Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cc2nc3ccccc3n2C)cc1
Temperature: 0 °C
Yield: 28 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (0.2 g, 0.75 mmol) in acetone was treated with potassium carbonate (0.31 g, 2.2 mmol), cooled to 0° C., treated dropwise with and methyl iodide (0.070 mL, 1.1 mmol), heated at 40° C. for 12 h, cooled to room temperature, and filtered. The filtrate was evaporated under reduced pressure. Purification of the resultant residue by column chromatography (silica, chloroform) afforded the title product (28%). 1H NMR (400 MHz, CDCl3): 7.98 (d, J=8.4 Hz, 2H), 7.7 (m, 1H), 7.37 (m,5H), 4.38 (s, 2H), 3.9 (s, 3H), 3.5 (s, 3H). [M+H] 281.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)/[C:9](=[N:13]/[OH:14])/[CH2:8][CH2:7][CH2:6]2)=[CH2:2].C([N-]C(C)C)(C)C.[Li+].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](OC)=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[C:25]1[CH:26]=[C:27]([C:28]2[O:14][N:13]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][C:8]=23)=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=4)[CH:32]=[CH:33][CH:34]=1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.151 g, 0.808 mmol) was added 5 mL of toluene and the contents were concentrated under reduced pressure. The resulting solid was kept under high vacuum for 10 min. The white solid was cooled to 0° C. and lithium diisopropylamide (2.0 M, 0.8 mL, 1.61 mmol) was added drop wise over a period of 3 min. The reaction mixture was stirred at 0° C. for 20 min., then methyl 3-(trifluoromethyl)benzoate (0.087 mL, 0.539 mmol) was added dropwise over a period of 1 min. at 0° C. After 10 min. at 0° C., concentrated sulfuric acid (0.2 mL) was added dropwise at 0° C. and the reaction was stirred for 20 minutes. Water (2 mL) was added and the homogenous solution was heated at 60° C. for ˜2 hr. The reaction mixture was stirred overnight at room temperature. The contents were concentrated under reduced pressure. Next, 5 mL of dioxane was added and the contents were heated at 100° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.15 g, 0.439 mmol, 82% yield) as a pale yellow solid. LC/MS M+1=342.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.O[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH: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>C1COCC1>[C:8]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH2:3][CH2:4]1)(=[O:10])[CH3:9]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-hydroxy-piperidin-1-yl)-ethanone (1.00 g, 6.90 mmol), 4-hydroxybenzaldehyde (0.854 g, 6.90 mmol) and triphenylphosphine (1.83 g, 6.90 mmol) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate (DIAD) (1.41 g, 6.90 mmol). The reaction mixture was stirred at room temperature for 16 hours, THF was evaporated, and the residue was purified by column chromatography, using dichloromethane:ethyl acetate:methanol (1:2:0.05) as eluent, to give 4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde. Yield: 0.40 g (23%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16].C(O)(=O)C.[ClH:26]>O>[Cl:26][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16]
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrite (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[Br:38][CH2:16][C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC#Cc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCC#Cc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 3-(4-Phenoxy-phenyl)-prop-2-yn-1-ol of Example 51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3 days. Evaporation of the solution, and chromatography of the residue gave the title compound as a brown oil: NMR (CDCl3) δ4.16 (s, 2H), 6.91 (d, J=2.1, 1H), 6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d, J=1.14, 1H), 7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98, 2H), 7.42 (d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C15H11BrO 287.155).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[C:9]([OH:11])[CH:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([CH:49]([CH3:53])[C:50]([OH:52])=O)[CH:43]=[CH:42]2>C(#N)C>[OH:11][C:9]1[CH:10]=[C:5]([CH:4]([OH:13])[CH2:3][N:2]([CH3:1])[C:50](=[O:52])[CH:49]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[CH:47][CH:48]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:45]=2)[CH3:53])[CH:6]=[CH:7][C:8]=1[OH:12]
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)N(C)CC(O)c3ccc(O)c(O)c3)ccc2c1
Reaction time: 0.17 h

