Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([NH:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH3:40]>C(O)C.CC(C)=O>[CH2:37]([N:41]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCNCCCC
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
To a solution of 0.85 g. (0.0024 mol.) of 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran in 25 ml. of dry acetone was added 0.96 g. (0.0048 mol.) of 1,3-dibromopropane and 0.66 g. (0.0048 mol.) of potassium carbonate. The mixture was refluxed for ca. 12 hours, then an additional 0.4 g. of 1,3-dibromopropane, 0.3 g. of potassium carbonate and 25 ml. of dry acetone were added and the mixture was refluxed for 5 hours. The reaction mixture was filtered and the solvent was removed in vacuo to give a residue which was dissolved in 2-4 ml. of ethanol to which 22-24 ml. of freshly distilled di-n-butylamine was added. The mixture was heated at 130° for 4 hours, then cooled and diluted with ethanol. The solvent and excess amine were removed by evaporation to give 0.23 g. of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>O1CCOCC1>[CH2:22]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(Cl)cc2n1
Solvent: C1COCCO1
Product: C=CCc1ccc2c(-c3ccccc3)cc(C#N)nc2c1

Procedure:
To a solution of 7-chloro-4-phenylquinoline-2-carbonitrile (3.3 g, 12.5 mmol) in dioxane (120 mL) was added tetrakistriphenylphosphine (3.6 g, 3.1 mmol) and allyltributyltin (11.5 mL, 38 mmol). The mixture was refluxed for 10 h, concentrated and purified on silica gel (eluting with dichloromethane/hexanes, 3:1) to give the title compound. MS (+ESI): 271 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[CH2:46][OH:47])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[CH2:46][O:47][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCc1cc(F)c(F)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(F)c(F)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (200 mg, 0.342 mmol) and (2-allyl-4,5-difluorophenyl)methanol (63.0 mg, 0.342 mmol) in DMF (2 mL) at 0° C. was added NaH (13.69 mg, 0.342 mmol). It was stirred at 0° C. for 2 h, then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4,5-difluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 43.6%) as an oil. LCMS (M+1)=641.5.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([O:10]C(=O)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CO.C1COCC1.C([O-])(=O)C.[Na+]>CCOCC>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Oc1ccc(C2CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc(C2CC2)cc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of acetic acid 4-cyclopropyl-phenyl ester (16.1 g, 0.0914 mol) in mixed solvent (40 mL, MeOH: THF=1:1) was added sodium acetate (19.4 g, 0.183 mol). The reaction mixture was stirred two hours. Solvent was evaporated under reduced pressure to provide a crude mixture, to which was then added Et2O. The solid was filtered and the filtrate was concentrated to afford the title compound as a yellow oil (12.1 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(F)c1F
Temperature: 25 °C

Procedure:
2,3-difluorobenzoic acid (9.47 g, 59.90 mmol) and H2SO4 (0.3 mL) in methanol (100 mL) were heated for 3 days in a 70° C. oil bath. The reaction was cooled to RT, then the solvent was removed under vacuum at 35° C. The crude residue was transferred to a separatory funnel with ether, washed with saturated sodium bicarbonate solution (2×50 mL), brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was redissolved in CH2Cl2, dried (MgSO4), filtered and concentrated under vacuum to yield 8.66 grams of methyl 2,3-difluorobenzoate as a clear liquid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li+].CCC[CH2-].[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:16]1([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C1CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
Diisopropylamine (6.37 mL, 44.7 mmol) in THF (50 mL) was cooled to 0° C. under argon. N-Butyllithium (16.7 mL, 2.5 M in hexane, 41.7 mmol) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of tetrahydro-2H-pyran-4-carboxylic acid (D8) (1.94 g, 14.9 mmol) in THF (10 mL) was added and a white precipitate was formed. The resulting mixture was then heated at 50° C. for 3 h. The reaction mixture was cooled to 0° C. and methyl iodide (2.80 mL, 44.7 mmol) was added dropwise. The reaction was then allowed to warm to rt and left to stir overnight. 10% aqueous citric acid solution (40 mL) was then added and the THF was removed by rotary evaporation. The residual aqueous mixture was extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give the title compound (D9) (1.26 g, 53%) as a yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:23])=[CH:16][CH:15]=1.[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=[O:23])=[CH:18][CH:19]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)OCCCCCCCl
Reactant: COCCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OCCCCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.7 %

