Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=C(C(O)=O)[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:1]([C:2]([Cl:4])=[O:3])[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(Cl)cnc(Cl)c2c1

Procedure:
Anal. Found: C, 49.59; H, 2.08; N, 5.74. Calc for C10H5Cl2NO2 : C, 49.62; H, 2.08; N, 5.78. ##STR170## Oxalyl chloride (144 μL, 1.65 mmol) was added to a suspension of 1,4-dichloro-7-isoquinolinecarboxylic acid (200 mg, 0.83 mmol) at room temperature in CH2Cl2 (10 mL), followed by DMF (1 drop). After 30 min the resultant clear solution was evaporated in vacuo to afford 1,4-dichloro-7-isoquinolinecarbonyl chloride which was used without further purification.
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](C)[C:33](=O)C(F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O.N[C@H](C(O)=O)CCCCN.[N+](C1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1S([O-])(=O)=O)([O-])=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:31][CH:30]([NH:32][CH3:33])[CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2)N(C)C(=O)C(F)(F)F
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 173 mg of keyhole limpet hemocyanin in 7 ml of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution were added 10.5 mL of dimethylsulfoxide (DMSO) dropwise, and the reaction temperature was maintained below room temperature. To the protein solution was added a solution of 40.2 mg of 1L in 1.5 mL of DMF dropwise. The mixture was allowed to stir at room temperature 18 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each for at least 6 hours each). The protein concentration was determined to be 2.9 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 34 mL of the conjugate was obtained. The extent of available lysine modification was determined to be 72% by the 2,4,6-trinitrobenzene sulfonate (TNBS) method (Habeeb AFSA, Anal. Biochem. 14:328-34, 1988).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:26])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(C)c(OCc3ccccc3)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)c(OCc3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 5-benzyloxy-4-methyl-1H-indole-2-carboxylate (3.50 g, 11.3 mmol), 60% sodium hydride (0.45 g, 11.3 mmol) and N,N-dimethylformamide (70 ml) was stirred at room temperature for 30 minutes, and then methyl iodide (3.21 g, 22.6 mmol) was added dropwise thereto, followed by stirring at room temperature for another 2.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane=3/97) to obtain 3.53 g of ethyl 5-benzyloxy-1,4-dimethyl-1H-indole-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[N:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:30][C:6]1[N:2]([CH3:1])[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]=1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
Methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (12.5 g, 42.6 mmol) was dissolved in methylene chloride (120 mL), to which was added NIS (10.6 g, 47 mmol) and 0.5 mL of TFA. After stirring for 5 min, the reaction was diluted with 120 mL of methylene chloride and quenched with aq NaHCO3. The organic layer was separated, washed with aq Na2S2O3, water, brine, dried over MgSO4, filtered, and concentrated to give 16.3 g of methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. 1H NMR (500 MHz, (CDCl3): 8.63 (m, 1H), 8.24 (d, 1H), 8.18 (s, 4H), 7.83 (m, 1H), 7.31 (m, 1H), 4.22 (s, 3H), 3.96 (s, 3H). LCMS: [M+1]=420.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][Mg]Br>CCOCC>[OH:10][C:9]1([CH3:12])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: O=C1CCCc2ccccc21
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CCCc2ccccc21
Yield: 84.6 %