Procedure:
Epinephrine (Aldrich, 3.18 grams [g], 17.3 millimoles [mmol]), 1-hydroxylbenzotriazole hydrate (Aldrich, 1.76 g, 12.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (Aldrich, 2.49 g, 12.9 mmol) were added to acetonitrile (200 milliliters [ml]). After stirring for 10 minutes, a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (Aldrich, 2.0 g, 8.66 mmol), in 50 ml of acetonitrile, was added dropwise. After stirring for 16 hours, the reaction mixture was concentrated in vacuo (under reduced pressure), and the residue was partitioned between water (100 ml) and methylene chloride (100 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2×50 ml) and ethyl acetate (50 ml). The combined organic extracts were treated with methanol until a clear solution was formed. This solution was dried (magnesium sulfate) and concentrated in vacuo. Flash chromatography of the residue (silica gel, 95:5, volume:volume [v:v], methylene chloride:methanol), and concentration of the appropriate fractions resulted in the formation of a solid. The solid was recrystallized from a mixture of ethyl acetate and hexane to give N-(2(3,4-dihydroxyphenyl)-2-hydroxyethyl)-N-methyl-2-(6-methoxy-2-naphthyl)propionamide, a mixture of diastereomers, as a white solid (0.95 g, 27% yield).
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C1C2CC(=[O:22])C(C2)C1.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:22]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: O=C1CC2CCC1C2
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 6.6 g (0.06 mole) of norcamphor and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene. The solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol, and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of the chromanol compound was heated at 150° C. to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained viscous liquid was purified by the chromatography on silica gel to obtain 6.3 g of a chromene compound of the following formula: ##STR70##
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[C:18]([C:21]1[C:26]([NH2:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:18]([C:21]1[C:26]([NH:27][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:6]([CH3:7])[CH3:8])[N:14]=2)=[O:17])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C(C)C)n2)c1C
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 125.2 %

Procedure:
POCl3 (0.88 mL, 9.53 mmol) was added at −25° C. drop wise over 5 min under nitrogen, to a stirred solution of 6-isopropylpyridine-2-carboxylic acid (106, 1.43 g, 8.66 mmol) and 6-acetyl-3-methoxy-2-methylaniline (1.55 g, 8.66 mmol) in dry pyridine (70 mL). The resulting solution was stirred at −10° C. for 2.5 h. Then, the reaction mixture was poured on ice, neutralized with aqueous sodium bicarbonate and extracted 3 times with AcOEt. The organic layers were combined, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (hexanes/AcOEt, 3:1) to give 3.54 g (72%) of the title compound 107: m/z=327 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH:17][C:18](=[O:27])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:4]=2)=[CH:30][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(C)=O)cc3)ccc2N)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
In a pressure vessel, N-[2-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxybenzamide (116) (170 mg, 0.462 mmol), 1-(4-bromophenyl)ethanone (184 mg, 0.923 mmol), (or any aryl bromide from the tables below), DME (4.6 mL per mmol of 116) and H2O (2.15 mL per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(PPh3)4 (27 mg, 0.023 mmol, 0.05 eq.) and Na2CO3 (147 mg, 1.38 mmol, 3.0 eq.) were then added and oxygen was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 75° C. overnight. The mixture was cooled at room temp., water was added and the mixture was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over MgSO4 and concentrated to give 42 mg (25%) of the title compound 117. 1H NMR (DMSO-d6) (ppm): 9.61 (s, 1H), 7.96 (dd, J=12.8, 8.8 Hz, 4H), 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.42 (dd, J=8.4, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 2.58 (s, 3H). MS (m/z): 360.41 (calc) 361.1 (MH+) (found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH3:11])[CH:6]=[C:5]([C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:4]=1.C([Li])CCC.[CH2:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[C:7]([O:9][CH2:10][CH3:11])[C:8]=1[CH:31]1[CH2:30][CH2:29][CH2:28][C:27](=[O:32])[CH2:26]1
Reactant: CCCCCCC(C)(C)c1cc(OC)cc(OCC)c1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCC(C)(C)c1cc(OC)c(C2CCCC(=O)C2)c(OCC)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Methoxy-3-(1,1-dimethylheptyl)-5-ethoxybenzene (IIa) (1500 mg, 5.4 mmol) was dissolved in dry ether (25 ml) and the solution was cooled to 0° C. The reaction was placed under nitrogen and butyl lithium (5.94 mmol, 3.6 ml of a solution in hexane) was injected into the reaction. The reaction mixture was brought to room temperature, and was stirred for 4 hrs. Cuprous bromide (360 mg, 2.5 mmol) was added in one portion. The reaction mixture turned dark and became homogeneous. After stirring for 5 min, 2-cyclohexanone (240 mg, 2.5 mmol) was injected into the solution, and the reaction mixture was stirred for 15 min at 0°. Ether (50 ml) and a saturated ammonium chloride solution (150 ml) were added. The organic layer was washed with brine, dried and evaporated to dryness. The oil obtained was purified by medium pressure liquid chromatography (230-400 mesh ASTM, silica gel 60" for column chromatography; elution with petroleum ether, b.p. 60°-80°) to yield the title compound, IIIa (66%).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[Na:12].C1C(=O)[N:17](OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.C(OCC)(=O)C>CS(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:15]([NH2:17])=[O:16])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2].[Na:12]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115 %

