Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=O)[CH3:29])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:26]1([C:27]2[C:3]([C:4]#[N:5])=[C:2]([NH2:6])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:16]=3)[CH:22]=2)[CH:25]=[CH:24][CH:23]=[CH:28][CH:29]=1
Reactant: N#CCC#N
Reactant: CC(=O)c1ccccc1Nc1cccc(OCc2ccccc2)c1
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cn(-c2cccc(OCc3ccccc3)c2)c1N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.95 g of sodium is dissolved in 200 ml of ethanol and subsequently first 2.98 g of malononitrile and then 11.96 g of 2'-(3-benzyloxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated, 4-phenyl-1-(3-benzyloxyphenyl)-2-amino-3-cyanopyrrole being obtained. The oily product is employed in the next stage without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30][CH2:31][C:32](=[O:39])[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(Cl)Cl.C(N(CC)CC)C.[N:51]([C:54]1[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=1)=[C:52]=[O:53]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30][CH2:31][C:32]([N:33]1[CH2:38][CH2:37][N:36]([C:52]([NH:51][C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)=[O:53])[CH2:35][CH2:34]1)=[O:39]
Reactant: O=C(COc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)N2CCN(C(=O)COc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 8 %

Procedure:
6-Chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (10.0 mg, 0.017 mmol) was stirred in N,N-dimethylformamide (0.5 mL) and methylene chloride (0.5 mL) with triethylamine (12.0 μL, 0.086 mmol), and 4-isocyanatobenzonitrile (2.7 mg, 0.019 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (8%). LCMS for C32H30ClN8O3 (M+H)+: m/z=609.2.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=O)[C:2]([NH2:4])=[O:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[N:1]1([C:2]([NH2:4])=[O:3])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:11][C:12]1=[O:14]
Reactant: NC(=O)Nc1ccccc1CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1C(=O)Cc2ccccc21
Yield: 34.6 %

Procedure:
To a solution of 194 mg (1.0 mmole) of 2-(2-ureidophenyl)acetic acid in 4 ml of trifluoroacetic acid was added 630 mg (3.0 mmole) of trifluoroacetic anhydride, and the mixture was then heated under reflux for ca. 1 hour. The reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was triturated under 5-8 ml of saturated sodium bicarbonate solution, and the material which remained out of solution was collected by filtration. The solid thus obtained was recrystallized from ethanol to give 61 mg of the title compound as colorless needles, m.p. 179°-180° C. (slight decomposition).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cnccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 15 %

