Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])(C)C.[Br:17]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:17][C:5]#[C:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)C#C[Si](C)(C)C)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)C#CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a stirred solution of trimethylsilyl p-tolylsulfonylacetylene (10 g, 40 mmol) in acetone (300 mL) was added silver nitrate (0.68 g, 4 mmol) followed by the addition of N-bromosuccinimide (7.6 g, 44 mmol) in one portion. The mixture was stirred at room temperature for 1 h. The resulting precipitate was filtered and washed with acetone. Silica gel (20 g) was added to the filtrate and the solvent was removed under reduced pressure. The residue was subjected to column chromatography with hexane/EtOAc (5:1) to afford the product as a light yellow solid (10 g, 96%). Mp. 99-101° C. 1H NMR (CDCl3) δ 7.87 (d, 2H, J=7.8 Hz), 7.39 (d, 2H, J=7.8 Hz), 2.47 (s, 3H); 13C NMR (CDCl3) δ 146.19, 138.16, 130.34, 127.83, 78.14, 61.70, 21.97.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-chlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (94% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.85, 7.43-7.46, 7.31-7.40, 7.00, 4.04-4.10, 3.75-3.94, 3.34-3.52, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 416 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][C:11]2=[O:26])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:26])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Solvent: CO
Product: CC(=O)c1ccc(N2CCNCC2=O)cc1

Procedure:
Dissolve benzyl 4-(4-acetylphenyl)-3-oxopiperazine-1-carboxylate (420 mg, 1.20 mmol) in MeOH (100 mL). Flush the flask with N2 and add 10% Pd/C (100 mg). Hydrogenate overnight under a hydrogen filled balloon. Remove the catalyst by filtration through Celite and wash with MeOH. Evaporate the solvent to yield the title compound. LC-MS (M+1): 219.13.
Reaction SMILES: Cl.[O:2]([CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[OH:2][CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)[Si](OCCC1(CCN2CCOCC2)CCCCC1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: OCCC1(CCN2CCOCC2)CCCCC1
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
After adding concentrated hydrochloric acid (0.5 mL, 6.0 mmol) to a solution of 4-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]morpholine (1.31 g, ca. 1.97 mmol) in methanol (10 mL) at room temperature, the mixture was stirred for 4.5 hours. The reaction mixture was then concentrated under reduced pressure, 1N hydrochloric acid (10 mL) was added to the obtained residue, and extraction was performed with diethyl ether. After adding 5N aqueous sodium hydroxide to the aqueous layer to adjust the pH to 12, extraction was performed with diethyl ether. The organic layer was dried (anhydrous sodium sulfate) and then the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (448 mg) (94% yield, 2 steps).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19](=[O:42])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)=[CH:22][CH:21]=2)[CH2:11][C:10]1=[O:43])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19](=[O:42])[C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:24][CH:25]=2)[CH2:11][C:10]1=[O:43])([OH:7])=[O:5]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)OC(C)(C)C)c4ccccc43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)O)c4ccccc43)cc2)cc1
Yield: 84.7 %

Procedure:
A solution of 1-(t-Butoxycarbonylmethyl)-4-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoxalin -2-one (370 mg) in aqueous trifluoroacetic acid (15 ml) was stirred at ambient temperature for 2 hours and the solvent was evaporated in vacuo. The residue was dissolved in chloroform and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column (2% methanol in chloroform). The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give 1-carboxymethyl 4-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoxalin-2-one (283 mg) as a white powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C[CH:7]1[CH2:12][CH2:11]C[CH:9](C)[C:8]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:2]1[CH:12]([CH3:11])[CH2:7][CH2:8][CH2:9][CH:3]1[CH3:4]
Reactant: [Li]CCCC
Reactant: CC1CCCC(C)C1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1C(C)CCCC1C
Yield: 48.3 %

