Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].[CH2:17]([OH:20])[C:18]#[CH:19].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([C:19]#[C:18][CH2:17][OH:20])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1ccc(Br)cc1F
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(CO)NC(=O)c1ccc(C#CCO)cc1F
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 113.1 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylethyl)-4-bromo-2-fluorobenzamide (0.29 g, 1.0 mmol) in triethylamine (5 ml), dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol), copper(I) iodide (0.009 g, 0.05 mmol) and 2-propyn-1-ol (0.085 g, 1.5 mmol) were added and stirred at 50° C. for 3.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over Na2SO4. After the solvent was evaporated under a reduced pressure, the residue was subjected to silica gel chromatography (hexane/ethyl acetate=1/2) to give the title compound (0.30 g, 94%).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:12].C(O)C>C(OCC)C>[C:5]([C:4](=[C:3]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][CH:16]=1)[S:9][CH3:10])[C:7]#[N:8])#[N:6]
Reactant: CCOc1ccc(N)cc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Solvent: CCOCC
Product: CCOc1ccc(NC(SC)=C(C#N)C#N)cc1
Temperature: 0 °C

Procedure:
A mixture of 17.03 g (0.1 mol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 12.94 ml (0.1 mol) of 4-ethoxy-aniline and 60 ml of ethanol is heated under reflux for 2 hours. Then, with stirring, 120 ml of diethyl ether are added dropwise to the reaction mixture, which is at approx. 30° C. The reaction mixture is then cooled to 0° C. The title compound precipitates in the form of colorless crystals and is filtered off, washed with diethyl ether and dried under a HV; m.p. 141-142° C.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30].[Na+].[I-]>CN(C=O)C.O>[OH:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
Into a 250 mL-3 neck flask fitted with a stirrer and thermometer, 400 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (10 mL) was added dropwise to 40 mg of NaH in DMF (30 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 290 mg of alpha-bromo 2-cyanotoluene in DMF (10 mL) was added dropwise followed by the addition of 184 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 612 mg of a brown oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yield intermediate title compound (161 mg, 28%) as a viscous oil. Ion spray M.S. 387.9 (M*−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].I[CH2:10][CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:11]
Reactant: CCI
Reactant: OCC1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCOCC1CO

Procedure:
Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in N,N-dimethylformamide was treated with K2CO3 (1.1 g) overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:3]([CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:4]=[N:5]1
Reactant: Cn1ncc(CCCNC=O)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(CCCNC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To a solution of N-[3-(5-amino-1-methylpyrazol-4-yl)propyl]formamide (3.64 g, 20 mmol) and triethylamine (2.23 g, 22 mmol) in methylene chloride (50 ml) was added triphenylmethyl chloride (6.13 g, 22 mmol). The mixture was stirred at room temperature for 90 minutes. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine, and 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give N-[3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propyl]formamide (6.8 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12])=O.C=O.[CH:23]([NH2:25])=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:25]=[CH:23][O:12][C:11]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20]
Reactant: O=C(c1ccc(Cl)cc1Cl)C(O)c1ccc(Cl)cc1Cl
Reactant: NC=O
Agent: C=O
Solvent: O
Product: Clc1ccc(-c2ncoc2-c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 205 °C

Procedure:
A mixture of (+/−)-2,2′,4,4′-tetrachlorobenzoin (1.0 gm, 2.9 mmol) from Step A and paraformaldehyde (0.70 gm, 24 mmol) in formamide (20 mL) was heated to 200-210° C. for 3 hr. The reaction was cooled to rt, diluted with water, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography, eluting first with 10% ethyl acetate in hexanes to afford 4,5-di-(2,4-dichlorophenyl)oxazole as a higher Rf byproduct and then with 75% ethyl acetate in hexanes to elute the title compound as an oil.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]([NH:7][C:8]([C@@H:10]([NH:15]C(C2C=CC3SC4C(=CC=CC=4)NC=3C=2)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:5][CH2:4][O:3]1.[C:32]1([C:46]([OH:48])=O)[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[S:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:1][CH:2]1[C@@H:6]([NH:7][C:8]([C@@H:10]([NH:15][C:46]([C:32]2[C:45]3[NH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:37][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[O:48])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O
Reactant: O=C(O)c1cccc2c1Nc1ccccc1S2
Product: CC(C)C[C@H](NC(=O)c1cccc2c1Nc1ccccc1S2)C(=O)N[C@H]1CCOC1O

