Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.Cl.Cl.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CCOC(C)=O>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[CH2:42][CH2:41]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(OC(F)F)ccc2o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC(F)F)ccc2o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
4,6-Dihydroxy-chromen-2-one (500 mg, 2.790 mmol) was dissolved in iPrOH (50 mL). KOH pellets (1.57 g, 27.90 mmol) were added and this mixture was stirred at 25° C. for 5 min. ClCHF2 (g) was bubbled through the reaction mixture for 5 min. The reaction was stirred an additional 10 min. at 25° C. followed by stirring for 30 min. at 60° C. The reaction mixture was diluted with EtOAc and washed with 1 N HCl (aq). The organic layer was dried over Na2SO4, concentrated, and partially purified via silica gel chromatography (20% CH3OH in CH2Cl2) to produce 490 mg of crude 6-difluoromethoxy-4-hydroxy-chromen-2-one. 626 mg of crude 6-difluoromethoxy-4-hydroxy-chromen-2-one was dissolved in CH2Cl2 (20 mL) under nitrogen, cooled to 0° C., and N,N-diisopropylethylamine (2.51 mL, 14.4 mmol) was added. Triflic anhydride (1.31 mL, 7.81 mmol) was added dropwise and the solution was stirred 30 min. at 0° C. The crude product was partially purified via silica gel chromatography (20% EtOAc in hexanes) to produce 682 mg of crude trifluoro-methanesulfonic acid 6-difluoromethoxy-2-oxo-2H-chromen-4-yl ester. 600 mg of crude trifluoro-methanesulfonic acid 6-difluoromethoxy-2-oxo-2H-chromen-4-yl ester was dissolved in CHCl3 (15 mL). 1-Naphthalen-2-ylmethyl-piperidin-4-ylamine dihydrochloride salt (448 mg, 1.43 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.30 mmol) were added and the resulting solution was stirred at 50° C. for 3 h. The reaction mixture was diluted with EtOAc and washed with H2O (3×) followed by saturated aqueous NaCl (1×). The combined organics were dried over Na2SO4, concentrated, and purified on a C-18 RP HPLC system to afford 50 mg of the title compound as a white solid. MS (ESI(+)Q1MS) m/z 451 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 7.77-7.91 (m, 5H), 7.32-7.54 (m, 5H), 6.86 (t, J=73 Hz, 1H), 5.34 (s, 1H), 3.74 (s, 2H), 3.48-3.60 (m, 1H), 2.98-3.08 (m, 2H), 2.21-2.33 (m, 2H), 2.00-2.10 (m, 2H), 1.69-1.83 (m, 2H). Compound II-125 was prepared similarly.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH2:22][CH3:23]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:25]([NH:24][CH2:21][CH2:22][CH3:23])=[O:26])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCCN=C=O
Product: CCCNC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared as described in Example 2 by reacting 1.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 0.339 g of n-propyl isocyanate. The product was purified by radial chromatography eluting with a gradient of 10-100% ethyl acetate/Hexane. MS(CI).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]([C:29]23[O:36][CH2:35][C:32]([CH3:37])([CH2:33][O:34]2)[CH2:31][O:30]3)[CH:6]1[CH3:38])=[O:4].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]([C:29]23[O:36][CH2:35][C:32]([CH3:37])([CH2:31][O:30]2)[CH2:33][O:34]3)[CH:6]1[CH3:38])=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(O)cc2)C(C23OCC(C)(CO2)CO3)C1C
Yield: 100.9 %

Procedure:
To an ethanol (15 ml) solution of 4-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (1.9 g, 3.48 mmol) was added 10% palladium hydroxide on carbon (370 mg). The mixture was shaken under about 20 psi hydrogen gas for about 1.5 hours. The resulting mixture was filtered through Celite® and concentrated in vacuo to give 1.55 g of the title compound (compound of formula XLV).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2([C:24]([NH2:26])=[O:25])[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:22][CH2:23]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC2(C(N)=O)CCNCC2)cc1
Reactant: BrCCc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2(C(N)=O)CCN(CCc3ccccc3)CC2)cc1
Reaction time: 4 h

Procedure:
