Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C@H:2]1[C@@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:3]1=[O:24].[OH-].[K+]>CO.[Pd]>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[CH2:2][C:3]1=[O:24]
Reactant: COc1ccc(CN2C(=O)[C@@H](Cl)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2C(=O)C[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1

Procedure:
A solution of 4.26 g (12.0 mmol) of (3S,4R)-3-chloro-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and 3 g (53 mmol) of potassium hydroxide in 50 ml of methanol is hydrogenated in the presence of 400 mg of 5 percent palladium/carbon for 1 hour at normal pressure. The catalyst is filtered off, the filtrate is diluted with ethyl acetate and washed with 1M phosphate buffer (pH 7) and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated, whereupon the residue is chromatographed on silica gel with ethyl acetate/hexane as the eluent. After two-fold crystallization from methylene chloride/hexane there is obtained (S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone as white crystals of melting point 85°-86°; [α]D20 =+50.3° (c=1, chloroform).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:1][C@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl cis-3-hydroxycyclobutanecarboxylate (1.32 g, 9.20 mmol), 4-methoxyphenol (3.43 g, 27.6 mmol) and triphenylphosphine (3.12 g, 11.9 mmol) in dry THF (25 ml) was added dropwise diethyl azodicarboxylate (2.07 g, 11.9 mmol) in dry THF (5 ml) under argon atmosphere at room temperature. After completion of addition, the mixture was heated to 80° C., maintained at the same temperature for 1 h, and then volatiles removed under reduced pressure. Chromatographic purification of the residue {SiO2, 150 g; hexane/ethyl acetate (20/1)} provided 1.96 g (85%) of ethyl trans-3-(4-methoxyphenoxy)cyclobutanecarboxylate as a colorless oil. 1H NMR δ56.85-6.69 (m, 4H), 4.90-4.80 (m, 1H), 4.18 (q, J=7.0 Hz. 2H), 3.76 (s, 3H), 3.20-3.09 (m, 1H), 2.78-2.62 (m, 2H), 2.5-2.35 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([OH:22])=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O1CCCC1>[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([NH:26][CH:23]1[CH2:25][CH2:24]1)=[O:22]
Reactant: Cn1ncc(C(=O)O)c1Cl
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)NC2CC2)c1Cl
Temperature: 25 °C
Yield: 116.9 %

Procedure:
Carbonyldiimidazole (3.6 grams, 0.022 mole) was added to a solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2.4 grams, 0.015 mole) in 40 ml. of tetrahydrofuran, and the solution was stirred at room temperature for twenty minutes. Cyclopropylamine (1.3 grams, 0.022 mole) was then added and the reaction mixture was stirred at room temperature for sixteen hours. Solvent was removed in vacuo and the residue was taken up in 250 ml. of chloroform, washed with water, washed with saturated brine, and dried using sodium sulfate and filter paper. The product was recrystallized from toluene, yielding 3.5 grams of 5-chloro-1-methyl-N-cyclopropyl-1H-pyrazole-4-carboxamide, mp=105°-107° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[O:26])[CH3:25])=[CH:15][CH:16]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CN(C)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (551 mg) in THF (50 ml) were added triethylamine (0.42 ml) and acetic anhydride (0.26 ml), and the resulting mixture was stirred at room temperature for 3 hours. After evaporation of THF, the residue was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]acetamide (472 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][CH:4]=1.O.[NH2:11][NH2:12]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:11][NH2:12])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(Cl)n1
Reactant: NN
Solvent: O
Product: COc1cccc(NN)n1
Yield: 25.5 %

