Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH2:16])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[N:35][CH:34]=[C:33]([Sn](C)(C)C)[N:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([O:30][C:31]1[N:32]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH2:16])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:3]=2)[CH:34]=[N:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: CC(C)Oc1cncc([Sn](C)(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(N)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Temperature: 90 °C
Yield: 58.8 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (250 mg, 0.52 mmol) and 2-isopropoxy-6-(trimethylstannyl)pyrazine (188 mg, 0.62 mmol) in dry DMF (2.5 mL) for 15 min. To the mixture was added CuI (99 mg, 0.52 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with water. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (150 mg, 59%). MS (ESI, pos. ion) m/z: 491.1 (M+1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.Cl.[C:10]12([CH2:20][CH2:21][N:22]([NH2:35])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>N1C=CC=CC=1>[C:5]([NH:35][N:22]([CH2:21][CH2:20][C:10]12[CH2:11][CH:12]3[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]3)[CH2:19]1)[CH2:17]2)[C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)=[O:24])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
Pyridine (2.0 ml) and acetic anhydride (1.0 ml) were added to 1-[2-(1-adamantyl)ethyl]-1-amino-3-[3-(4-pyridyl)propyl]urea dihydrochloride (Compound No. 3-3) (0.20 g, 0.47 mmol) at room temperature, and the mixture was stirred for 15 minutes. The solvent was evaporated under reduced pressure from the reaction mixture, and the residue was distributed with ethyl acetate (10 ml) and water (10 ml). The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (10 ml) and saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatographyto give 0.11 g (58%) of the titled compound.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[NH2:11].[Cu][C:13]#[N:14].[NH4+].[OH-].ClCCl>CN(C=O)C>[NH2:11][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: Nc1cc2c(cc1I)CCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1N)CCC2
Temperature: 160 °C
Yield: 59 %

Procedure:
To a solution of 6-iodoindan-5-amine (135 mg, 0.52 mmol) in DMF (2 mL), was added copper (I) cyanide (93 mg, 1.04 mmol). The mixture was heated at 160° C. for 1.5 h. The reaction mixture was poured into 10% NH4OH. An equal amount of dichloromethane was added and resulting mixture was filtered. The filtrate was partitioned between two layers. The aqueous layer was extracted with dichloromethane (1×). The combined organic layers were concentrated in vacuo. The residue was dissolved in ethyl ether. The ether layer was washed with aqueous sodium bisulfite, dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) yielding 6-aminoindane-5-carbonitrile (48.5 mg, 59%). LCMS calc.=158.08; found=159.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 6.64 (s, 1H), 4.25 (br, s, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.09-2.03 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20](=[O:21])[N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][OH:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCNc1ccc(Br)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N(CCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.3 g (6 mmol) 2-(4-bromo-phenylamino)-ethanol are dissolved in 150 mL toluene, treated with 0.93 mL (1.1 eq.) benzyloxycarbonylchloride and 6.3 mL (1.05 eq.) 1N aqueous sodium hydroxide solution. The reaction mixture is stirred at room temperature for 18 hours, then the aqueous phase separated and extracted with ethyl acetate and water. The combined organic phases are washed with water and brine, then evaporated to dryness to yield 2.1 g crude (4-bromo-phenyl)-(2-hydroxy-ethyl)-carbamic acid benzyl ester, which is reacted further without additional purification by dissolution in 100 mL dichloromethane, addition of 5 mL (excess) pyridine, cooling to 5° C. and dropwise addition in 10 minutes of 2.45 g p-toluenesulfonic acid anhydride in 20 mL dichloromethane. The reaction mixture is stirred an additional 2 hours at room temperature and poured onto ice, then extracted at 10° C. with dichloromethane and an aqueous solution of sodium bicarbonate. The combined organic phases are dried with sodium sulfate and evaporated to yield the desired product as a light brownish resin, which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][C:8]([C:17]([OH:19])=[O:18])=[CH:7][C:6]2=1>[Pd].CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C:17]([OH:19])=[O:18])[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CO3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)CC(C(=O)O)CO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
10% Palladium on activated carbon (140 mg, 0.14 mmol, 0.05 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid (700 mg, 2.72 mmol, 1.0 eq) in methanol (20 mL) and tetrahydrofuran (20 mL). The resulting mixture is stirred under hydrogen flow (3 bars) at room temperature for 48 hours. The catalyst is then removed by filtration and the solution is concentrated to afford 6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid as a light yellow semisolid (520 mg, 74% yield) which is directly engaged in the next step.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([CH:9]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:8].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2>O1CCCC1>[CH:7]([CH:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH2:8]
Reactant: C=CC(OCCCO)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(OCCCOc1ncnc2nc[nH]c12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Potassium tert-butoxide (35.64 g, 0.317 mol) was added to a stirred solution of 3-(vinylbenzyloxy)-1-propanol (mixture of meta and para isomers) (30.51 g, 0.158 mol) in dry tetrahydrofuran (300 ml) under an atmosphere of nitrogen. After 15 min 6-chloropurine (24.55 g, 0.159 mol) was added, and, after stirring for 15 min at room temperature, the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and then the solvent was removed in vacuo. First water (600 ml) then concentrated hydrochloric acid (17 ml) were added to the residue and stirred for 15 min. The acidic mixture was neutralized with saturated sodium hydrogen carbonate solution. After stirring for 15 min the solid was removed by filtration from the neutral suspension and dried. The solid was extracted with hot tetrahydrofuran (400 ml) for 2 hr and then the undissolved material was removed by filtration whilst hot. The filtrate was concentrated in vacuo and the residue (40.5 g of a yellow solid) recrystallized from tetrahydrofuran. This gave the title compound (27.78 g, 89.6 mmol, 56%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:17])=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 73 %

