Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2].[Cl:17][C:18]([Cl:24])([S:22]Cl)[CH:19]([Cl:21])[Cl:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:22][C:18]([Cl:24])([Cl:17])[CH:19]([Cl:21])[Cl:20])[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)c1cccc2ccccc12
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)C(=O)c1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5.0 g (0.024 N-cyanomethyl-1-naphthamide (the product of Example 11) and 6.2 g (0.026 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 125 ml methylene chloride, 3.0 g (0.030 mole) triethylamine in 25 ml methylene chloride were dropped in over 40 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate, and stripped down to a volume of 50 ml. The methylene chloride solution was then chromatographed on a column containing about 125 g silica gel, eluting with methylene chloride. The eluate was stripped to give 4.3 g of the above-identified product as an amber glass which tended to crystallize slowly.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
Add TFA (6.54 g, 57.4 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acid tert-butyl ester (1.05 g, 2.87 mmol) in DCM (20 ml) and stir at ambient temperature for four hours. Concentrate mixture on rotary evaporator and purify on cation exchange column (10 g, Varian) to give the title compound (519 mg) as a white solid. Mass spectrum (ion spray): m/z=284 (M+1); 1HNMR (DMSO-d6): 8.58 (s, 1H), 8.21 (d, 1H), 8.06 (br s, 1H), 7.44 (br s, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 3.05 (m, 1H), 2.84 (m, 2H), 2.77 (m, 1H), 2.62 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.71 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:15]=[O:16])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of 2-methoxythiophene (79 mg, 0.69 mmol) in 3.5 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.30 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 20 minutes, dimethylformamide (0.27 mL, 3.5 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 25 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×25 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-12% ethyl acetate in hexanes) to give 5-methoxy-2-thiophenecarbaldehyde (71 mg, 72%). Used without further characterization.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>[OH-].[Na+]>[O:15]1[CH:13]([CH2:11][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)[CH2:14]1
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reaction time: 8 h

Procedure:
p-Nitrophenol (139 g, 1.0 mol) was dissolved in 1.5 l 0.8M sodium hydroxide. Epichlorohydrin, IX, (117 ml, 1.5 mol) was added and the mixture stirred vigorously overnight. The homogenous solution was then extracted three times with 300 ml chloroform and the organic fractions combined and dried over magnesium sulfate. After removal of the drying agent by filtration, evaporation of the filtrate gave a yellow oil which crystallized on standing. The oily crystals were triturated with methanol and filtered to yield 55.6 g of the desired compound as white crystals shown to be homogenous by thin layer chromatography (60:40 ethyl acetate/hexanes, Rf =0.77) m.p. 62°-65° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4][N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.CC(C)([O-])C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:4][N:3]=2)[CH2:26][CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)cc(OC)c23)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccccc4)CC3)c3cc(OC)cc(OC)c23)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 46.4 %

