Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C@@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step 3 (1.00 g, 2.49 mmol) in MeOH (10 mL) was added 2N NaOH (3.30 mL, 6.60 mmol). The resulting pink solution was stirred at ambient temperature overnight. The solvent was removed in vacuo. The crude oil was dissolved in water (20 mL) and the pH was adjusted to 7 with 2N HCl solution. The crude residue was extracted into ethyl acetate. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using MeOH/dichloromethane (gradient system) to give the free base of the title compound as a yellowish-brown oil. To the subsequent oil was added 2M HCl in diethyl ether (20 mL). The resulting mixture was stirred at ambient temperature for 6 hours. The solvents were decanted. The remaining off-white solid was triturated in diethyl ether (30 mL) overnight. The slurry was filtered, washed with diethyl ether (10 mL×3) and dried in vacuo at 45° C. overnight to afford the title compound as a white solid (0.61 g, 58%). 1H NMR (400 MHz, DMSO-d6); δ 1.72-2.02 (m, 5H), 2.22 (m, 1H), 2.37 (m, 2H), 3.13 (m, 2H), 3.46 (m, 1H), 3.61 (m, 1H), 3.85 (m, 1H), 3.88 (s, 2H), 4.27 (m, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 10.47 (br s, 1H), 12.33 (br s, 1H); MS (m/z) 388.4 (M+1); LC (100.0%); HPLC (99.5%); Elemental Analysis (Calc) C, 62.27; H, 6.41; N, 3.30 (Found) C, 62.46; H, 6.47; N, 3.26.
Reaction SMILES: C1(C(O)=O)CC1.[CH:7]1([C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:22])[N:19]([CH:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=2)[CH2:24][C:25](O)=[O:26])[CH2:18]3)=[O:11])[CH2:9][CH2:8]1.C1N=C[N:43](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:25]([CH2:24][CH:23]([N:19]1[C:20](=[O:22])[C:21]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])[CH2:18]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=1)(=[O:26])[NH2:43]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)C1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 69.6 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1′-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl)}-amide was prepared by the procedure of example 6 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and NH4OH (0.25 ml, 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.56 g, 70%): mp, 179-181° C.; 1H NMR (CDCl3): δ 0.92 (m, 2H, c-CH2), 1.44 (t, J=6.8 Hz, 3H, OCH2CH3), 1.68 (m, 1H, c-CH), 2.99 (dd, J=5, 15 Hz, 1H, CH2), 3.44 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.58 (m, 1H, CHN), 6.07 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.98 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.31, 14.6, 16.2, 38.9, 48.6, 53.9, 64.8, 101.57, 102.3, 113.2, 116.7, 117.3, 117.8, 119.2, 122.9, 113.5, 137.3, 138.1, 141.4, 141.2, 150.9, 170.9, 171.4, 172.7; Anal. Calcd. for C24H25F2N3O5: C, 60.88; H, 5.32; N, 8.87; Found: C, 60.82; H, 5.11; N, 8.80.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2].[OH-:20].[K+]>O.C(O)C.CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:3]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:20])=[O:2]
Reactant: O=Cc1cccc2c(=O)c(-c3ccccc3)coc12
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2c(=O)c(-c3ccccc3)coc12

Procedure:
A solution of 38.22 g of silver nitrate in 75 ml of water was added dropwise, under stirring, at 20°-25° C., to a solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared as described by G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter. 20, 393 (1985)) in 150 ml of 85% ethanol and 450 ml of N,N-dimethylformamide. Then, a solution of 32.67 g of 85% potassium hydroxide in 195 ml of water was added dropwise under stirring at 15°-20° C. After additional stirring at room temperature, the reaction mixture was filtered by suction; the mother liquor was acidified with 37% hydrochloric acid and diluted with 1.2 l of water. Filtration by suction and washing with water to neutrality gave the title compound as a crude. The crude was suspended in 150 ml of ethyl acetate and stirred with 444 ml of 0.3M aqueous sodium hydrogen carbonate solution until clear layers were obtained. The aqueous layer was washed with 75 ml of ethyl acetate, then made acidic with 37% hydrochloric acid, filtered and dried at 60°-65° C. to give 19, 12 g of the title compound that melted at (215) 218° C. A sample, crystallized from ethanol, showed the same melting point, m.p. (215) 218° C.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:17][C@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na:29][Na].[OH-].[Na+].C(O)C>CO.O>[Na+:29].[Na+:29].[CH2:1]([C@@H:8]([CH2:17][C@H:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:19]([OH:21])=[O:20])[C:9]([NH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C@@H:8]([CH2:17][C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Reactant: [Na][Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C([O-])CCNC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O