Procedure:
Methyltriphenylphosphonium bromide (286 g, 0.80 mole) was suspended in ether (1500 ml) and treated with n-butyllithium (1.6M in ether; 500 ml, 0.80 mole), followed by 2,6-dimethylcyclohexanone (50.4 g, 0.40 mole), following the procedure described in Example 12, Part A. The crude product was distilled to give 1-methylene-2,6-dimethylcyclohexane (24 g), b.p. 146°-154° C./760 mm.
Reaction SMILES: Br[CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:20])[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.O>[N:21]([CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:20])[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CN=[N+]=[N-])C2C
Yield: 75.4 %

Procedure:
A solution of 2-bromomethyl-3,5,8,8-tetramethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.8 g, 5.3 mmol) and 90% sodium azide (3.1 g, 42 mmol) in dimethylformamide (30 ml) was stirred at 150° C. for 2 hours. The reaction mixture was poured in water, followed by extracting with ethyl acetate. The extract was washed with water, and dried. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane. 1.2 g of the title compound was obtained as colorless needles (75.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[O:16][C:7]1=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]1[C:5]2=[O:20].Br[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.OCC1SC(B(O)O)=CC=1>>[O:20]=[C:5]1[C:6]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=2)[O:16][C:17]2[C:4]1=[CH:3][C:2]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)=[CH:19][CH:18]=2
Reactant: O=c1c2cc(Br)ccc2oc2nc3ccccc3cc12
Reactant: O=Cc1ccc(Br)cc1
Agent: OCc1ccc(B(O)O)s1
Product: O=Cc1ccc(-c2ccc3oc4nc5ccccc5cc4c(=O)c3c2)cc1
Yield: 52 %

Procedure:
When the product of Step B and 4-carbaldehyde-boronic were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 52% yield, as off white solid. 1H-NMR (CDCl3) 10.08 (s, 1H); 9.33 (s, 1H); 8.6 (d, 1H, J=2.34 Hz); 8.14-8.05 (m, 3H); 8.00 (d, 2H, J=8.25 Hz); 7.96-7.89 (m, 1H); 7.85 (d, 2H, J=8.22 Hz); 7.74 (d, 1H, J=8.7 Hz); 7.64 (t, 1H, J=7.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:11][CH:12](OC)OC.Br>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: COC(CBr)OC
Agent: Br
Solvent: CCO
Solvent: O
Product: Brc1cc(I)c2nccn2c1
Temperature: 25 °C

Procedure:
5-bromo-3-iodopyridin-2-amine (1.0 g, 3.34 mmol) and 2-bromo-1,1-dimethoxyethane were dissolved in ethanol (20 ml). To this solution was added a 50% mixture of HBr in water (4 ml). The mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature and filtered. The residue was suspended in DCM (10 ml) and stirred with the saturated aqueous solution of Na2CO3. The organic layer was separated and washed with saturated brine, dried over sodium sulfate and concentrated. The desired product was obtained as a yellow solid (950 mg, yield 88%). LC-MS: 323 [M+1]+, tR=1.299 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-bromobenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[BH4-].[Na+].O.[CH3:11][CH:12](O)[CH3:13]>CC(C)=O>[CH3:7][C:4]1[S:3][C:2]([NH:1][CH:12]([CH3:13])[CH3:11])=[N:6][N:5]=1
Reactant: Cc1nnc(N)s1
Reactant: CC(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(NC(C)C)s1