Procedure:
3 g (15 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added to a solution of 3.1 g (15 mmol) of 6-chlorohexyl(2E)-3-(4-hydroxyphenyl)prop-2-enoate, 0.186 g (1.5 mmol) of 4-dimethylaminopyridine in 70 mL of dichloromethane at 0° C. To this mixture, 5.1 g (15 mmol) of 4-(2-methoxyethoxy)benzoic acid in 40 mL of dichloromethane are added at 10° C. The solution is allowed to stir at room temperature for 22 hours. The reaction mixture is then partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using cyclohexane: ethylacetate 4:1 yielded 5.3 g (73%) of pure 4-{(1E)-3-[(6-chlorohexyl)oxy]-3-oxoprop-1-enyl}phenyl 4-(2-methoxyethoxy)benzoate as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.CS(O)(=O)=O.C(N([CH2:36][CH3:37])CC)C.[C:38](OCC)(=O)C>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:36]([CH3:37])([CH3:38])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C
Temperature: 45 °C
Reaction time: 4 h

Procedure:
Dry ingenol (15.00 g, 90%, 38.75 mmol) was dissolved in acetone (630 mL) with stirring, and the solution was heated to 45° C. A solution of methanesulfonic acid (0.745 g, 7.75 mmol) in acetone (10 mL) was added during 5 seconds. The solution was stirred at 45° C. for an additional 95 seconds, before a solution of triethylamine (1.35 mL, 0.98 g, 9.69 mmol) in acetone (10 mL) was added during 5 seconds. The mixture was cooled to 20° C., and ethyl acetate (500 mL) was added. Most of the reaction solvent (650 mL) was distilled off under vacuum. Water (200 mL) was added to the remaining solution, and the mixture was agitated for 2 minutes. The water layer was removed, and the water wash was repeated once before the organic phase was concentrated under vacuum. The crude product contained 84% of the title compound as determined by 1H NMR spectroscopy. The residue was dissolved in toluene (75 mL) by heating to reflux temperature followed by slow cooling to 5° C. After 4 hours standing, the formed crystals were filtered off, rinsed with 5° C. toluene (2×5 mL) and dried under vacuum at 20° C. until constant weight. After 18 hours, ingenol-5,20-acetonide (8.97 g) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.I[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CC#N.O>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:5]1
Reactant: Ic1cnccn1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1CN(c2c(C=O)cc(-c3cnccn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 68 %

Procedure:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (16 grams, 41 mmol), 2-iodopyrazine (Aldrich, 6 grams, 29.1 mmol), sodium carbonate (9.3 grams, 87 mmol) and Pd(PPh3)2Cl2 (Aldrich, 0.82 gram, 1.2 mmol) were suspended in a 1:1 mixture of CH3CN/H2O. The reaction mixture was then purged with nitrogen and heated at 85° C. overnight. Upon completion the reaction was partitioned between H2O and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with 5-40% ethyl acetate in hexanes to obtain 6.6 grams of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.2 Hz, 6H), 3.09 (m, 4H), 3.84 (m, 1H), 8.28 (dd, J=8.1, 2.1 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.66 (dd, J=2.4, 1.7 Hz, 1H), 9.01 (s, 1 H), 10.22 (s, 1H); MS(APCl+) m/z 334 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=O)[CH2:10][CH2:9][CH2:8]3.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=[N:16][OH:17])[CH2:10][CH2:9][CH2:8]3
Reactant: O=C1CCCc2cc3c(cc21)OCC3
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1.Br[CH2:17][C:18]([NH:20]C1C=CC(Br)=CC=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 223.1 %

