Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=[O:7])[CH:3]=[N:2]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:2]1[CH:3]=[C:4]([C:6]([OH:8])=[O:7])[CH:5]=[N:1]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1cnn(C2CCCCO2)c1
Temperature: 80 °C

Procedure:
To 1.00 g (7.14 mmol) ethyl 4-pyrazolecarboxylate and 0.98 mL (10.7 mml) 3,4-dihydro-2H-pyran an 20 mL THF are added 0.94 mL (12.1 mmol) TFA and the reaction mixture is stirred at 80° C. over night. Afterwards the reaction mixture is diluted with DCM and charged with aq. NaHCO3 solution. The layers are separated and the org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][NH:2][C:3]([F:5])=[O:4].[Cl:6][C:7]([Cl:11])([Cl:10])[S:8]Cl.CCOP(OC1C=CC2C(C)=CC(OC=2C=1)=O)(OCC)=S>>[CH3:1][N:2]([S:8][C:7]([Cl:11])([Cl:10])[Cl:6])[C:3]([F:5])=[O:4]
Reactant: CNC(=O)F
Reactant: ClSC(Cl)(Cl)Cl
Agent: CCOP(=S)(OCC)Oc1ccc2c(C)cc(=O)oc2c1
Product: CN(SC(Cl)(Cl)Cl)C(=O)F

Procedure:
N-Methyl-N-trichloromethanesulfenylcarbamoyl fluoride was prepared from methylcarbamoyl fluoride and trichloromethanesulfenyl chloride according to the method reported in West Germany Pat. No. 1.297,095 (Farbenfabriken Bayer, A. G), June 12, 1969.
Reaction SMILES: N1(C(OC(C)(C)C)=O)C[CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[C:22]([O:26][C:27]([N:29]1CCC(C(O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(O)C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:29]1([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:4][CH2:3][CH:2]([C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:7])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Oc2ccccc2)C1
Yield: 83 %

Procedure:
The compound 24 was prepared according to the method described for compound 22 employing 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (500 mg, 2.32 mmol), phenol (198 mg, 2.12 mmol) and DCC (522 mg, 2.53) to give pale white solid compound 24 (510 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 1.84-1.57 (m, 1H), 2.21 (m, 2H), 3.17-3.70 (m, 4H), 7.00 (s, 1H), 7.02 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>C1COCC1.[Pd]>[F:20][C:19]([F:21])([F:22])[CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: FC(F)(F)CCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1ccc(OCCCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
60 g (193 mmol) of 1-(benzyloxy)-4-(4,4,4-trifluorobutoxy)benzene, and 7.61 g of Pd/C are dissolved in 900 mL of THF. 5 mL of triethylamine are added to the suspension. The reaction is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtrated of 400 g of hyflo. The organic phase is concentrated under reduced pressure. Filtration of the residue on 900 g silica gel using toluene:ethyl acetate 4:1 as eluent and concentration under reduced pressure yields 41 g of 4-(4,4,4-trifluorobutoxy)phenol as a reddish oil.
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: Cc1nc2nccn2c(O)c1-c1c(F)cccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nccn2c(Cl)c1-c1c(F)cccc1Cl

Procedure:
A mixture of 0.16 g of 5-hydroxy-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine, 0.20 g of N,N-diethylaniline and 2 ml of phosphorus oxychloride was refluxed under heating for 26 hours. The reaction mixture was concentrated, and dichloromethane and aqueous saturated sodium bicarbonate solution were added to the residue. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel chromatography to give 45mg of 5-chloro-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[CH2:17]([OH:20])[CH2:18][OH:19].N1C(C)=CC=CC=1C>O.[B-](F)(F)(F)F.[Ag+]>[OH:19][CH2:18][CH2:17][O:20][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: OCCO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=C(O)CCCCCCC1=CC(OCCO)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29° C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatography of the residue on silica gel gives an oil, λ maxMeOH = 216 mμ (8350); ν max = 3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm -1 (olefin group).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[CH:20][C:12]=3[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:20][C:12]=3[C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 1-iodo-3,4-methylenedioxybenzene 0.14 g,cesium carbonate 0.22 g, tris(dibenzylideneacetone)dipalladium(0) 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg,and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg were added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoate. Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoic acid 12 mg of white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 23.4 %

Procedure:
To a solution of 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (73 mg, 239 μmol, prepared as described in example 38) in NMP (796 μL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (206.4 mg, 956 μmol) in 4 portions approximately every 12 h over 48 h and heated at 140° C. in the periods between additions. After 48 h, the mixture was diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (3×), concentrated in vacuo, and purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (27 mg, 56 μmol, 23%) as a light brown solid. MS (EI/CI) m/z: 486.2 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:21].BrBr>CO.C([O-])(O)=O.[Na+]>[Br:21][CH:18]([C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1)=[O:20])[CH3:19]
Reactant: CCC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(Br)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 3 (3.3 g, 11.6 mmol) in CH3OH (50 ml) under Ar with 48% HBr (100 μL) was added dropwise at room temperature bromine (1.9 g, 11.8 mmol). After stirring overnight, the solution was poured in saturated NaHCO3 and the aqueous solution extracted with EtOAc (3×). The combined organic extracts were backwashed with brine, dried, filtered and concentrated to dryness to yield 4.3 g of 4.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[C:13]([C:25]([O:27]CC)=[O:26])[C:12]2=[O:30])=[CH:2]1.[OH-].[K+]>C(O)C.O.Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[C:13]([C:25]([OH:27])=[O:26])[C:12]2=[O:30])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 110.2 %