Procedure:
The experimental protocol used is identical to that described for compound 17, with 10H-phenothiazine-1-carboxylic acid replacing 10H-phenothiazine-2-carboxylic acid. Yellow powder. Melting point: 99-101 ° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+:4]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br)([O-:6])=[O:5].Cl>CO>[CH3:1][O:2][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
125 g of 30% strength sodium methylate solution (0.69 mol) in methanol are added dropwise to 130 g (0.6 mol) of o-nitrobenzyl bromide in 200 ml of methanol. During this procedure, the reaction mixture heats up to about 50° C. Stirring is continued for a further 3 hours, the reaction mixture being cooled to room temperature, after which ice water is added to the reaction vessel and the reaction mixture is neutralized by adding dilute hydrochloric acid. The aqueous phase is extracted with three times with ether, and the organic phase is dried over MgSO4 and evaporated down. 101 g (0.6 mol, quantitative yield) of the title compound are obtained as a residue in the form of a brownish oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14]C)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(I)c1
Yield: 99.7 %

Procedure:
3-Iodophenol (4.00 g, 18.2 mmol), ethyl bromoacetate (2.98 g, 18.2 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were refluxed in acetone (40 ml) for 2 hours. The reaction mixtute was poured into water and extracted with ethyl acetate. The organic layer was dried, and filtered. The filtrate was concentrated and the residue was purified with silica gel chromatography to give the subject compound (5.30 g, 99%).
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C(Cl)(Cl)Cl>[C:27]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[C:23]([C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)=[O:44])[CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2(c3ccccc3)c3ccccc3-n3c4ccccc4c4cccc2c43)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A degassed solution of 6.1 g (18 mmol) of 8,8-diphenyl-8H-indolo-[3,2,1-de]acridine in 40 ml of chloroform is cooled to 0° C., and 5 g (37 mmol) of AlCl3 are added. 3.9 g of benzoyl chloride are then added dropwise at this temperature, and the mixture is stirred for 8 h. 50 ml of water are added to the mixture, and the organic phase is separated off, filtered through silica gel and evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 13.7 g (27 mmol), corresponding to 90% of theory.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:6][CH:5]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:10]([O:17][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCBr
Reactant: OC(COc1ccc(Cl)cc1)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCOC(COc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 56% dispersion of sodium hydride in mineral oil (480 mg.) is added under nitrogen to a solution of 2.52 g. of 1-[3'-(4"-chlorophenoxy)-2'-hydroxypropyl]imidazole in 6 ml. dry hexamethylphosphoramide. After stirring for 1 hours at room temperature, the temperature is increased to 45° C. and stirring is continued for 2 hours. The solution is then cooled in an ice bath and 2.5 g. of 1-bromodecane in 1 ml. of hexamethylphosphoramide is added. Thereafter, the solution is stirred for 2 hours at room temperature and then for 16 hours at 50° C. The reaction mixture is poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is chromatographed on silica gel. Elution with 20% acetone in dichloromethane yields 1-[3'-(4"-chlorophenoxy)-2'-(n-decyloxy)propyl]imidazole.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].Br[CH2:10][C:11]#[N:12]>C1COCC1>[OH:7][CH2:6][C:5]#[C:4][CH2:3][O:8][CH2:10][C:11]#[N:12]
Reactant: OCC#CCO
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.5 g, 188 mmol) was added to a solution of 2-butyne-1,4-diol (16.1 g, 187 mmol) in THF (150 mL) at 0° C. under nitrogen. After 1 h at 0° C., bromoacetonitrile (8.33 mL, 120 mmol) was added slowly and the reaction was allowed to warm to rt. After 22 h at rt, the reaction was quenched with 1 N HCl (150 mL) and extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 4.35 μg (29%) of (4-hydroxy-but-2-ynyloxy)-acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH2:15][C@@H:9]3[C:8]([CH3:20])([CH3:19])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:42]1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=[O:48]>C1COCC1>[OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13]([C:16]([O:18][N:42]4[C:46](=[O:47])[CH2:45][CH2:44][C:43]4=[O:48])=[O:17])=[CH:14][CH2:15][C@@H:9]3[C:8]([CH3:19])([CH3:20])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)O)C[C@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)ON3C(=O)CCC3=O)C[C@H]21
Reaction time: 43 h