Procedure:
DMF (20 ml) was added to 1-(4-hydroxyphenyl)ethanone (1.81 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol), and potassium carbonate (4.25 g, 30.7 mmol), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (3.44 g). The title compound was obtained by similar operations as in Reference Example 20, Reference Example 21, Example 10 and Example 6 and using this compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:7][CH2:11][CH:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
To a solution of 0.6 g (3.7 mmol) of diethylamino-sulfur trifluoride in 5 ml dichloromethane cooled at -78° C. under nitrogen was added dropwise a solution of 1 g (3.4 mmol) of 2-hydroxymethyl-1,4-di-phenylmethyl piperazine in 5 ml dichloromethane. The temperature of the solution was allowed to warm to -50° C. in 30 mn then to C. in 1 hr 30 min. The solution was stirred two more hours at room temperature and cooled back to +5° C. A few drops of aqueous saturated solution of sodium bicarbonate were added until basic pH. The organic layer was washed twice with water, dried over magnesium sulfate, the solvent removed to give 1.10 g of an oil which was purified by chromatography using dichloromethane/ethyl acetate (95:5) to afford 0.46 g (42%) of title compound.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: CC(C)CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.1 g of 1-bromo-3-methylbutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2-(3-methylbutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (77)).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[S:15][C:16]([C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][C:23]=2[F:33])=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20]>>[C:11]([C:8]1([C:6]2[N:7]=[C:2]([NH:13][C:14]3[S:15][C:16]([C:22]4[C:23]([F:33])=[CH:24][C:25]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:26][C:27]=4[F:28])=[CH:17][C:18]=3[C:19]([NH2:21])=[O:20])[CH:3]=[CH:4][CH:5]=2)[CH2:10][CH2:9]1)#[N:12]
Reactant: N#CC1(c2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C4(C#N)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 1-(6-bromopyridin-2-yl)cyclopropanecarbonitrile (107 mg, 0.48 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22].[H][H]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)NN
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 92 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-(hydrazinecarbonyl)piperidine-1-carboxylate (630 mg, prepared following a procedure analogous to Reference Example; Hydrogen addition), 648 mg of the title compound was afforded (yield 92%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:24])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:34]1([N:40]([CH3:49])[C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:7]([NH:8][C:46](=[O:47])[CH:41]([N:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH3:49])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:6](=[O:24])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C1CCCCC1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
O-Benzyl-L-tyrosine-t-butyl-amide (Ia, 0.5 g, 1.53 mmol) was dissolved in DMF (8 mL) and treated with diisopropylethylamine (0.8 mL, 4.6 mmol), N-cyclohexyl-N-methyl-leucine (Iid, 0.34 g, 1.53 mmol), and HBTU (0.58 g, 1.53 mmol). The reaction was stirred for 2 hours, then diluted with EtOAc (100 mL), washed with saturated bicarbonate solution (2×100 mL), brine (100 mL), dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 50% EtOAC/hexane. The resulting material was chromatographed again on silica gel eluting with 8% acetone/CH2Cl2 to give 0.11 g (14%) of the title compound. MS: 537 (M+1 for C33H49N3O3); TLC: SiO2, Rf 0.57 (10% MeOH/CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.Cl[CH2:21][C:22](=[O:24])[CH3:23].O.ClCCl>N1C=CC=CC=1>[CH2:21]([S:17][CH:16]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:18])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:19])[C:22]([CH3:23])=[O:24]
Reactant: CC(=O)CCl
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 72.9 %

Procedure:
In 10 ml pyridine was dissolved 1.5 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 0.6 g of chloroacetone was added dropwise to the mixture with stirring with cooling at 5° to 10° C. over a period of 10 minutes. After cooling was continued at room temperature for 2 hours, water was added to the mixture for extraction with dichloromethane. The dichloromethane layer was separated out, washed with dilute hydrochloric acid and water, successively, and dried over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with a mixed solvent of ether and hexane and dried, thereby producing 1.3 g (yield of 73%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccsc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: O=C(Cc1ccc(Cl)c(Cl)c1)c1cccs1

Procedure:
Using the procedure described in Example 4A, 100.0 g of 3,4-dichlorophenylacetic acid, 242.0 g of thiophene and 144.0 g of trifluoroacetic anhydride gave from methanol 61.7 g of 2-(3,4-dichlorophenyl)-1-(2-thienyl)ethanone, m.p. 59.5-60.5.