Procedure:
N-[(R*,R* -2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid, melting at 122°-124°. N-[(R*,R*)-2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid is converted to the disodium salt by the following procedure: To the solution of 0.38 g of the diacid in 25 ml of methanol:water (2:1) is added 2.0 ml of 1.00N sodium hydroxide. The solution is concentrated to give a solid. Ethanol is added and the suspension is concentrated and the solid is dried at 50° under high vacuum to yield the N-[(R*,R*)-2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid disodium salt.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][CH2:11]/[C:12](=[CH:14]/[CH2:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])\[CH3:19])/[CH3:13])/[CH3:8])[CH3:3].[H][H]>[Ni].CCCCCC>[CH3:30][CH:28]([CH2:27][CH2:26][CH2:25][CH:23]([CH2:22][CH2:21][CH2:20][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:19])[CH3:24])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: [Ni]
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
A tubular reactor of 1.2 cm in inner diameter and 10 cm in length was packed with 10 g of carrier-supported nickel catalyst. Hydrogenation was carried out by feeding into the reactor the n-hexane solution of squalene and hydrogen gas to obtain a squalane solution in n-hexane. Samples were taken out for 30 hours after the temperature was stabilized at 200° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](Cl)=[O:22])=[CH:15][CH:14]=1.[OH-].[NH4+:30]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:30])=[O:22])=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzoyl chloride (0.05 mol) in tetrahydrofuran (300 ml) is treated with concentrated ammonium hydroxide (25 ml). The reaction mixture is stirred overnight at room temperature and then evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K+].C(#N)C.CC(N(C)C)=O.P(Cl)(Cl)([Cl:27])=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 0 °C
Yield: 84 %

Procedure:
To a mixture of 1280 g of potassium 4-chloro-3-nitrobenzenesulfonate, 1150 ml of acetonitrile, 250 ml of sulforan, and 30 ml of dimethylacetamide was added dropwise 1250 ml of phosphorus oxychloride while maintaining the internal temperature thereof at 60° C. to 70° C. Then, after performing reaction for 3 hours at 73° C., the reaction mixture was cooled with water and after gradually adding thereto 400 ml of water, the reaction mixture was poured into 5 liters of ice-water. Crystals deposited were filtered by filtration, washed with water, and then dried to provide 1060 g of the above-described product with a yield of 84%. The melting point thereof was 55° C. to 56° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1>[Fe].C(O)C.O>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: Cn1ncc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1ncc2cc(N)ccc21
Yield: 71.1 %

Procedure:
Iron (3.62 g, 64.7 mmol) and concentrated hydrochloric acid (0.1 mL) were added to ethanol/water (20 mL/20 mL), and refluxed for 1 hour. The mixed reaction solution was added with 1-methyl-5-nitro-1H-indazole (2.29 g, 12.9 mmol) obtained in <Step 1> above, and further refluxed for 3 hours or more. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with chloroform/2-propanol=4/1(v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=4/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.35 g, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:24]=1
Reactant: O=C(O)c1cnccn1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of pyrazine-2-carboxylic acid (1.26 g, 10 mmol) and 1,1′-carbonyldiimidazole (2.14 g, 13 mmol) in N,N-dimethylformamide (8 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3 g, 10 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.82 g, 45%) as a light yellow solid: LC/MS m/e calcd for C23H22N4O3 (M+H)+: 403.46, observed: 403.5.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>C(O)C>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[NH:18][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1sc2ncnc(O)c2c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1sc2ncnc(NC3Cc4ccccc4C3)c2c1C
Yield: 64 %

Procedure:
Using 4-hydroxy-5,6-dimethylthieno[2,3-d]pyrimidine (180 mg, 1.0 mmol), phosphorus oxychloride (1.0 ml), 2-aminoindan (270 mg, 2.0 mmol), triethylamine (0.84 ml, 6.0 mmol) and dry ethanol (5 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (190 mg, 0.64 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([I:15])=[C:5]([C:10]([I:14])=[CH:11][C:12]=1[I:13])[C:6]([O:8]C)=[O:7].[OH-].[Li+].Cl>O1CCOCC1.CO.O>[CH3:1][O:2][C:3]1[C:4]([I:15])=[C:5]([C:10]([I:14])=[CH:11][C:12]=1[I:13])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(I)cc(I)c(OC)c1I
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COc1c(I)cc(I)c(C(=O)O)c1I
Temperature: 60 °C
Reaction time: 72 h