Procedure:
400 mg (1.2 mmol) of 4-chloro-6,8-dimethoxy-1-(4-methoxyphenyl)phthalazine dissolved in 5 mL of toluene, 276 mg (1.4 mmol) of 4-amino-1-benzylpiperidine, 163 mg (1.7 mmol) of sodium tert-butoxide, 6 mg (0.009 mmol) of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and 5.5 mg (0.006 mmol) of tris(dibenzylideneacetone)dipalladium are successively introduced into a tube under argon. The tube is hermetically sealed and the mixture is stirred at 80° C. for 24 hours. After cooling to room temperature, the reaction medium is hydrolysed with sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is washed with water and with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (solvent: 95/5 (v/v) dichloromethane/methanol). The oily product obtained forms a solid by trituration in ethyl ether. 270 mg of product are obtained in the form of a beige-coloured powder.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:6]2[CH2:7][N:8]([C:27](=[O:28])[CH2:26][CH2:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:20]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)CCc1cccc(CCc2ccccc2)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1cccc(CCc2ccccc2)c1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.163 g (1.021 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.29 g (1.1 mmol) of 3-(3-phenethylphenyl)propionic acid and 0.57 ml (4.1 mmol) of triethylamine in 30 ml of dichloromethane, 0.23 ml (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate =6/1 to 3/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH:19]=[C:20]([CH3:22])[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:19]=[C:20]([CH3:22])[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC(C)=CBr
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (565 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from 1-bromo-2-methyl-propene (0.51 mL), a small iodine flake, and magnesium powder (146 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:1]1([N:4]([CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCBr
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)NC5CC5)c4)sc4c3CCCC4)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(cyclopropylsulfamoyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 111 mg of methyl 5-bromopentanoate, 105 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 80° C. overnight. Further, 42 mg of tetrabutyl ammonium iodide was added thereto, followed by stirring at 100° C. for 3 hours. In addition, 370 mg of methyl 5-bromopentanoate, 140 mg of tetrabutyl ammonium iodide, and 262 mg of potassium carbonate were added thereto, followed by stirring at 100° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 213 mg of methyl 4-{2-[4-({[2-({3-[cyclopropyl(5-methoxy-5-oxopentyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a yellow solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([O:10]C)=[O:9])[CH2:5]1)=[N+:2]=[N-:3].O.[OH-].[Na+]>CO>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1

Procedure:
To a solution of trans methyl 3-azidocyclobutane carboxylate (2.38 g, 15.3 mmol) in methanol (5 ml) was added water (5 ml). The resulting cloudy mixture was stirred vigorously and treated dropwise (0.5 h) with an aqueous solution of sodium hydroxide (1N, 15.3 ml) at such a rate that the temperature was kept under 25° C. The reaction mixture was stirred at 23° C. for 2 h and the methanol was evaporated in vacuo to a slightly yellow residue which was diluted with water (10 ml). The aqueous solution was washed with ether (2×10 ml), acidified with 1N hydrochloric acid and extracted with dichloromethane (4×25 ml). The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to a colorless oil which solidified on standing; 2.02 g, 93%; mp 39°-41° C. Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.78; found: C 42.41; H 5.02, N 29.59; ir (KBr) νmax : 2100 (N3) and 1705 cm-1 with shoulder at 1735 (C=O of carboxylic acid); 1Hmr (CDCl3) δ: 4.19 (1H, m, H-1) and 3.5-2.0 ppm (5H, H-2, H-3, H-4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[O:20]1CCC[CH2:21]1>>[CH3:10][O:9][C:6]1[C:7]2[NH:8][C:21](=[O:20])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:5]=1
Reactant: C1CCOC1
Reactant: CCCN(CCC)CCc1ccc(OC)c(N)c1N
Product: CCCN(CCC)CCc1ccc(OC)c2[nH]c(=O)[nH]c12

Procedure:
530 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dipropylamine is heated under reflux for one hour with 30 ml of tetrahydrofuran and 500 mg of N,N'-carbonyldiimidazole. After concentration, the residue is combined with methanol and water, again concentrated, and dried over phosphorus pentoxide, yielding 530 mg of 7-methoxy-4-[2-(N,N-dipropylamino)ethyl]-2,3-dihydro-2-benzimidazolone, mp 35° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][CH2:21][OH:22])([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:17][C:18](=[O:19])[O:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)(CCO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CC2(CCO1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
9-benzyloxycarbonyl-2-oxo-3-oxa-9-azaspiro[5.5]undecane is prepared by reaction of 1-benzyloxycarbonyl-4,4-bis-(2-hydroxyethyl)piperidine with 4-methylmorpholine-N-oxide in methylene chloride/acetonitrile in the presence of tetrapropylammonium perruthenate and pulverized molecular sieve.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1B(O)O.[CH3:20][O:21][C:22]1[C:23]([O:54][CH3:55])=[CH:24][C:25]2[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:30](=O)[C@@H:29]3[CH2:41][C:42](OS(C(F)(F)F)(=O)=O)=[CH:43][N:28]3[C:27](=[O:52])[C:26]=2[CH:53]=1>C(O)C.O.C1C=CC=CC=1.C(OCC)(=O)C.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:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:42]1[CH2:41][CH:29]2[N:28]([CH:43]=1)[C:27](=[O:52])[C:26]1[CH:53]=[C:22]([O:21][CH3:20])[C:23]([O:54][CH3:55])=[CH:24][C:25]=1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH2:30]2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1cc2c(cc1OC)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(OS(=O)(=O)C(F)(F)F)=CN1C2=O
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: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)N(COCC[Si](C)(C)C)CC1CC(c3ccc4ccccc4c3)=CN1C2=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Sodium carbonate (300 mg, 2.83 mmol), 2-napthaleneboronic acid (171 mg, 0.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg) were added to a solution of 9 (517 mg, 0.93 mmol) in ethanol/water/benzene (20/20/20 mL) and stirred at room temperature for 96 hours. The reaction mixture was diluted with ethyl acetate (220 mL) and washed with water (50 mL) and brine (50 mL) and dried over magnesium sulphate. The crude product was purified by flash column chromatography using 70% ethyl acetate in hexane as eluent to give the pure product 10 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.Cl.CN(C)CC(O)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 90 °C
Yield: 128.3 %