Procedure:
A solution of 98.0 g (0.670 mol) of α-tetralone in 800 ml of anhydrous ether was added over 30 min to a solution of 285 ml (0.855 mol) of 3.0M methyl magnesium bromide in ether under N2 whilst stirring magnetically. After completion of the addition, the reaction was heated to reflux for 30 min, allowed to cool, then quenched with 120 ml of saturated ammonium chloride solution. The ether layer was decanted from an offwhite solid, washed with water (400 ml), then with saturated sodium chloride solution, dried (K2CO3) and evaporated in vacuo to leave 91.9 g (85%) of an orange solid. NMR δ(CDCl3) 1.57 (3H, s), 1.77 (1H, s), 1.80-2.00 (4H, m), 2.80 (2H, m), 7.08 (1H, d of d), 7.18 (1H, t of d), 7.23 (1H, t of d), 7.60 (1 H, d of d).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5](N)=[N:6][CH:7]=1.N(OCCC(C)C)=O.C[Si](C)(C)[Br:26].C(=O)(O)[O-].[Na+]>BrCBr.CCCCCCC>[Br:26][C:5]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: BrCBr
Product: Clc1ccc(-c2nc(Br)cnc2Br)cc1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a suspension of 12.00 g (0.033 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 80 ml dibromomethane was added 5.93 g isoamyl nitrite. To the resulting mixture was added dropwise during ca 45 min a solution of 7.75 g trimethylbromosilane in 20 ml dibromomethane with stirring at ambient temperature. The mixture was stirred at room temperature for 2 h. To the resulting dark solution was added 100 ml of a 10% aqueous sodium bicarbonate. The phases were separated and the organic phase washed with brine. To the organic phase was added silica gel (ca. 100 g) and the solvent was removed under aspirator vacuum. The product was purified by chromatography with dichloromethane:heptane=1:3 to yield 11.93 g (79% yield) 2,5-dibromo-3-(4-chloro-phenyl)-pyrazine as white crystals melting at 123-125° C. and as a byproduct 0.300 g 5-bromo-3-(4-chloro-phenyl)-2-(3-methyl-butoxy)-pyrazine as a yellow oil. MS (ISP) (M+H+)=357.0 and 355.0.
Reaction SMILES: [CH3:1][C@:2]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[C:10]([O:9][C:8]([NH:7][C@@:2]1([CH3:1])[CH2:6][CH2:5][N:4]([C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:3]1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
tert-Butyl [(3S)-3-methylpyrrolidin-3-yl]carbamate (I-345) (240 mg, 1.20 mmol) was dissolved in diethyl ether (12 ml), then an aqueous saturated sodium hydrogencarbonate solution (12 ml) was added, and at room temperature, benzyloxycarbonyl chloride (222 μl, 1.56 mmol) was added, followed by stirring at room temperature for 16 hours. The reaction liquid was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (400 mg, 100%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:25](O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:25])[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CN1CCC(Nc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
Combine (3-(1-methylpiperidin-4-ylamino)phenyl)carbamic acid tert-butyl ester (Preparation 9, 1.15 g, 3.77 mmol), methanol (15 mL) and formaldehyde (37% aq., 0.92 mL, 11.3 mmol). Stir at room temperature for 45 min. Cool to 0° C. Add acetic acid (0.22 mL, 3.77 mmol) and sodium cyanoborohydride (414 mg, 6.59 mmol). Stir at room temperature overnight. Concentrate to dryness. Dissolve the residue in a 2/1 mixture of ethyl acetate and hexanes (20 mL) and wash with sodium hydroxide (1N aq., 2×20 mL). Separate the organic layer and dry over magnesium sulfate. Filter and concentrate under reduced pressure. Purify through flash chromatography eluting with a 20/1 mixture of dichloromethane and 2M ammonia in methanol to provide the title compound (990 mg, 82%): mass spectrum (ion spray): m/z=320.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[Mg].[CH3:14][C:15]([CH3:17])=[O:16].Cl>CCOCC>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][C:15]([CH3:17])([OH:16])[CH3:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1cccc(C(F)(F)F)c1
Yield: 73 %