Procedure:
n-Butyllithium (2.5 M in hexane, 2 mL) is added to a mixture of 3-bromo-4-(trifluoromethyl)pyridine (Matrix Scientific, 1 g, 0.022 mol) and triisopropylborate (1.25 mL) in anhydrous THF (9 mL) at −78° C. under nitrogen. The reaction mixture is stirred at −78° C. for 3.5 hr before warming gradually to room temperature. The reaction is quenched with water (9 mL). The organic solvent is removed under reduced pressure. The resulting aqueous phase is treated with NaOH (10 N) to obtain pH 10, washed with diethyl ether (1×8 mL), and aqueous phase is acidified to pH 5 using acetic acid. The solution is extracted with EtOAc (1×25 mL) and the organic layer is dried and evaporated to dryness to give the title compound (0.150 g, 15% yield). LCMS m/z=192.2 [M+H]+, tR=0.36 min.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].C[O:16][C:17](=O)[CH2:18][C@:19]1([CH3:40])[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([CH3:39])[C:23]([CH3:38])=[C:24]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH3:29])[O:20]1.[OH-].[Na+].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:31]([O:30][C:24]1[C:25]([CH3:29])=[C:26]2[C:21](=[C:22]([CH3:39])[C:23]=1[CH3:38])[O:20][C@:19]([CH3:40])([CH2:18][CH2:17][OH:16])[CH2:28][CH2:27]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCO)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 70% solution of sodium bis (2-methoxyethoxy)-aluminum hydride in benzene (35 ml.) was stirred with ice bath cooling while a solution of 20.55 g. (0.0558 mole) of (S)-(-)-methyl-6-benzyloxy-2,5,7,8-tetramethyl- chroman-2-acetate in 50 ml. of benzene was added dropwise over 80 minutes keeping the temperature below 20° C. The resulting solution was stirred at room temperature for 2 hours then cautiously poured onto a mixture of ice and 1 N aqueous NaOH. Work-up by means of ether extraction in the manner of Example 1 afforded 19.8 g. of viscous colorless oil. This material was triturated with petroleum ether (30°-60° C.) and the resulting solid was filtered, washed with petroleum ether and dried under high vacuum giving 14.95 g. (78.7%) of (S)-(-)-6-benzylosy-2,5,7,8-tetramethyl-chroman-2-ethanol as a colorless solid, m.p. 55°-56° C.; [α]25D - 16.21° (c 2.03, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.Cl[CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].CC(C)([O-])C.[K+].C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:18][CH2:19][CH2:20][C:21]2=[O:22])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cc(N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCCC2=O)ccc1Br
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A stirred solution of 4-bromo-3-methylaniline (50.3 g, 0.27 mole) and triethylamine (41.1 ml, 0.30 mole) in THE (250 ml) at 0° C. under argon was treated dropwise with 4-chlorobutyryl chloride (33.4 ml, 0.30 mole). The mixture was stirred for 1 hour at 0-5° C., then potassium t-butoxide (82.5 g, 0.74 mole) was added portionwise over 20 minutes, maintaining temperature below 25° C. The reaction mixture was stirred at 25° C. for a further 2.5 hrs, then treated with water (100 ml), followed after 0.25 hrs with 10% aqueous Na2CO3 solution and then extracted with ethyl acetate. The extract was washed with water, 5M HCl acid, then brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow solid (61.6 g, 89%).
Reaction SMILES: N#N.[NH:3]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)\[CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.B(Br)(Br)Br>C(Cl)Cl>[OH:22][C:18]1[CH:17]=[C:16](/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:3][N:4]=[CH:5]3)[CH:21]=[CH:20][CH:19]=1
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(OC)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 10-mL recovery flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with (E)-3-(4-((E)-1-(1H-indazol-5-yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylic acid (30 mg, 0.07 mmol, Compound 7) and DCM (1.4 mL). This solution was cooled down to 0° C. in an ice-bath. Then, BBr3 (88 mg, 0.35 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. Upon completion, the reaction was quenched with methanol (5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure to give the crude product that was directly purified on a reversed phased C-18 column eluted with 40-100% acetonitrile in water in the presence of 0.1% TFA affording the title compound as an off-white solid (11 mg). 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.32 (br, 1H), 9.23 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.52 (d, 1H), 7.45-7.35 (m, 3H), 7.12 (d, 1H), 7.00 (t, 1H), 6.90 (d, 2H), 6.59-6.53 (m, 3H), 6.36 (d, 1H), 2.37 (q, 2H), 0.89 (t, 3H); LCMS: 411 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O1CCCCC1[O:27][C:28]([C:30]12[CH2:37][CH2:36][C:33]([NH:38][CH2:39][C:40]([N:42]3[CH2:46][C@@H:45]([F:47])[CH2:44][C@H:43]3[C:48]#[N:49])=[O:41])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:29].Cl>O1CCOCC1.O>[CH2:10]([O:17][C:18]([N:38]([CH2:39][C:40]([N:42]1[CH2:46][C@@H:45]([F:47])[CH2:44][C@H:43]1[C:48]#[N:49])=[O:41])[C:33]12[CH2:36][CH2:37][C:30]([C:28]([OH:29])=[O:27])([CH2:35][CH2:34]1)[CH2:31][CH2:32]2)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyldiisopropylamine (194 μL) and benzylchloroformate (137 μL) were added dropwise to (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (379 mg) in dioxane (5 mL) while the solution was cooled in water. The mixture was stirred at room temperature for 1 hour, followed by addition of 1N hydrochloric acid (0.1 mL) and stirring at room temperature for additional 1 hour. The solvent was evaporated under reduced pressure. The resulting crystal was then washed with diisopropylether and water and was dried under reduced pressure. The dried crystal was purified by silica gel chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (335 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: CCO
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of 10 g (42.4 mmol) of 1,3-dibromobenzene, 10.43 g (42.4 mmol) of pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, The mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 10.9 g (72%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[Cl:10]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:10][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1CCl