Procedure:
90 g (0.626 mol) of 6-methoxy-2-chloropyridine and 313.4 g of hydrazine hydrate were refluxed for 18 hours with stirring. The reaction mixture was cooled and the oil of the bottom layer was separated. The top layer was extracted three times with diethyl ether (total volume of 450 ml). The oil and the bottom layer left after extraction with diethyl ether were distilled under reduced pressure to remove the hydrazine hydrate. The residue was dissolved in 150 ml of a 20% aqueous solution of potassium hydroxide and extracted twice with diethyl ether (total volume 300 ml). The ether extract was dried with potassium hydroxide and combined with the ether solution. The mixture was distilled to afford 22.2 g of the desired product having a boiling point of 144° to 150° C./19-20 mmHg (yield 25%). Upon cooling, the product crystallized providing crystals having a melting point of about 30° to 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][Cl:17])[N:9]=[CH:8][NH:7][C:6]2=[O:18].Cl.[CH3:20][OH:21]>CC(C)=O>[ClH:17].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:7]1[CH2:6][CH2:5][O:21][CH2:20][CH2:8]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: CO
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 1,000 mL volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 90 g (0.284 mol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 94 mL (1.13 mol) of hydrochloric acid (12 mol/L, and 180 mL of methanol. The resulting mixture was stirred for one hour at room temperature. After the reaction was complete, 360 mL of acetone was added to the reaction mixture. The resulting mixture was cooled to 5° C. and stirred for one hour. The precipitated crystalline product was filtered to give 113 g of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one hydrochloride as a crude crystalline product (purity: 99.16% in terms of area percentage determined by high performance liquid chromatography). Subsequently, 105 g of the crude crystalline product was mixed with 700 mL of methanol. The mixture was stirred at 60° C. for one hour. After the stirring was complete, the mixture was cooled to room temperature, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure to give 98 g of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one hydrochloride (purity: 99.74% in terms of area percentage determined by high performance liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:31]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Reactant: NNCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with benzylhydrazine (CAS Reg. No. 555-96-4) to give the title compound as brown solid. MS (ESI): m/z=418.2 [M+H]+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: CCCCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 4-(n-butyl)benzoyl chloride (1.967 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 6 hours. The reaction mixture was treated in the same manner as described in Example 120 to obtain 863 mg of the title compound (yield: 32%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]([CH:25]=O)=[CH:21][CH:22]=[CH:23][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(-c2ccccc2N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: c1ccc(-c2ccccc2CN2CCN(c3ccccc3-c3ccccc3)CC2)cc1

Procedure:
148 mg of the target compound (0.37 mmol, 66.5%) was obtained using 1-(biphenyl-2-yl)piperazine (260 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17].BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1CCC(O)=O>CC(C)=O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[CH2:14][CH:15]([CH3:21])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)CC1=C(Br)C(=O)c2ccccc2C1=O
Agent: O=C(O)CCC1=C(Br)C(=O)c2ccccc2C1=O
Solvent: CC(C)=O
Product: CC(CC1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 69b was prepared from racemic 68b (0.027 g, 0.08 mmol) as described above for 69a to give 0.016 g (0.05 mmol, 63%) of the product as a yellow solid following flash chromatography (1:4 acetone:hexanes 0 to 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: COC1C=CC(C[S:10][C@@H:11]2[C@@H:15]([OH:16])[C@H:14]([CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[O:13][CH2:12]2)=CC=1.C(O)(=O)C.C1(OC)C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:19]([NH:18][CH2:17][C@@H:14]2[O:13][CH2:12][C@H:11]([SH:10])[C@H:15]2[OH:16])=[O:20])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: COc1ccc(CS[C@H]2CO[C@@H](CNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@@H]2O)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NC[C@@H]1OC[C@H](S)[C@H]1O)OCc1ccc([N+](=O)[O-])cc1
Yield: 73.3 %

Procedure:
The title compound is prepared by the procedure of Example 202 using 0.462 g of product from Example 326, 12 ml of 80% aqueous acetic acid, 0.187 g of anisole, and 0.443 g of mercuric trifluoroacetate to give after chromatography (Silica gel: 50-80% ethyl acetate/hexane) 0.248 g of the desired product.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([CH2:13][N:14]([CH2:25][C:26]([O:28][CH3:29])=[O:27])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=O)(C)C.C[O-].[Na+]>CO.C(OCC)(=O)C>[OH:4][C:5]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[N:14][CH:13]=[C:12]2[C:7]=1[N:8]=[CH:9][CH:10]=[CH:11]2
Reactant: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ncc2cccnc2c1O
Reaction time: 1.5 h