Procedure:
A mixture solution of 2.2 g of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid, 1.67 ml of 1-benzyl-4-aminopiperidine, 10.47 g of 25% propane-phosphonic acid anhydride and 4.76 ml of triethylamine in 40 ml of methylene chloride was stirred over night at room temperature. Then, 20 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 2.48 g (73%) of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]-N-(1-benzyl-4-piperidinyl)acetamide. Then, a mixture of 438 mg of the compound obtained and 40 mg of 20%-palladium hydroxide on carbon in 4 ml of methanol was stirred for 6 hours under 5 atm of hydrogen. Then, the catalyst was filtered off a Celite (trade name) pud and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=10:1) to give 293 mg (81%) of the above-mentioned compound (21).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]=[CH:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:11]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](Cl)[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]=[CH:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:29][CH:30]=1
Reactant: OCCN1CCN(CC=Cc2ccco2)CC1
Reactant: Fc1ccc(C(Cl)c2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCN2CCN(CC=Cc3ccco3)CC2)c2cccs2)cc1

Procedure:
1.16 g (0.0084 mol) potassium carbonate were added to a solution of 1.00 g (0.0042 mol) 1-(2-hydroxyethyl)-4-[3-(2-furyl)-2-propenyl]piperazine and 1.16 g (0.0084 mol) (4-fluorophenyl)(2-thienyl)methylchloride in 50 ml toluene. The mixture was refluxed for 16 h, then cooled, diluted with 50 ml toluene and washed twice with water. The crude product obtained by evaporation in vacuo was chromatographed on silicagel (elution with dichloromethane/methanol/acetic acid 95/5/3). The combined pure fractions were adjusted to pH 12 by addition of 2N sodium hydroxide solution, subsequently washed with water and brine and concentrated in vacuo. The oily residue was redissolved in acetonitrile and precipitated by addition of an excess of a solution of maleic acid in acetonitrile. 0.340 g (12% of the theoretical yield) of the title compound were obtained as the dimaleate salt, m.p. 169°-71° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[NH2:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:12]([O:26][CH3:27])=[CH:11][C:10]=1[C:28]([N:30]1[CH:34]=[C:33](/[CH:35]=[CH:36]/[CH3:37])[CH2:32][C@H:31]1[CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Si:40]([O:39][CH2:38][C@@H:31]1[CH2:32][C:33](/[CH:35]=[CH:36]/[CH3:37])=[CH:34][N:30]1[C:28]([C:10]1[CH:11]=[C:12]([O:26][CH3:27])[C:13]([O:15][Si:16]([CH:17]([CH3:19])[CH3:18])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:22])=[CH:14][C:9]=1[NH:8][C:2](=[O:3])[O:4][CH2:5][CH:6]=[CH2:7])=[O:29])([C:43]([CH3:44])([CH3:46])[CH3:45])([CH3:41])[CH3:42]
Reactant: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2N)[C@H](CO[Si](C)(C)C(C)(C)C)C1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc1C(=O)N1C=C(/C=C/C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Allyl chloroformate (0.83 g, 6.88 mmol, 1.1 eq) was added to a solution of the amine 7 (3.6 g, 6.26 mmol, 1.0 eq) in dry DCM (80 mL) containing dry pyridine (1.09 g, 13.77 mmol, 2.2 eq) at −78° C. The dry ice was removed and the reaction mixture allowed to warm to room temperature. After stirring for a further 15 minutes, LC/MS indicated complete reaction. The organic phase was washed successively with 0.01N HCl (50 mL), saturated sodium bicarbonate (50 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to leave a pale yellow oil which was used in the next step without further purification (4.12 g, assumed 100% yield). LC/MS (4.862 min (ES+)), m/z: 659.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]([C:11]#[N:12])[CH3:10])(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>ClCCl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[NH2:12][CH2:11][C@@H:9]([CH3:10])[C:8]#[N:7]
Reactant: C[C@@H](C#N)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C#N)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
((R)-2-Cyano-2-methyl-ethyl)-carbamic acid tert-butyl ester (42 mg, 0.23 mmol) was dissolved in dichloromethane (1.2 ml) and cooled in an ice bath. Trifluoroacetic acid (0.7 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated and dried under high vacuum to afford (R)-3-amino-2-methyl-propionitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCBr
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-2-chloroethane (127 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (107 mg, yield 30%).