Procedure:
A solution of 15 g of 2,3-dimethylpyridine 1-oxide in 75 ml of chloroform was boiled at reflux and treated as rapidly as possible with 37 ml of trichloroacetyl chloride (the acid chloride was added through the reflux condenser). The reaction mixture was heated under reflux for 2.5 hours, subsequently poured into a mixture of ice and sodium bicarbonate and the resulting solution was washed several times with methylene chloride. The organic phase was dried with sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel with methylene chloride, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2-chloromethyl-3-methylpyridine obtained was processed directly.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[CH2:16]([C:18]([CH2:23]O)([CH2:21]O)[CH2:19][CH3:20])O.C1CC=CC=1>>[CH3:20][CH2:19][C:18]([CH2:23][O:14][C:11]([CH:12]=[CH2:13])=[O:15])([CH2:21][O:9][C:6]([CH:7]=[CH2:8])=[O:10])[CH2:16][O:4][C:1]([CH:2]=[CH2:3])=[O:5]
Reactant: CCC(CO)(CO)CO
Reactant: C=CC(=O)O
Agent: C1=CCC=C1
Product: C=CC(=O)OCC(CC)(COC(=O)C=C)COC(=O)C=C

Procedure:
Trimethylolpropane triacrylate (177.8 g, 0.60 mole) and cyclopentadiene (112.0 g, 1.8 mole) were stirred at 25-40° C. for 21 hours to obtain Diels-Alder adduct of TMPTA-CPD. The obtained TMPTA-CPD (165.0 g, 0.33 mole), fumaric acid (38.3 g, 0.33 mole) and THQ (0.07 g) were heated to 190° C. in 3 hours under nitrogen and held for 12 hours to obtain a tricarboxylic acid with an acid number of 55 mg KOH/g, glycidyl methacrylate (28.4 g, 0.20 mole) and triethyl benzyl ammonium chloride (0.15 g) were heated to 110-120° C. and held for 2 hours to obtain an acrylic ester with an acid number of 22. The resulting acrylic ester was dissolved in styrene with 0.04 g of THQ to obtain a resin with 30% styrene. The resin solution has a viscosity of 430 cps, gel time 9.0 min, cure time 12.0 min, and peak exotherm 210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 24 h
Yield: 53 %

Procedure:
Under an argon atmosphere, 4-bromo-4′-hydroxybiphenyl (3.0 g, 12 mmol), 1-bromopentane (3.6 g, 24 mmol), and potassium carbonate (1.66 g, 12 mmol) were dissolved in acetone (60 mL) and stirred under a reflux condition for 24 hours. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4-Bromo-4′-pentyloxybiphenyl (A1) was obtained (1.99 g, yield: 53%). The obtained product (A1) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=7.53-7.51 (d, 2H), 7.48-7.46 (d, 2H), 7.42-7.40 (d, 2H), 7.00-6.95 (d, 2H), 4.01-3.98 (t, 2H), 1.81 (m, 2H), 1.42 (m, 4H), and 0.94 (t, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:21][CH2:20][CH2:19][C@:15]45[C:16]=2[C:17]=1[O:18][C@H:14]4[C:13](=[O:22])[CH2:12][C@@H:11]([CH3:23])[C@@:10]35[O:24][CH3:25].[CH:26]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:26]1([CH2:30][N:21]2[CH2:20][CH2:19][C@:15]34[C:16]5[C:17]6[O:18][C@H:14]3[C:13](=[O:22])[CH2:12][C@@H:11]([CH3:23])[C@@:10]4([O:24][CH3:25])[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:3][CH3:2])[CH2:29][CH2:28][CH2:27]1
Reactant: BrCC1CCC1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)NCC[C@]314
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(CC2CCC2)CC[C@]314

Procedure:
A mixture of 3,14-dimethoxy-4,5α-epoxy-8α-methylmorphinan-6-one hydrochloride (4) (3.4 g, 9.29 mmol), cyclobutylmethyl bromide (3.4 g, 22.8 mmol), sodium bicarbonate (5.0 g, 59.5 mmol) and 100 milliliters of dimethylformamide was heated at 105° to 100° C. while being stirred and maintained under a nitrogen atmosphere. The reaction mixture was heated for 18 hours, after which the inorganic material was removed by filtration and the filter cake was washed twice with dimethylformamide (100 ml). The filtrate and washings were combined and distilled under high vacuum (bath temperatures 35° C.) and the material which remained was taken up with ethyl acetate (300 ml)/H2O (80 ml) and made basic by the addition of saturated sodium bicarbonate solution. After separating the organic layer, the aqueous phase was re-extracted with ethyl acetate (2×150 ml). The combined ethyl acetate extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 3.1 g (84% theory) of the crude desired product. This material was purified by chromatography on silica gel using benzene followed by 50:50 benzene/chloroform, chloroform and graded (2% to 50%) methanol/chloroform mixtures. Those fractions containing pure product were combined and evaporated to give 1.39 g (38% theory) of the desired compound as a foamy solid. A portion of the product was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].Cl.Cl.[Cl:18][CH:19]([CH3:33])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.Cl>C(O)C.C(Cl)(Cl)Cl.O>[ClH:18].[CH3:33][CH:19]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CC(Cl)CN1CCN(c2ccccc2)CC1
Reactant: NC(=O)c1ccccc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(CN1CCN(c2ccccc2)CC1)Nc1ccccc1C(N)=O
Reaction time: 8 h