Procedure:
To a solution of 4-bromobiphenyl (1.00 g, 4.29 mmol), 4-methoxyphenol (0.35 g, 2.82 mmol) and cesium carbonate (1.85 g, 5.68 mmol) in dioxane (10 mL) was added N,N-dimethylglycine hydrochloride (0.04 g, 0.26 mmol). The vessel was purged with nitrogen before Cu(I) iodide (0.02 g, 0.11 mmol) was added. The reaction mixture was heated to 90° C. overnight. The reaction mixture was diluted with water and ethyl acetate. The organic portion was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (1.00 g, 100%) as a light green solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:28][N:29](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:39]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:39][NH:29][CH:28]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(C(F)(F)F)c2)ccn1
Yield: 96 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 8.71 g (20.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(3-trifluoromethylphenyl)-2-propen-1-one obtained in Example 25-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 7.76 g of the title compound as a white powder. (Yield: 96%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([OH:36])(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[CH:37](=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].Cl>O1CCCC1>[OH:55][CH:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:19]([OH:36])=[O:35]
Reactant: CCCCCCCCC=CCCCCCCCC=O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC=CCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
Diisopropyl amine (5.04 ml, 36.02 millimole) and dry tetrahydrofuran (30 ml) were introduced into a reaction vessel sufficiently substituted by argon gas. The reaction mixture was cooled to -78° C., and then 1.6M butyl lithium/hexane solution (23.64 ml, 37.82 millimole) was added dropwise thereto. The cooling bath was removed and the solution was allowed to warm to 0° C. and stirred for 30 minutes at the same temperature. The lithium diisopropylamide/tetrahydrofuran solution was again cooled to -78° C., and palmitic acid (4.62 g, 18.02 millimole) in dry tetrahydrofuran (60 ml) was added thereto, and the reaction mixture was stirred for 15 minutes at the same temperature (-78° C.). Then, the reaction temperature was raised to room temperature, and the reaction was continued for 1 hour. The reaction mixture was again cooled to -78° C., and 9-octadecenal (4 g, 15.02 millimole) in dry tetrahydrofuran (60 ml) was added dropwise thereto. The obtained mixture was reacted for 4 hours under the same conditions, and allowed to warm to 0° C., and the reaction was stopped by adding 1N hydrochloric acid (200 ml). The reaction mixture was extracted thrice with chloroform. The organic phase was washed twice with water and then dried over anhydrous sodium sulfate. The inorganic salt was filtered off and the solvent was distilled off from the filtrate. The obtained residue was dissolved in a developing solvent and fractionated through silicagel chromatography (n-hexane:ethyl acetate=8:2→chloroform:methanol=95:5) to give 3-hydroxy-2-n-tetradecyl-11-icosenoic acid (II)(3.73 g, yield 47.5%) in the form of white viscous solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.