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mole) in IPA (700 ml) and acetone (100 ml) was treated with sodium borohydride (20 g) in portions with stirring and cooling. The reaction mixture was then stirred and heated to reflux for 31/2 hours. The solution was then poured into water (3 L) and extracted with ether (× 3). The ethereal solution was dried, filtered and evaporated to give the title compound as a cream solid. m.p. 145° C.
Reaction SMILES: S1CCCC1.[Br-].[Al+3].[Br-].[Br-].C[O:11][C:12](=[O:28])[C:13]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[O:24][CH2:23][C:22]([C:26]#[N:27])=[CH:21]2)=[O:14].Cl>CCl>[C:26]([C:22]1[CH2:23][O:24][C:25]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:13](=[O:14])[C:12]([OH:28])=[O:11])#[N:27]
Reactant: COC(=O)C(=O)Oc1cccc2c1OCC(C#N)=C2
Agent: CCl
Agent: Cl
Agent: [Al+3]
Solvent: C1CCSC1
Product: N#CC1=Cc2cccc(OC(=O)C(=O)O)c2OC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Ten ml of tetrahydrothiophene was cooled with ice, to which 13.4 g of pulverized anhydrous aluminium bromide was gradually added. After stirring for 5 minutes, a temperature was brought to room temperature and then a solution of 2.6 g of 3-cyano-2-oxo-8-chromenyloxyacetic acid methyl ester dissolved in 30 ml of methyl chloride was gradually added. After stirring for 2 hours, the reaction mixture was poured into a mixture of 20 ml of concentrated hydrochloric acid and 200 ml of ice water and a precipitate was filtered, which was recrystallized to give a desired compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].CCN(CC)CC.CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 67.1 %

Procedure:
459 mg of 4-fluoronitrobenzene, 500 mg of β-alanine ethyl ester and 1.15 ml of Et3N were added to a solution of 10 ml of N-methylpyrrolidinone (NMP). The reaction medium was heated at 70° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, re-slurried in water and then dried over P2O5. 520 mg of ethyl 3-(4-nitrophenylamino)propionate (6) were obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C>O>[OH:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1
Reactant: CC(=O)OCC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)C(CO)=CS[C@H]12
Reaction time: 4.25 h
Yield: 52.5 %

Procedure:
A suspension of 3-acetoxymethyl-7β-(2-thienylacetamido) ceph-2-em-4-carboxylic acid (42 g.) in water (400 ml.) was flushed with nitrogen and potassium carbonate (43 g.) added. The mixture was treated with water (200 ml.) to effect complete solution and methanol (50 ml.) added, The solution was stored at 37° for 4.25 hours and then at 22° for 17 hours. The methanol was removed in vacuo and the mixture diluted with water (200 ml.) and stirred with ethyl acetate (800 ml.). The pH of the mixture was adjusted to 2.5 with orthophosphoric acid and the organic layer separated and washed with water and dried. The ethyl acetate was evaporated in vacuo until crystallisation of the product started, and the mixture cooled. Filtration gave the title compound (19.7 g., 52.5%) as fine needles, m.p. 151.5°-152° (decomp), [α]D + 465° (tetrahydrofuran), λmax. 234 nm. (ε 14,400 ), νmax. 3250 (NH and bonded OH), 2600 and 1725 (CO2H), 1755 (β-lactam) and 1650 and 1520 cm.-1 (CONH), τ (D2O-sodium bicarbonate) 2.65 and 3.0 (thienyl, 3-proton complex), 3.7 (C(2) --H, broad s), 4.62 (C(7) --H, d, J 4.5 Hz), 4.74 (C(6) --H, d, J 4.5 Hz), 5.15 (C(4) --H, broad s), 5.8 (CH2OH, broad s) and 6.12(CH2CONH, s). (Found: C, 47.4; H, 4.05; N, 7.65; S, 18.0; Calc. for C14H14N2O5S2 : C, 47.5; H, 3.9; N, 7.9; S, 18.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g, 1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in 30 mL dichloromethane and cool to 0° C. Treat the reaction mixture with benzoyl chloride (276 mg, 1.96 mmol) and stir overnight during which the temperature was allowed to warn to room temperature. Concentrate to residue and chromatograph the residue on silica gel eluting with 0.5% MeOH in CHCl3 to give the title compound as a solid: ISMS 410 (M+1); 1H NMR (CDCl3) 7.86-7.85 (m, 2H), 7.79 (s, 1H), 7.72-7.68 (m, 2H), 7.60-7.57 (m, 2H), 7.46-7.42 (m, 1H), 7.4-7.36 (m, 3H), 7.13-7.11 (d, 1H), 6.89-6.88 (m, 1H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:34][CH3:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:34][CH3:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COC1(c2ccc(I)cc2)CCCOCC1
Product: COC(=O)C(C/C=C/c1ccc(C2(OC)CCCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 85.6 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (46 mg) was reacted with 4-(4-iodophenyl)-4-methoxyoxepane (60 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxyoxepan-4-yl)phenyl]pent-4-enoic acid methyl ester (66 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [F:1][C:2]([F:22])([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[N+:19]([O-])=O)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].CO.C1CCCCC1.CCOC(C)=O>C1(C)C=CC=CC=1.[Pd]>[F:22][C:2]([F:1])([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH2:16])=[CH:11][C:10]=1[NH2:19])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: CN(C)C(=O)C(F)(F)Oc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CO
Product: CN(C)C(=O)C(F)(F)Oc1cc(F)c(N)cc1N
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-N,N-dimethyl-acetamide (22.0 g, 68.1 mmol) in toluene (200 g) was added and Pd/C (10% Pd, dry catalyst, 0.7 g, 0.7 mmol). Thereafter, MeOH (80 g) was added and the mixture stirred under an atmosphere of hydrogen (pressure of 0.1 bar) at 45° C. for 90 min. After completion of the reaction the pressure was released, the catalyst was filtered off and the filtrate was evaporated to dryness. The product (17.3 g, 84% pure by NMR, 55.2 mmol, 81% yield) was obtained as an off-white solid. If desired, the purity can be increased by chromatography (SiO2, cyclohexane/EtOAc mixtures).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[C:5]([OH:7])=O.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23].Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:21]([NH:25][C:5](=[O:7])[CH:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][C:2](=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=C(CC(NC(=O)C(F)(F)F)C(=O)O)c1ccccc1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)C(CC(=O)c1ccccc1)NC(=O)C(F)(F)F
Yield: 30.3 %