A mixture of 33.35 parts of (2-bromoethyl)benzene, 35 parts of 4-[N-(4-methylphenyl)amino]-4-piperidinecarboxamide, 20 parts of N,N-diethylethanamine and 225 parts of N,N-dimethylacetamide is stirred for 4 hours at 70°-80° C. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is poured onto water, whereupon the product is precipitated. It is filtered off and suspended twice in water. The product is filtered off again, washed with 2,2'-oxybispropane and dried, yielding 4-[N-(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxamide; mp. 163.1° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:12]1[CH2:17][CH2:16][CH:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 4-hydroxybenzoate (30 g, 197 mmol, 1.0 mole equivalents), tetrahydro-4-pyranol (24 ml, 251 mmol, 1.3 mole equivalents) and triphenylphosphine (78 g, 297 mmol, 1.5 mole equivalents) in tetrahydrofuran (600 ml) at room temperature, was added diisopropyl azodicarboxylate (58 ml, 298 mmol, 1.5 mole equivalents) over a period of 15 minutes. The reaction mixture was stirred for 24 hours at room temperature. Another portion of diisopropyl azodicarboxylate (5 ml) and tetrahydro-4-pyranol (2 ml) was added and the reaction mixture was stirred for another 2 hours at room temperature. The reaction mixture was then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate (500 ml) and ethyl acetate (500 ml). The organic phase was washed with water (2×250 ml), dried (magnesium sulfate), and was then concentrated in vacuo to give the crude product, methyl 4-(tetrahydro-2H-pyran-4-yloxy)benzoate, as a thick yellow oil (182 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][N:16](C=O)C.O>[C-]#N.[Zn+2].[C-]#N>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A mixture of 2.0 g (7.43 mmol) of 3-bromo-5-(trifluoromethyl)benzoic acid [US 2006/0069261-A1, compound 1.2], 995 mg (8.48 mmol) of zinc cyanide and 859 mg (0.743 mmol) of tetrakis-(triphenylphosphine)palladium(0) in 75 ml of DMF/water (99:1) was initially degassed and then, under an atmosphere of argon, heated at 120° C. for 3 h. After cooling to RT, the mixture was diluted with about 300 ml of water and extracted three times with in each case about 150 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness on a rotary evaporator. The product was isolated by preparative HPLC (Method 9). Evaporation of the product fractions and drying of the residue under high vacuum gave 421 mg (26% of theory) of the title compound.
Reaction SMILES: C1(N)C=CC=C(N)C=1.NC1C=CC=CC=1.[C:16]1([C:28](Cl)=[O:29])[CH:21]=[C:20]([C:22](Cl)=[O:23])[CH:19]=[C:18](C(Cl)=O)[CH:17]=1.[C:31](Cl)(=[O:34])C=C>CN1CCCC1=O.O>[C:28](=[C:16]1[CH2:17][CH:18]=[CH:19][C:20](=[C:22]=[O:23])[C:21]1=[C:31]=[O:34])=[O:29]
Reactant: C=CC(=O)Cl
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: Nc1cccc(N)c1
Solvent: Nc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C=C1C=CCC(=C=O)C1=C=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, a 1,000 mL four-neck flask was charged with 20.37 g (188.3 mmol) of 1,3-phenylenediamine (DuPont K.K.), 28.06 g (301.3 mmol) of aniline (Junsei Chemical Co., Ltd.) and 250.4 g of N-methyl-2-pyrrolidone (Junsei Chemical Co., Ltd.), after which the flask contents were cooled to 5° C. Separately, in a 500 mL four-neck flask and under a nitrogen atmosphere, 40 g (150.7 mmol) of 1,3,5-benzenetricarbonyl trichloride (Wako Pure Chemical Industries, Ltd.) was dissolved in 250.4 g of N-methyl-2-pyrrolidone (Junsei Chemical Co., Ltd.), after which the solution was cooled to −20° C. and subsequently added dropwise to the amine solution at an internal temperature of 5 to 10° C. over a period of 30 minutes, thereby effecting polymerization. Following dropwise addition, the mixture was stirred for 1 hour at 10° C. or below. To this was added dropwise 27.27 g (301.3 mmol) of acryloyl chloride (Tokyo Chemical Industry) at an internal temperature of 5 to 10° C. over a period of 20 minutes, after which the mixture was stirred for 2 hours at 45° C. The reaction mixture was added to 2,000 g of pure water and re-precipitated, and the precipitate thus obtained was collected by filtration then dried at 150° C. for 3 hours in a vacuum desiccator. The resulting moist product was again dissolved in 240 g of DMAc and stirred at 45° C. for 1 hour. The DMAc solution was allowed to cool to 30° C., then added to 2,000 g of pure water and re-precipitated. The resulting precipitate was collected by filtration and dried at 150° C. for 10 hours in a vacuum desiccator, giving 52.7 g of the target tricarbonylbenzene-based hyperbranched polymer (abbreviated below as “HPmDA-Acry”). FIG. 8 shows the measured 1H-NMR spectrum for HPmDA-Acry.