Procedure:
With reference to scheme 3, to a solution of (XVIII) (6 mg, 0.017 mmol) in dry THF (2 mL), under argon, was added dicyclohexylcarbodiimide (Aldrich; 13 mg, 0.063 mmol) and N-hydroxysuccinimide (Aldrich; 11 mg, 0.096 mmol). The resulting reaction mixture was stirred for 43 h, filtered from dicyclohexylurea, and the filtrate evaporated in vacuo to afford white solids. This material was digested with a small volume of THF and the insoluble part (urea) was filtered off. The filtrate was evaporated in vacuo to dryness and the process repeated to give a foam which was subjected to preparative TLC on silica, eluting with EtOAc-hexanes (1:1), to give 5 mg, 67%, of the NHS ester as an off-white foam.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:21][CH2:22][C:23]([CH2:33][CH3:34])([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([C:23]([S:29]([CH3:32])(=[O:30])=[O:31])([CH2:33][CH2:34][N:16]1[CH:17]=[CH:18][C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:14][C:15]1=[O:19])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: Oc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)C(CC)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 55 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
Cesium carbonate (0.71 g, 2.2 mmol, 4.0 equiv) was added to a solution of the 4-phenylpyridin-2-ol (0.10 g, 0.58 mmol, 1.05 equiv) and ethyl 4-bromo-2-ethyl-2-(methylsulfonyl)butanoate (0.17 g, 0.55 mmol, 1.0 equiv) in tetrahydrofuran (5 mL). The resulting mixture was heated to 55° C. and allowed to stir for 3 days. The reaction was diluted with ethyl acetate (20 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (4:1-0:1 heptane/ethyl acetate) to provide a light yellow oil (43 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=7.42 Hz, 3H) 1.33 (t, J=7.13 Hz, 3H) 2.07-2.19 (m, 1H) 2.26-2.36 (m, 1H) 2.44 (ddd, J=14.89, 11.18, 4.98 Hz, 1H) 2.59-2.71 (m, 1H) 3.15 (s, 3H) 4.19-4.37 (m, 4H) 6.45 (dd, J=7.03, 1.56 Hz, 1H) 6.72-6.78 (m, 1H) 7.38-7.48 (m, 4H) 7.53-7.60 (m, 2H).
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.C1CCN2C(=NCCC2)CC1.[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43][CH:44]=O)[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43]/[CH:44]=[CH:11]/[C:12]#[N:13])[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:26]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC=O)cc(Cl)c1Cl)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(C/C=C/C#N)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a THF (0.1 M) suspension of anhydrous lithium chloride (1.2 eq.) was added sequentially diethyl(cyanomethyl)phosphonate (1.2 eq.) and DBU (1 eq.). The resulting suspension was stirred at RT for 15 min before 1,1-dimethylethyl cyclopropyl{[2,3-dichloro-5-(2-oxoethyl)phenyl]methyl}carbamate (1 eq.) from the previous step was added dropwise as a THF (0.1 M) solution. The resulting pink suspension was allowed to stir at RT for 12 h before it was carefully quenched with 1 N aq. HCl and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:9][C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:1]=[O:2])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccsc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccsc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Formyl-2-thiophenecarboxylic acid (4.68 g) was dissolved in N,N-dimethylformamide (30 ml), and benzyl bromide (3.9 ml) and potassium carbonate (4.15 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water, and then extracted with diethyl ether. The extract was washed with 5% potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3-formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g). 3-Formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g) was dissolved in ethanol (50 ml), and hydroxylamine hydrochloride (0.83 g) and pyridine (0.97 ml) were added. The mixture was stirred under reflux for 3 hours, and concentrated under reduced pressure. The residue was poured into water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-aldoxime-2-thiophenecarboxylic acid benzyl ester (2.61 g). This product was dissolved in acetic anhydride (20 ml), and the mixture was stirred at 160° C. for 10 hours. The mixture was cooled, poured into water (100 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyano-2-thiophenecarboxylic acid benzyl ester (2.01 g). This product was dissolved in tetrahydrofuran (40 ml), and 5% Pd--C (wet) (0.25 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 72 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 3-cyano-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1c(OCCCCCBr)ccc2ccc(OCC(=O)OCC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OCC)cc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 94 °C
Yield: 81.3 %

Procedure:
A mixture of 0.454 g (2.2 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.09 g (2.2 mmol) of 2-[(5-bromopentyl)oxy]-7-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, 1.23 g (8.9 mmol) of anhydrous granular potassium carbonate and 32.5 mL of 2-butanone was heated at 94° C. for 22 hr. After being cooled to room temperature, the mixture was filtered through some anhydrous magnesium sulfate. The solids were washed thoroughly with ethyl acetate and the filtrate and washes were combined and concentrated in vacuo. The residue was flash chromatographed on 200 g of silica gel, eluting with hexane-ethyl acetate (2:1) affording 1.11 g (81%) of the title compound as a white solid, mp 68°-69.5° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)CCOCCOCCOCCOCCOCCOCCC(=O)O

Procedure:
A solution of 3-{2-[2-(2-{2-[2-(2-tert-Butoxycarbonyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (6 g, 18.6 mmol) in anisole (20 ml) was cooled in an ice bath and trifluoroacetic acid (65 g) was added. After 3 hrs at RT volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 5% sodium bicarbonate solution. The aqueous layer was acidified with 1 N HCl, saturated with NaCl and then extracted with ethyl acetate (3×50 ml). Combined organic layers were washed with brine and dried over sodium sulfate. Removal of volatiles under the reduced pressure provided the product as colorless liquid which solidified upon refrigeration (3.8 g, 82%).