Procedure:
A solution of sodium sulfanilic acid (195 mg; 1 mmol) in dry DMSO (3 ml) was added dropwise to a solution of N,N′-disuccinimidyl carbonate (530 mg; 2 mmol) in dry DMSO (4 ml) and the resulting brownish solution stirred at room temperature for 20 hours. A solution of PAMAM 4.0 (EDA) (75 mg; 0.011 mmol) in dry DMSO (1 ml) added and the solution stirred for a further 18 hours. The solution was then concentrated under high vacuum (10−5 mmHg; 35°) to give a yellowish semi-solid. The crude product was dissolved in DMSO (4 ml) and the solution added to 200 ml of well stirred ethyl acetate. The precipitated white solid was collected by filtration and washed with ethyl acetate (2×) and ether (2×), then dried to give a white powder (275 mg). This material was further purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfophenylurea groups (106 mg). 1H nmr (D2O): δ 2.31; 2.55; 2.75; 3.19; 7.32 (d, J=9 Hz); 7.63 (d, J=9 Hz). 13C nmr (D2O): δ 36.3; 40.7; 43.3; 43.8; 53.7; 55.7; 123.3; 130.9; 140.9; 146.0; 161.4; 178.2; 178.6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a suspension of Intermediate 71a (2.28 g, 9.49 mmol) in EtOAc (25 mL) and aqueous NaOH (1M, 23.7 mL, 23.7 mmol) was added 2,2,2-trichloroethyl chloroformate (1.57 mL, 11.4 mmol) dropwise over 2 min. A precipitate formed which redissolved after 15 min, then the orange solution was stirred at RT for 90 min. 2,2,2-Trichloroethyl chloroformate (0.391 mL, 2.85 mmol) was added and the orange mixture stirred at RT for 16h. The layers were separated and the aqueous extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange-red oil. Recrystallisation from cyclohexane gave an off-white solid (3.12 g, 79%). LCMS (Method 3): Rt 4.46 min, m/z 415, 417 [MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[N:4]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:26])[F:27])=[CH:18][CH:19]=3)=[O:25])=[CH:9][CH:8]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-morpholinoaniline (270 mg, 1.5 mmol) in dry methylene chloride is added 4-trifluoromethoxy-phenyl isocyanate (229 μl, 1.5 mmol) at room temperature. After stirring at room temperature for 2 hours, the solvent is removed by rotary evaporator. The crude product, 1-(4-Morpholin-4-yl-phenyl)-3-(4-trifluoromethoxy-phenyl)-urea, is recrystallized in methanol to give a white solid (424 mg, 74% yield); 1H NMR (400 MHz, d-DMSO) δ3.00 (dd, J=4.7, 4.8 Hz, 4H), 3.71 (dd, J=4.5, 4.9 Hz, 4H), 6.87 (d, J=9.0 Hz, 2H), 7.24 (d, 2H), 7.29 (d, 2H), 7.5 (m, 2H), 8.44 (s, 1H), 8.75 (s, 1H); MS (ES+) m/e 382.1 (M+H+).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[NH:11][C:10](=[O:12])[C:5]3=[CH:6][CH:7]=[CH:8][C:9]=1[N:4]23.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]2[C:3]3=[CH:2][N:1]=[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([N:4]34)[C:10]2=[O:12])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: O=c1[nH]c2cnc3cccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1c(=O)c2cccc3ncc1n32
Yield: 20.9 %

Procedure:
To a suspension of 81 mg (0.51 mmol) of 3,4-dihydro-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of DMF was added, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 151 mg (0.51 mmol) of N-(5-bromopentyl)phthalimide in 1 ml of DMF. The mixture was stirred for two hours at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to afford 40 mg of the desired compound (20.9%, a colorless solid).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC to give the title product (32%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 4.72 min. δH(300 MHz; CDCl3): 3.44 (s, 3H), 6.76 (d, 1H), 6.81 (bs, 1H), 7.12 (d, 2H), 7.27-7.45 (m, 6H), 7.63 (dd, 1H), 8.42 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([CH:8]([C:18](=O)[CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)#[N:2].[CH2:24]([C:26]1[N:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[CH3:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:28]3[N:27]([C:26]([CH2:24][CH3:25])=[CH:30][CH:29]=3)[N:31]=[C:18]([CH3:19])[C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:21]=[CH:22][CH:23]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(C(C)=O)C(=O)c1cccc(C#N)c1
Reactant: CCc1cccn1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cccc(C#N)c1
Yield: 83.8 %

Procedure:
To a solution of ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.18 g) in toluene (30 mL) was added 2-ethyl-1H-pyrrol-1-amine (1.17 g) and p-toluenesulfonic acid monohydrate (96 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The mixture was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluting with hexane-ethyl acetate=20-1, 15-1, and 10-1 to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (3.29 g, 83.8%) as an yellow oil.