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20][C:21]([NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[N:22][C:23]([C:25]3[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=3)=[O:24])[NH:17][N:16]=2)=[C:11]([F:40])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:40][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:19]=[C:18]([NH:20][C:21]([NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[N:22][C:23]([C:25]2[C:26]([C:31]([F:33])([F:34])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=2)=[O:24])[NH:17][N:16]=1
Reactant: CC(C)CNC(=NC(=O)c1cn(C)nc1C(F)(F)F)Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)CNC(=NC(=O)c1cn(C)nc1C(F)(F)F)Nc1cc(-c2ccc(O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 32.8 %

Procedure:
N-(((3-(4-(Benzyloxy)-2-fluorophenyl)-1H-pyrazol-5-yl)amino)(isobutylamino)methylene)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (62 mg, 0.111 mmol) was dissolved in methanol (2 mL), and nitrogen gas was bubbled through briefly. 10% Palladium on carbon (59 mg, 0.5 equivalent) was then added, followed by ammonium formate (70 mg, 10 equivalents). The reaction vessel was sealed and then heated to 65° C. for 1 hour. Then, the crude mixture was cooled, and filtered through a plug of celite. The filtrate was concentrated onto silica gel and the crude product purified by chromatography (gradient: 9:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to provide the title compound as a white solid (17 mg, 33% yield). 1H NMR (DMSO-d6) δ 12.90 (s, 1H), 12.50 (s, 1H), 10.32 (bs, 1H), 8.83 (t, 1H), 8.28 (s, 1H), 7.55 (t, 1H), 6.65 (m, 2H), 6.35 (s, 1H), 3.89 (s, 3H), 3.39 (m, 2H), 1.83 (m, 1H), 0.94 (d, 6H). MS: calc.=467.42; obs. M+H=468.13. HPLC (Method E): retention time was 4.971 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:11][C:10]([CH3:26])=[N:9]2)=[CH:4][C:3]=1[CH3:27].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][C:10]([CH3:26])=[N:9]2)=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(Cl)c(C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C2CCNCC2)n(-c2ccc(Cl)c(C)c2)n1

Procedure:
The product from step B (145.7 mg, 0.373 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (100 uL, 1.298 mmol) was added dropwise with stirring. The reaction solution was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was purified by RP-HPLC(C18; acetonitrile, water, 0.1% TFA) to afford the title compound. HPLC/MS: 291.0/293.0 (M+1), Rt=2.09 (LC4).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[CH3:21][C:22]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=1[CH2:24][N:3]1[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1ccc(C)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 2,5-dimethylbenzyl bromide (0.289 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (15-50%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (96.4 mg, 0.254 mmol, 35.0% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.19 (s, 3H) 2.40 (s, 3H) 2.84 (s, 3H) 3.13-3.27 (m, 4H) 3.78-3.86 (m, 4H) 5.70 (s, 2H) 6.54 (s, 1H) 7.09 (d, J=7.83 Hz, 1H) 7.20 (d, J=7.58 Hz, 1H) 7.25 (d, J=2.27 Hz, 1H) 7.83 (d, 1H). MS (ES+) m/e 379.8 [M+H]+.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([CH:38]=[O:39])=[CH:36][N:35]=[N:34]1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([CH:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1nncc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.71 mL, 1.1 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (490 mg, 1.1 mmol, Intermediate 4: step d) in tetrahydrofuran (11 mL) at −78° C. After 2 minutes, a solution of 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (140 mg, 1.1 mmol, Intermediate 18) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 1 hour, water (10 mL) and ethyl acetate (60 mL) were added. The biphasic mixture was stirred for 10 minutes. Half-saturated aqueous sodium chloride solution (50 mL) was added and the layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (4 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 100% hexanes initially, grading to 100% ethyl acetate provided the title compound as a white foam which was impure. The foam was suspended in methanol (20 mL) and the suspension was sonicated for 5 minutes. The solids were collected by filtration and rinsed with methanol (5 mL). The collected solids were dried to provide the title compound as a white solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.42 (d, J=2.5 Hz, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.75-7.71 (m, 2H), 7.72-7.67 (m, 2H), 7.37-7.32 (m, 3H), 6.55 (d, J=5.2 Hz, 1H), 6.53-6.49 (m, 1H), 6.22 (d, J=5.2 Hz, 1H), 4.30 (s, 2H), 4.04 (s, 3H), 3.97 (s, 3H); MS (ESI): mass calcd. for C24H21ClN6O2, 460.1; m/z found, 461.1 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C(Cl)Cl>[Br:46][CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(C2=NCCO2)cc(Cl)c1OCCCCCc1cc(CBr)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
3-(Hydroxymethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (540 mg, 1.25 μmnol) in DCM (5 ml), prepared according to a literature procedure J. Med. Chem. (1990) 33, 1306-1311, was added rapidly to triphenylphosphine (410 mg, 1.56 mmol) and N-bromosuccinimide (278 mg, 1.56 mmol) in DCM (15 ml) at 0° C. The reaction was allowed to warm to room temperature, then after 3 hours the product was adsorbed onto silica gel and chromatographed on silica gel, eluent 1:1 ethyl acetate/hexane to give the brominated compound, 3-(bromomethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole as an off white solid (408 mg, 0.88 mmol) in 70% yield, Rf=0.25. 1H mm (D6 acetone): δ=8.01 (s, 2H); 6.46 (s, 1H); 4.69 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.00 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES):(M+H)+ 461,463,465. Neat 3,6,9-trioxa-11-azidoundecanol (237 mg, 1.08 mmol) prepared according to a literature procedure J Org. Chem. (1991) 56 4326, was added to a solution of sodium hydride (1.6 mmol) in DMF (3 ml) and stirred for 3 hours under argon. Tetrabutylammonium iodide (40 mg, 0.11 mmol) and a solution of the brominated compound (500 mg, 1.08 mmol) in DMF (3 ml) was added to the reaction. After 3 hours the reaction was quenched with water (1 ml) then partitioned between ethyl acetate (150 ml) and water (30 ml). The organic phase was washed with brine (30 ml), dried (Na2SO4) and concentrated to give a yellow brown oil. Chromatography of the crude residue twice on silica gel (50 g), eluent 2:1-3:1 ethyl acetate/hexane then 1:1 DCM/hexane gave 3-(1-azido-3,6,9,12-tetraoxamidecyl)-5-[5-[2,6-dichloro-4(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (Compound 1) (400 mg, 0.67 mmol) in 62% yield. 1H nmr (D6 acetone): δ=8.01 (s, 2H); 6.34 (s, 1H); 4.70 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.8 (m, 14H); 3.52 (t, 2H); 2.95 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES): (M+H)+ 600.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1B(O)O.[I:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1>CO>[I:13][C:14]1[N:15]=[CH:16][N:17]([C:3]2[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH:18]=1
Reactant: Ic1c[nH]cn1
Reactant: OB(O)c1cc(F)cc(F)c1F
Solvent: CO
Product: Fc1cc(F)c(F)c(-n2cnc(I)c2)c1
Reaction time: 21 h
Yield: 26.9 %

Procedure:
Following a procedure similar to that outlined in Synthesis 2008, 795-799: A mixture of 2,3,5-trifluorophenylboronic acid (0.302 g, 1.72 mmol), 4-iodo-1H-imidazole (0.498 g, 2.57 mmol), 2 mL of methanol, and Cu2O (0.049 g, 0.34 mmol) was stirred under air for 21 h, then filtered through Celite and concentrated to an oily white solid. Column chromatography (0->33% EtOAc/hexanes) afforded 0.150 g (27%) of 4-iodo-1-(2,3,5-trifluorophenyl)-1H-imidazole as a white solid. MS: (M+H)+=325.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[CH3:17]C1C=C(C)C=CC=1NN>>[ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([CH3:17])[CH:4]=1
Reactant: Cc1ccc(NN)c(C)c1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1cc(C)c2[nH]cc(CCN)c2c1

Procedure:
5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,4-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material. ##STR51##