Procedure:
A solution of 3-trifluoromethylbenzyl chloride (25.0g; 0.128 mole) in ether (130 ml) was added dropwise during 50 minutes to magnesium (3.11 g; 0.128 mole) in a three-necked dry flask equipped with stirrer and reflux condenser. The spontaneous reflux was allowed to continue for another half an hour. The solution was cooled and acetone (7.45; 0.128 mole) was added dropwise (8 minutes) and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (100 ml) and concentrated hydrochloric acid (11 ml). The phases were separated. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was fractioned affording 1-(3-trifluoromethylphenyl)-2-methyl-2-propanol. (B.p. 63°-64° C/1.0 mm Hg, M.p. 55°-56° C recryst. from petroleum ether.) Yield: 73%; 20.3 g.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH2:3].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[CH3:3][C:2]1([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:17][CH2:1]1
Reactant: C=C(C)CCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCC1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of 2-methyl-1-heptene 4 (17 g, 0.15 mol) in methylene chloride (300 mL) at 0° C. was added meta-chloroperbenzoic acid (37 g, 0.18 mol) in portions. The reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature overnight. It was cooled in an ice bath and then filtered. The filtrate was washed with 5% sodium hydroxide, saturated sodium chloride and dried over magnesium sulfate; 7.8 g of 2-methyl-1-heptene oxide 5 was obtained after HPLC purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: C1=COCCC1
Reactant: CC(C)OC(=O)[C@@H]1CCC[C@H](CO)C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)[C@@H]1CCC[C@H](COC2CCCCO2)C1
Reaction time: 8 h

Procedure:
100 g of isopropyl (1R,3S)-3-hydroxymethylcyclohexanecarboxylate and 46.2 g of dihydropyran are dissolved in 500 ml of dichloromethane and, at 0° C., 4.75 g of toluenesulfonic acid monohydrate are added. The solution is stirred overnight and then sat. sodium bicarbonate solution is added. The organic phase is separated off, diluted with MTBE and washed with sat. sodium chloride solution, dried over MgSO4 and concentrated, resulting in 140 g of isopropyl (1R,3S)-3-(tetrahydropyran-2-yloxymethyl)cyclohexanecarboxylate as brown oil.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]Br.[Cl:12][C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:22][CH2:23][NH:24][CH2:25][C:16]=3[C:15]=2[CH:14]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[CH2:22][CH2:23][N:24]([CH2:10][CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:25][C:16]=3[C:15]=2[CH:14]=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CNCC3
Reactant: BrCCCc1ccccn1
Agent: Br
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2[nH]c3c(c2c1)CN(CCCc1ccccn1)CC3

Procedure:
The title compound was prepared following the procedure of Example 1 with the exception that 3-pyridinylpropyl bromide hydrobromide was used instead of 4-pyridinylbutyl bromide hydrobromide and 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The product as converted to the dihydrochloride salt; mp. 240°-242° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.C1CCCCC1.CN(C)[CH:38]=[O:39].[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:38]=[O:39])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(Br)cc1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-bromo-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (20 g, 50.2 mmol) dissolved in tetrahydrofuran (200 mL) under a nitrogen atmosphere at −78° C. was added 1.3 M sec-BuLi in cyclohexane (100.5 mmol, 77.3 mL) dropwise. The solution was allowed to stir at −78° C. for 30 minutes. Anhydrous N,N-dimethylformamide (150.6 mmol, 11.6 mL) was added in one portion and the solution was allowed to warm to room temperature. After stirring for 30 minutes the mixture was poured over saturated NH4Cl solution and extracted with diethyl ether (3×). The organic layers were combined, washed with water (1×), saturated brine (2×), dried over Na2SO4 and concentrated to a crude yellow oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give impure [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester as a clear oil used directly in the following procedure. (11.62 g crude).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[C:20]([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH3:20][O:18][C:17](=[O:19])[C@H:6]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Thionyl chloride (4.25 mL, 58.10 mmol, 2.4 eq) was added dropwise to a suspension of L-tryptophan (5.0 g, 24.48 mmol, 1.0 eq) in dry MeOH (50 mL) at −15° C. The cold bath was removed and the solution was stirred at room temperature for 24 h, then concentrated under vacuum at 40° C. gave a residue which was dissolved in H2O (75 mL) and then neutralized with Na2CO3 to a pH 8. Extraction with CHCl3 (3×50 mL) and dried over anhydrous MgSO4. Evaporation of the solvent gave the L-tryptophan methyl ester as a brick-red viscous oil (5.37 g, 98%); IR (liquid film) ν 1755 (CO), 3290 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.78 (2H, s, —NH2), 3.10 (1H, dd, J=6.8 and 14.8 Hz, —CHαTrp), 3.32 (1H, dd, J=6.0 and 14.8 Hz, —CHβTrp), 3.80 (3H, s, OMe), 4.50 (1H, t, J=6.8 Hz, —CH—), 7.06 (1H, t, J=7.4 Hz, H-5′), 7.13 (1H, t, J=7.4 Hz, H-6′), 7.23 (1H, s, H-2′), 7.39 (1H, d, J=7.8 Hz, H-7′), 7.55 (1H, d, J=7.8 Hz, H-4′) and 8.47 (1H, s, pyrrol NH), which was sufficiently pure and used directly in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[CH:15][CH:14]=1.[Cl:29]CCl>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([Cl:29])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
To (0.05 mol) of 3-(4-(2-quinolinylmethyloxy)benzyl)benzoic acid in dichloromethane solution (500 mol) and chilled in an ice bath is added thionyl chliride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[Cl:12].[CH2:13](N(CC)CC)[CH3:14]>C(O)C>[Cl:12][C:7]1[C:6]2[C:11](=[C:2]([CH:13]=[CH2:14])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: Clc1ccnc2c(Br)cccc12
Solvent: CCO
Product: C=Cc1cccc2c(Cl)ccnc12
Yield: 27.2 %