Procedure:
A mixture of 75 g. 2-aminobenzamide, 138 g. sodium acetate, 174 g. 1-(2-chloropropyl)-4-phenylpiperazine dihydrochloride, and 455 ml. water was refluxed 4 hours and left overnight at room temperature. Chloroform (200 ml.) was added, the mixture stirred, then filtered. The solid was washed with chloroform which dissolved most of it. The chloroform was separated, the aqueous layer washed with chloroform. The combined chloroform extracts were washed with water, dried, and concentrated to dryness. The residue was recrystallized from 1800 ml. ethanol and again from 2200 ml. ethanol to give 26.3 g., m. 197-8° . A 3rd recrystallization from 1600 ml. ethanol gave 22.4 g. m. 196-8.5° . A 10 g. portion of this was suspended in 100 ml. 95% ethanol, heated to near reflux and 15 ml. 10% hydrochloric acid added. The mixture was cooled with stirring and the solid filtered, washed with ethanol, and dried over P2O5 under vacuum to give 10.8 g., m. 274-81° (dec.)
Reaction SMILES: [C:1]1([OH:8])[C:5](=[O:6])[C:3](=[O:4])[C:2]=1[OH:7].OC[CH2:11][C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:24]=2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19]3>C(O)CCC>[C:1]1([OH:8])[C:2](=[O:7])[C:3](=[O:4])[C:5]=1[OH:6].[OH:4][CH2:11][C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:24]=2[C:22]([N:23]=1)=[CH:21][CH:20]=[CH:19]3
Reactant: OCCC1=Nc2cccc3cccc(c23)N1
Agent: O=c1c(O)c(O)c1=O
Solvent: CCCCO
Product: OCC1=Nc2cccc3cccc(c23)N1

Procedure:
To a 100 ml round bottom flask equipped with Teflon coated stir magnetic and a condenser was charged 1 g squaric acid (MW=114) and 45 g butanol. The round bottom flask was placed in an 80° C. oil bath. After the squaric acid dissolved, 4.0 g of the hydroxyethyl perimidine was added, as shown in the reaction below. The reaction progress was monitored by uv-vis spectrum. The peak at about 812 nm grew and peak at 354 decreased. The reaction was stopped when the 812 nm peak was considered maximized.
Reaction SMILES: [N+:1]([C@@:4]([C:20]([OH:22])=[O:21])([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:5]([N+:12]([O-:14])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:28].C[N:44]([CH3:47])[CH:45]=[O:46]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:45]1(=[O:46])[NH:44][C:47](=[O:28])[CH:15]=[CH:4]1.[N+:1]([C@@:4]([C:20]([OH:22])=[O:21])([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:5]([N+:12]([O-:14])=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: NCCCC[C@@](C(=O)O)(N(c1ccccc1)[N+](=O)[O-])[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C1C=CC(=O)N1

Procedure:
An aliquot (1.5 ml) of 8.8 mM dinitrophenyl-L-lysine (Tokyo Kasei, Tokyo, Japan) in 0.1M sodium phosphate buffer, pH 7.0, containing 5 mM EDTA was incubated with 0.15 ml of 8.8 mM N-succinimidyl-6-maleimidohexanoate (Dojin Kagaku, Kumamoto, Japan) in N,N-dimethylformamide at 30° C. for 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([N+:15]([O-])=O)[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1>CO.[Pt]>[NH2:15][C:8]1[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[N:3]=[C:2]([Cl:1])[NH:6][C:5]=2[CH:7]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(Cl)nc12
Agent: [Pt]
Solvent: CO
Product: COC(=O)c1cc(N)cc2[nH]c(Cl)nc12
Reaction time: 4 h
Yield: 101.6 %

Procedure:
To a solution of methyl 2-chloro-6-nitro-1H-benzimidazole-4-carboxylate (0.87 g) in MeOH (100 mL), was added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (0.19 g), and the mixture was stirred under hydrogen atmosphere (0.2 MPa) for 4 hours. The reaction mixture was filtered off through celite and washed with MeOH. The mother liquid was concentrated to obtain the titled compound (0.78 g) as yellow powder.