Procedure:
To a solution of the compound (0.20 g, 0.45 mmol) of Example 53 in ethanol (2.0 mL), aqueous 50% w/v potassium hydroxide solution (0.5 mL) was added at ambient temperature. The mixture was stirred at 95° C. for 3 h. Cooled to ambient temperature, diluted with water and conc. hydrochloric acid was added dropwise to neutralize. The precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.19 g, y. 98%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=1.[C:12]([C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]([C@@H:16]1[CH2:17][CH2:18][C@H:19]([NH:22][C:2]2[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
32.3 g (0.15 mol) of 4,5-dichloro-6-(1-chloroethyl)pyrimidine(EP 543 402) were stirred in 200 ml of toluene with 23.3 g (0.15 mol) of cis-4-tert-butylcyclohexylamine and 20.2 g (0.20 mol) of triethylamine at from 80° to 90° C. for 6 hours. The mixture was extracted by stirring with water and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel, to give 36.3 g (73.2% of theory) of a colorless oil.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)Cl.[Cl:25][C:26]1[CH:31]=[C:30](I)[CH:29]=[CH:28][N:27]=1.IC1C=CC=CN=1>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu](I)I>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a de-gassed suspension of zinc powder (912 mg, 14 mmol) in DMA (2.3 mL) was added drop-wise a solution of chlorotrimethylsilane and 1,2-dibromoethane (0.1 mL, 7:5 v/v ratio) and the resultant mixture was stirred at room temperature for 15 minutes. To this mixture was then added dropwise to a solution of 3-iodoazetidine-1-carboxylic acid tert-butyl ester (3.2 g, 11.3 mmol) in DMA (8.0 mL) and the resultant mixture was stirred at room temperature for 15 minutes. In a separate flask, PdCl2(dppf)2.DCM (196 mg, 0.24 mmol) and then copper iodide (92 mg, 0.48 mmol) were added to a degassed solution of 2-chloro-4-iodopyridine in DMA (20 mL). After allowing to age for 30 minutes, the zinc suspension above was added to the iodopyridine solution and the reaction mixture was allowed to stir at room temperature for 2 hours. The resultant mixture was quenched by adding saturated ammonium chloride solution and was then extracted with TBME (×2). The combined organic washings were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-25% ethyl acetate in cyclohexane) to afford the title compound as a white solid (1.2 g, 56%). LCMS (Method F): RT=3.71 min, m/z: 414 [M+H+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.IC1C=CC(I)=CC=1.FC1C=CC=CN=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: Ic1ccc(-c2ccccn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Fc1ccccn1
Agent: Ic1ccc(I)cc1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Yield: 89 %