Procedure:
In a 250 mL round-bottom flask equipped with a condenser, methyl 3-methoxy-2,4,6-triiodobenzoate (11.07 g) was dissolved in a 3:1 mixture of dioxane/ MeOH (88 mL). Lithium hydroxide (1.71 g) dissolved in 22 mL H2O was added and the reaction mixture was stirred for 72 h at 60° C. Dioxane and methanol were evaporated and the residue was diluted with 100 mL H2O. The aqueous solution was filtered and the filtrate was extracted with Et2O (2×100 mL). The ether layers were combined and dried over MgSO4. Evaporation of solvent gave 7.64 g of un-reacted starting material (69%). The aqueous layer was acidified to pH 2 with 2N HCl and was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4. Evaporation of solvent gave the desired acid. Yield 3.14 g (29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(=O)OCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][O:15][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)(=[O:11])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1=COCCC1
Reactant: COc1ccc(S(=O)(=O)CCO)cc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1Br
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To the title compound of step 3 (1.0 g, 3.4 mmol) in CH2Cl2 (10 mL) was added 3,4-dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridinium p-toluensulfonate (64.6 mg, 0.34 mmol). After stirring at r.t. 12 h, the mixture was subjected to CH2Cl2 extractive work up & silica gel chromatography (PE: EA=1:0-5:1) to give the title compound (1.1 g, 85.6%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.51 (dd, J1=4.0 Hz, J2=2.4 Hz, 1H), 4.09-4.03 (m, 1H), 3.98 (s, 3H), 3.84-3.79 (m, 1H), 3.79-3.74 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.42 (m, 2H), 1.58-1.37 (m, 6H). LCMS: 401.0, 403.0 (M+Na)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00 g, 22.2 mmol) and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbon tetrachloride (25 mL) and add AIBN radical initiator (300 mg). Stir and maintain under a nitrogen atmosphere at 80-90° C. or optionally irradiate with a sunlamp until a vigorous exotherm occurs at which point momentarily remove until reflux subsides and then reapply the heat. Reflux for 30 minutes and add another potion of N-bromosuccinimide (100 mg) while maintaining reflux and reflux an additional 15 minutes. Cool to room temperature and precipitate the succinimide from the solution by allowing to stand overnight. Filter and wash the succinimide (2.25 g) with carbon tetrachloride (20 mL). Combine the filtrates and evaporate the solvent in vacuo to give the title compound as a yellow oil (6.80 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.BrCCBr.[Mg].Br[CH2:17][C:18]([CH3:20])=[CH2:19]>O1CCCC1>[CH3:19][C:18](=[CH2:17])[CH2:20][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: C=C(C)CBr
Reactant: Brc1ccc2c(c1)CCO2
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(C)Cc1ccc2c(c1)CCO2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2,3-dihydrobenzofuran (50 grams, 0.251 mole), and 1,2-dibromoethane (2.2 ml) in tetrahydrofuran (250 ml) was added dropwise to a stirred suspension of magnesium turnings (7.5 grams, 0.31 gram-atoms) in tetrahydrofuran (50 ml) over a period of 45 minutes. During the addition the reaction temperature was maintained at 30° C. The solution was cooled in an ice-bath and 3-bromo-2-methylpropene was added all at once. After stirring overnight, the reaction was quenched with cold 2% hydrochloric acid and the mixture was extracted with ether. Evaporation of solvent gave 5-(2-methylallyl)-2,3-dihydrobenzofuran as an oil (43.4 grams, 99%). M+ 174.
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C(F)(F)C([O:9][C:10](=O)[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=O>FC(F)(F)C(F)(F)C(F)(F)C(O)=O>[F:17][C:12]([F:18])([C:13]([F:14])([F:15])[F:16])[C:11]([F:20])([F:19])[C:10]([O:1][O:2][C:10](=[O:9])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])=[O:9]
Reactant: OO
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with heptafluorobutyric anhydride to give bis(heptafluorobutanoyl) peroxide (δ−82.6, −118.4, −128.2) in heptafluorobutyric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][C:45]=1[CH2:51][CH3:52].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:26])[F:28])[CH:5]=[CH:6][CH:7]=2)=[CH:46][C:45]=1[CH2:51][CH3:52]
Reactant: CC(C)(C)[Si](C)(C)OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)ccc1Cl
Yield: 23.1 %

Procedure:
A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248 mmol), 4chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzene complex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of the desired 3-[[3-(4chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H23CIF7NO3: 566.1332 [M+H]+, found: 566.1332. 1H NMR (CDCl3) δ1.18 (t, 3H), 2.69 (q, 2H), 3.50-3.61 (m, 1H), 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 4.63 (s, 2H), 5.88 (tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H), 7.0-7.34 (m, 5H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]([Cu])#[N:21].CN(C)C=O.C(OCC)(=O)C>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]#[N:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1.621 g, 5 mmol; prepared as shown in Scheme 2, according to US 2004/0254215 A1; 1H NMR (200 MHz, CD3OD) δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4.49 (t, J=7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2 Hz, 3H)), CuCN (905 mg, 10 mmol) and dimethylformamide (20 mL) was refluxed with stirring under nitrogen for 5 min. After cooling to ambient temperature the mixture was diluted with water (300 mL). Then ethyl acetate (150 mL) was added and the mixture was shaken thoroughly for 5 min before it was filtered through a pad of celite. The organic phase of the filtrate was separated, and dried over MgSO4 before silica gel was added. The mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with dichloromethane gave the title compound as a yellowish solid (627 mg); MS-(−)-ion: M−1=269.2.