-3(S)-(ethynyl)-propionic acid ethyl ester 2-9 (Zablokie et al, J. Med. Chem., 1995, 38, 2378) to afford the title compound 17-12.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22]C(=O)C)([O-:3])=[O:2]>S(=O)(=O)(O)O>[NH2:22][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][C:12]=2[Cl:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 66.1 %

Procedure:
To concentrated sulphuric acid (350 ml), N-[2-nitro-5(2-chloro-4-{trifluoromethyl}phenoxy)phenyl]acetamide (75.5 g; 0.2 mole) is added in small portions in the course of twenty minutes. The temperature rises to 30° C. The reaction mixture is then heated to 50° C. for 2 hours and, after being cooled, is then poured onto ice/water (1 kg). The solid thus obtained is purified by chromatography to give 1-amino-2-nitro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene (44 g), m.p. 100° C. Yield 69%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:13]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
Ethyl pyrazole-4-carboxylate (W. Holtzer, G. Seiringer, J. Heterocyclic Chem., 1993, 30, 865) (1.7 g, 12.1 mmol) and NaH (680 mg, 60% in mineral oil, 16.94 mmol) reacted in dry DMF for 1 h. Then, trityl chloride (3.373 g, 12.1 mmol) was added, and the reaction mixture stirred for 3 days at room temperature. The title compound was recovered as described in example 2a for 3,5-dimethyl-4-ethylacetate-1-tritylpyrazole. Yield: 82% (3.79 g, 4 mmol).
Reaction SMILES: [ClH:1].Cl.Cl.NCCC[N:8]([CH2:14][C:15]1[C:16]2[C:21]([CH:22]=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].Cl.Cl.Cl.NCCCCN(CC1C2C(C=C3C=1C=CC=C3)=CC=CC=2)CCCCN.Cl.Cl.Cl.NCCCCN(CC1C2C(C=C3C=1C=CC=C3)=CC=CC=2)CCCCCN.Cl.Cl.Cl.NCCCCNCCCCNCC1C2C(=CC=CC=2)C=CC=1.Cl.Cl.Cl.NCCCCNCCCCNCC1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.Cl.Cl.Cl.C1C2C(=CC3C(C=2CNCCCCNC2CCC(N)CC2)=CC=CC=3)C=CC=1>>[ClH:1].[ClH:1].[CH:27]1[C:28]2[C:23](=[CH:22][C:21]3[C:16]([C:15]=2[CH2:14][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][CH:26]=1
Reactant: NCCCCN(CCCN)Cc1c2ccccc2cc2ccccc12
Agent: Cl
Agent: NC1CCC(NCCCCNCc2c3ccccc3cc3ccccc23)CC1
Agent: NCCCCCN(CCCCN)Cc1c2ccccc2cc2ccccc12
Product: NCCCCNCc1c2ccccc2cc2ccccc12

Procedure:
As is apparent from the above Tables 1–3, a limited class of N-alkylarylpolyamine compounds (i.e. N-naphthylalkyl, N-anthracenylalkyl and N-pyrenylalkyl) have unique properties of surprising cytotoxicity, unexpected selectivity in killing cancer cells (especially cells with high polyamine transport activity), and/or facilitate the delivery of known toxic agents into cancer cells. As shown in Table 2, the N-(3-Amino-propyl)-N-anthracen-9-ylmethyl-butane-1,4-diamine, trihydrochloride (8d), N-(4-Amino-butyl)-N-anthracen-9-ylmethyl-butane-1,4-diamine, trihydrochloride (8e), N-(4-Amino-butyl)-N-anthracen-9-ylmethyl-pentane-1,5-diamine, trihydrochloride (8g), N-(4-Amino-butyl)-N′-naphthalen-1-ylmethyl-butane-1,4-diamine trihydrochloride (27b), N-(4-Amino-butyl)-N′-pyren-1-ylmethyl-butane-1,4-diamine trihydrochloride (27d), and N-{4-[(Anthracen-9-ylmethyl)-amino]-butyl}-cyclohexane-1,4-diamine trihydrochloride (31) have outstanding selectivity in targeting and killing cells with active polyamine transporters.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[CH:6]1[OH:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCC1(CCCC)CCc2c(O)cccc2C1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (9.59 g) in dry diethyl ether (100 ml) was added lithium aluminium hydride (1.33 g) slowly at 0° C .under a nitrogen atmosphere. The suspension was stirred for 3 hours at 0° C. and then poured into ice. The mixture was acidified with aqueous 1N hydrochloric acid and the separated oil was extracted with diethyl ether. The extract was washed with brine and aqueous sodium bicarbonate solution. The solvent was dried and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (elution by CH2Cl2 and then 2% CH3OH in CH2Cl2) to yield 2,2-dibutyl-5-hydroxy-1,2,3,4-tetrahydro-1-naphthol (9.05 g) as crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCNCC1
Agent: Cl
Product: O=C1CCN(Cc2ccccc2Br)CC1
Yield: 82.2 %

Procedure:
According to the procedure described for Intermediate 31, alkylation of 4-piperidone hydrochloride (1.0 g, 4.0 mmol) with 1-bromo-2-bromomethylbenzene (543 mg, 4.0 mmol) afforded the title compound (882 mg, 82% yield). HR-MS (m/z, MH+): measured 268.15
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([N+:16]([O-:18])=[O:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31](B(O)O)=[CH:30][C:29]=2[CH:36]=1)[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:31]2[O:32][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][O:22][CH2:20][CH3:21])=[CH:36][C:29]=3[CH:30]=2)=[C:11]([N+:16]([O-:18])=[O:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3[N+](=O)[O-])cc2c1
Yield: 90.2 %

Procedure:
By following the same procedure as described in Example 1 (step d), was prepared using (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (12) (100 mg, 0.30 mmol) and 5-ethoxymethoxy-benzofuran-2-boronic acid (4) (92.5 mg, 0.39 mmol). Work-up as described in example 1d, followed by purification of the crude product by flash column chromatography using 10-25% ethyl acetate in hexane. Evaporation of solvent afforded 120 mg of the desired compound (13) as yellowish solid.