Procedure:
The strategy for a sample convergent synthesis of a highly branched first generation organometallic dendrimer of the invention is shown in FIGS. 1 and 2. Taking FIG. 1 as an example, 2-(4-iodophenyl)pyridine (1) was prepared in a 40% yield by reaction of the mono-lithiated 1,4-diiodobenzene with 2-fluoropyridine. Trimethylsilylacetylene was then coupled with (1) under Sonogashira conditions to afford 2-(4-trimethylsilylethynylphenyl)pyridine (2) in an 89% yield. The acetylene was easily deprotected with either tetra-n-butylammonium fluoride in tetrahydrofuran or by treatment with aqueous potassium hydroxide in a methanol/dichloromethane mixture. Both methods gave 2-(4-acetylenylphenyl)pyridine (3) in an isolated yield of 80%. The dendronised ligand (5) was then formed by reaction of 3 with 2,3,4,5-tetraphenylcyclopentadienone (4). The reaction was heated at 220° C. for two to three hours using diphenyl ether as the solvent after which (5) was isolated in a 93% yield. The complexation of (5) to form the fac-tris(2-phenylpyridyl)iridium (III) cored dendrimer utilised the standard two step procedure. In the first step 2.5 equivalents of (5) was reacted with iridium trichloride trihydrate in aqueous 2-ethoxyethanol heated at reflux to give a mixture of the bis-iridium bis-chloro dimer and unreacted ligand. This mixture was then reacted with an excess of (5) in the presence of silver trifluoromethylsulfonate in diglyme at 130° C. to give, after purification, the desired dendrimer (6) in a 63% yield for the two steps. Gel permeation chromatography (GPC) showed that the dendrimer was mono-disperse and the facial nature of the dendrimer was confirmed by 1H NMR by comparison with spectra reported for other dendrimers with fac-tris(2-phenylpyridyl)iridium (III) cores.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH3:18])[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:21][CH2:22][C:23](=[O:26])[CH2:24][CH3:25].O>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH2:18][C:23]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:21])[CH2:14][CH2:15][CH2:16]2)=[CH:11][CH:12]=1
Reactant: CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC(O)(CC)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2.7M solution of butyllithium in hexane (24 ml) was added under nitrogen to a stirred solution of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone oxime [prepared as described in Example 84 (7.2 g)] in dry tetrahydrofuran (100 ml) over a period of 45 minutes whilst maintaining the temperature in the range -3° to 0° C. The mixture was stirred at 0° C. for 1 hour and then cooled to -5° C. A solution of dry pentan-3-one (3.4 ml) in dry tetrahydrofuran (10 ml) was added, the temperature of the mixture was allowed to rise to ambient and the mixture was stirred under nitrogen for 16 hours. The mixture was cooled to below 10° C. and water (100 ml) was added dropwise under nitrogen. The mixture was extracted with ether, the extracts dried and evaporated and the residue triturated with ice-cold petroleum ether (b.p. 40°-60° C.) to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-3-hydroxypentan-1-one oxime (m.p. 113°-115° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[CH:8]=1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.O1CCCC1>[CH:29]1([CH2:32][N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][C:9]=3[CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[CH2:18][CH2:17]2)[CH2:31][CH2:30]1
Reactant: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(CC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 1-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg, 0.026 mmol) produced in Example (100b), cyclopropanecarbaldehyde (0.004 mL, 0.054 mmol) and tetrahydrofuran (2 mL) were added sodium triacetoxyborohydride (14 mg, 0.066 mmol) and acetic acid (0.002 mL, 0.035 mmol) in that order, followed by stirring for 40 minutes at room temperature. Ethyl acetate, saturated aqueous sodium hydrogencarbonate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was concentrated by blowing nitrogen. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-cyclopropylmethyl-4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solution was concentrated by blowing nitrogen gas, and diethyl ether was added to the obtained residue to produce a solid. After triturating the solid by sonication, the supernatant diethyl ether solution was removed. The solid residue was dried by blowing nitrogen, to give 3 mg of the title compound as a light yellow solid.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([O:42][C:43]3[C:48]([C:49]([NH:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([C:59]([CH3:64])([CH3:63])[C:60]([OH:62])=O)=[CH:55][CH:54]=4)=[O:50])=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:41][C:36]=2[O:35][CH2:34]1>O1CCCC1>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([O:42][C:43]3[N:44]=[CH:45][CH:46]=[CH:47][C:48]=3[C:49]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([C:59]([C:60](=[O:62])[NH2:3])([CH3:63])[CH3:64])=[CH:55][CH:54]=3)=[O:50])=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C(=O)O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C(N)=O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g), 1-hydoxybenzo-triazole hydrate (1.24 g), and were combined and suspended in anhydrous tetrahydrofuran (45 mL). N,N-Diisopropylethylamine (5.93 mL) was added to the suspension, which was stirred for 0.5 h. 2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid (0.340 g) was added to the suspension, and the reaction mixture stirred at ambient temperature overnight. Anhydrous ammonia gas was bubbled into the solution for 20 min, generating a white precipitate, and then the reaction mixture was concentrated in vacuo. Water was added to the reaction mixture, and it was extracted with dichloromethane (7×30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate) and further purified by silica gel chromatography (ethyl acetate:hexanes 17:3) to yield the title compound (0.150 g).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[OH:15].ClCl.[N+]([O-])(O)=[O:19]>O>[CH3:6][C:7]1[C:8](=[O:15])[C:9]([CH3:14])=[CH:10][C:11](=[O:19])[C:12]=1[CH3:13]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=[N+]([O-])O
Agent: ClCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 2 h

Procedure:
1000 g of carbon tetrachloride was charged in a 5-liter four neck flask equipped with a stirrer, a condenser, a chlorine-bubbling pipe and a thermometer, and 408 g (3 moles) of 2,3,6-trimethylphenol was dissolved therein. Thereafter, 210 g (3 moles) of chlorine gas was bubbled thereinto at 40°C in 2 hours. After the completion of the bubbling, a mixture of 210 g of a commercially available nitric acid (63 percent by weight) and 600 g of water was immediately added dropwise thereto at 40°C for 2 hours. After the completion of the dropwise addition, the stirring was continued for further 1 hour. Then, the reaction solution was allowed to stand, and the separated lower layer of carbon tetrachloride was taken out, and washed with water, followed by distilling off carbon tetrachloride. Thus, 460 g of the residue was obtained as a red oil, in which 405 g of 2,3,6-trimethyl-p-benzoquinone was included. (90 percent in yield).