Procedure:
A solution of 4-oxo-4-phenyl-2-[(trifluoroacetyl)amino]butanoic acid (3.9 g, 13.5 mmol), isobutylamine (2.68 mL, 27.0 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.17 g, 27.0 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (3.64 g, 27.0 mmol), and N,N-diisopropylethylamine (11.7 mL, 67.4 mmol) was stirred overnight at room temperature in dimethylformamide (20 mL). The reaction was worked up with methylene chloride and saturated sodium bicarbonate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, 0 to 20% ethyl acetate in hexane gradient elution), gave the title compound as a yellow solid (1.41 g). MS 345 (M+1). 1H NMR (500 MHz, CDCl3) □ 7.95 (d, J=7.3 Hz, 2H), 7.92 (bs, 1H), 7.63 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.7 Hz, 2H), 6.86 (bs, 1H), 5.02-4.99 (m, 1H), 3.78 (dd, J=18.3, 2.4 Hz, 1H), 3.33 (dd, J=18.3, 9.0 Hz, 1H), 3.10 (t, J=6.4 Hz, 2H), 1.81-1.73 (m, 1H), 0.88 (d, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O>[C:39]([O:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:16])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:20])(=[O:41])[CH3:40]
Reactant: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2CO)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2COC(C)=O)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
395 mg (0.9 mmol) of allyl 4-[α-hydroxymethyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methylcarbamoyl]benzoate, 15 ml of pyridine and 200 μl (1.8 mmol) of acetic anhydride were introduced into a round-bottomed flask. The mixture was stirred at room temperature for 8 hours, the reaction medium was poured into water, and extracted with ethyl ether. The organic phase was decanted off, washed with water, dried over magnesium sulfate and evaporated. 435 mg (100%) of the expected compound were recovered in the form of a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([PH:17](=[O:34])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:19]=2)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=1[Br:82])(=O)=O.C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[C:24]([C:22]1[CH:23]=[C:18]([P:17](=[O:34])([C:7]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=2[Br:82])[CH:19]=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[O:28][CH3:29])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1c(C(C)(C)C)cc([PH](=O)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1C(C)(C)C
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)(C)C)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Into a four-neck flask were weighed 28.71 g (59.0 mmol) of bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of 1,3-diphenylphosphinopropane. The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of the 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of N,N-diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (30.83 g, a white viscous solid). Yield 97.7%.