Procedure:
A suspension of 975 mg (4.02 mmol) 8-bromo-4-chloroquinoline (commercially available from Ubichem Research Ltd, Budapest, Hungary), 166 mg (0.20 mmol) PdCl2dppfCH2Cl2, 833 mg (6.00 mmol) potassium vinyl tetrafluoroborate and 0.57 ml (4.10 mmol) triethylamine in 20 ml ethanol was heated at reflux for 3 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (hexane/ethyl acetate 9:1) to yield 207 mg (27%) of the title compound as white crystals. MS: 189.1 (M+). 1H-NMR (300 MHz, CDCl3): 5.53 (d, J=11.1 Hz, 1H); 5.95 (d, J=17.7 Hz, 1H); 7.51 (d, J=4.6 Hz. 1H); 7.63 (t, J=7.9 Hz, 1H); 7.96 (dd, J=17.7, 11.1 Hz, 1H); 7.97 (d, J=7.1 Hz, 1H); 8.19 (d, J=8.5 Hz, 1H); 8.80 (d, J=4.6 Hz, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:19]1[C:26](Cl)=[N:25][C:23]([Cl:24])=[N:22][C:20]=1[Cl:21]>O1CCCC1>[Cl:21][C:20]1[N:22]=[C:23]([Cl:24])[N:25]=[C:26]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[N:19]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1nc(Cl)nc(Cl)n1
Temperature: 65 °C

Procedure:
2.7 g of magnesium was added to 200 ml of tetrahydrofuran and stirred until the magnesium was completely dissolved. To the solution was added dropwise a solution of bromohexadecane (31.1 g) in tetrahydrofuran (200 ml). Thereafter, the resulting solution was heated to 65° C. and reacted for 6 hours with stirring. The reaction solution was slowly added dropwise to a solution of cyanuric chloride (15 g) in tetrahydrofuran (250 ml), and reacted for 12 hours. After completion of the reaction, the resulting solution was evaporated under reduced pressure to obtain a concentrate and then the concentrate was purified by distillation in vacuo to yield pure 2,4-dichloro-6-hexadecyl-1,3,5-triazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:52]2[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
The solution of 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (Aldrich) (21.88 g, 95.4 mmol), triethylamine (13.3 mL, 95.4 mmol) and HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] (38.36 g, 101.0 mmol) in dry dimethylformamide (100 mL) was stirred at room temperature for five minutes before N-methyl-piperazine (10.6 mL, 95.5 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (350 mL), extracted with ethyl acetate (3×250 mL), the combined organic layers were washed with saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol=9:1 as eluent to yield 25.8 g (87%) of the title compound as an oil.