Reaction SMILES: [CH:1]([CH:3]=O)=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:9]([NH2:15])[C:8]=1[NH2:16]>O>[CH3:12][O:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH3:5])=[C:8]2[C:9]=1[N:15]=[CH:1][CH:3]=[N:16]2
Reactant: COc1ccc(OC)c(N)c1N
Reactant: O=CC=O
Solvent: O
Product: COc1ccc(OC)c2nccnc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of 10 g (0.17 mol) of glyoxal in 50 ml of water was added to 5 g (0.03 mol) of 2,3-diaminohydroquinone dimethyl ether, and stirred at 50° C. for 1 hour. After allowing to cool to room temperature, the reaction solution was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from benzene gave 4.3 g (75%) of the title compound. m.p. 145°-150° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[N+:33]([C:36]([CH3:41])([CH2:39]O)[CH2:37][OH:38])([O-:35])=[O:34]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:39][C:36]([CH3:41])([N+:33]([O-:35])=[O:34])[CH2:37][OH:38])=[O:30])[CH:22]=[CH:21]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)[N+](=O)[O-])ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9 mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) in CH2Cl2 (50 mL) and TEF (50 mL) was stirred at ambient temperature overnight. The solvent was evaporated and EtOAc (100 mL) was added to the resulting crude material, cooled in a dry-ice bath and the byproduct, dicyclohexyl urea was removed by filtration. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture of diasteromers) as an oil (2.77 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 7.69–7.60 (m, 3H), 7.34–7.3 (m, 1H), 7.14–7.08 (m, 2H), 4.44 (d, J=4.2 Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d, J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.14, 174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87, 125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04, 18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.[CH2:31]([C:35]1([CH2:73][CH3:74])[CH2:41][S:40](=[O:43])(=[O:42])[C:39]2[CH:44]=[CH:45][C:46]([N:48]([CH3:50])[CH3:49])=[CH:47][C:38]=2[CH:37]([C:51]2[CH:52]=[C:53]([NH:57][C:58]([CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][C:69](O)=[O:70])=[O:59])[CH:54]=[CH:55][CH:56]=2)[CH:36]1[OH:72])[CH2:32][CH2:33][CH3:34]>ClCCl.CO>[CH2:31]([C:35]1([CH2:73][CH3:74])[CH2:41][S:40](=[O:43])(=[O:42])[C:39]2[CH:44]=[CH:45][C:46]([N:48]([CH3:50])[CH3:49])=[CH:47][C:38]=2[CH:37]([C:51]2[CH:52]=[C:53]([NH:57][C:58]([CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][C:69]([NH:1][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH:10]([CH2:21][CH2:22][CH:23]([OH:30])[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:11](=[O:20])[N:12]4[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:5][CH:4]=3)=[O:70])=[O:59])[CH:54]=[CH:55][CH:56]=2)[CH:36]1[OH:72])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCCOCC(=O)O)c2)C1O
Reactant: NCc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCCOCC(=O)NCc3ccc(C4C(CCC(O)c5ccccc5)C(=O)N4c4ccc(F)cc4)cc3)c2)C1O

Procedure:
Preparation analogous to example II, starting from 83 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-(3-hydroxy-3-phenylpropyl)azetidin-2-one and 130 mg of [2-(2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylcarbamoyl]methoxy}ethoxy)ethoxy]acetic acid; chromatography: SiO2, dichloromethane/methanol=20:1; product of melting point 120° C. and molecular weight 1021.3 (C57H67FN4O10S); MS (ESI+): 1021 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]#[N:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:29](N)[CH2:30][NH2:31]>>[NH:17]1[CH2:29][CH2:30][N:31]=[C:16]1[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: NCCN
Reactant: N#Cc1cc2ccccc2n1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(-n2c(C3=NCCN3)cc3ccccc32)cc1
Temperature: 200 °C

Procedure:
A stirred mixture of 1-phenyl-1H-indole-2-carbonitrile (15 g) and ethylenediamine monotosylate (17.6 g) was heated at 200° C. for 2 hours. After cooling, the reaction mixture was partitioned between toluene (100 ml) and dilute hydrochloric acid (400 ml). The aqueous layer was extracted with diethyl ether, cooled in an ice bath then basified with concentrated ammonia and reextracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried and the solvent removed in vacuo. The residue was purified by chromatography on neutral alumina (grade III) eluting with 1% methanol in dichloromethane, followed by trituration with toluene to give 2-(2-imidazolin-2-yl)-1-phenyl-1H-indole as a white solid: yield 16.6 g (90%); mp 180.5°-182° C. The hydrochloride salt was prepared as described above: yield 16.3 g (95%); mp 263.5°-265.5° C.