Procedure:
3-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-pyridine-2-carboxylic acid isopropyl ester (1.02 mol) was dissolved in dry methanol (4000 ml) and cooled to zero degrees under nitrogen. Then via addition funnel, sodium methoxide (137.8 g, 2.5 mol) was added slowly to avoid any exotherm. The reaction was stirred at zero degrees, and checked by HPLC after 1.5 hours and was found to be completed. The solvent was removed in vacuo to obtain a reddish-orange oil, which was partitioned between water (1L) and ethyl acetate (1L). The organic layer was back extracted with saturated sodium bicarbonate solution. The pH of the aqueous layer was adjusted to 7, and the layer was maintained at this pH while extracting with methylene chloride. The organic layer was dried with Na2SO4, filtered, and the solvent was removed in vacuo to obtain a tan solid. The solid was dissolved in hot ethyl acetate, and the solution was filtered while hot to filter out any insoluble material. The product precipitated upon cooling. The precipitate was then filtered and dried in a vacuum oven. The filtrate was recrystallized by concentrating the filtrate and redissolving the resulting solid in a minimal amount of methylene chloride. Sufficient ethyl acetate was added to turn the solution slightly cloudy, after which the solution was boiled to reduce the volume, cooled, and the resulting crystals were filtered out and dried in a vacuum oven.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:6]=1[NH2:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1[nH]ncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-1H-pyrazol-5-amine (1 g, 6.17 mmol) in THF (20 mL) at 0° C. was added NaH (0.494 g, 12.35 mmol) and stirred at the same temperature for 30 mins To this mixture was then added SEM-Cl (1.095 mL, 6.17 mmol) and slowly allowed to raise to rt and stirred at rt for 1 h. The reaction mix was then quenched with Satd. NH4Cl and then extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography afforded 221A (1.45 g, 80% yield) as a pale yellow oil. MS (ESI) m/z: 292.0 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nn1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nn1
Yield: 54.9 %

Procedure:
A solution of the compound (153 mg, 0.46 mmol) obtained in Example 64-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (103 mg, quant.) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]([CH3:35])[C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (25 mg, 0.049 mmol) in DCM (1 ml) was added TFA (250 μl). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified via preparative TLC (5% MeOH/DCM) to give 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoic acid (0.0174 g, 0.0382 mmol, 78%). 1H NMR (400 MHz, CDCl3): 8.04 (bs, N—H), 7.96 (s, 1H), 7.64-7.71 (m, 3H), 7.61 (s, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.6, 2.2H; 1H), 7.08 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.5 Hz, 1H), 3.74 (q, J=7.4 Hz, 1H), 1.53 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2)#[N:2].[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:9]1)=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1ccc2c(c1)CCNC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(C#N)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-cyano-1,2,3,4-tetrahydro-isoquinoline (CA [166398-34-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:12]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(C(=O)O)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 32.7 %

Procedure:
A solution of tert-butyl 6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate (9.03 g, 25 mmol) in trifluoroacetic acid (30 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylic acid (3.50 g, 82.0%) as crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([C:9]2[C:10]([CH2:18]O)=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1.O.C(OCC)(=O)C>C1COCC1.Cl>[CH3:21][O:20][C:7]1[C:8]2[C:9]3[CH:17]=[C:13]4[O:14][CH2:15][O:16][C:12]4=[CH:11][C:10]=3[CH2:18][O:1][CH2:2][C:3]=2[CH:4]=[C:5]([O:24][CH3:25])[C:6]=1[O:22][CH3:23]
Reactant: COc1cc(CO)c(-c2cc3c(cc2CO)OCO3)c(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)-c1cc3c(cc1COC2)OCO3
Yield: 65 %

Procedure:
A solution of (6-(6-(hydroxymethyl)-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxol-5-yl)methanol (170 mg, 0.48 mmol) in THF (2 mL), 2M HCl (2 mL) and concentrated hydrochloric acid (1 mL) was stirred under reflux for 3 hours. Water (15 mL) and ethyl acetate (15 mL) were added to the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography of the residue over silica gel (20 g), eluting with hexane-ethyl acetate (4:1), followed by crystallisation (ethyl acetate) yielded the title compound as large clear crystals (103 mg, 64%); m.p. 154-156° C.; Elemental Analysis Found: C, 65.3; H, 5.5 (C18H18O6 requires C, 65.45; H, 5.49%); NMR Spectrum δH (300 MHz, CDCl3) 7.21 (1H, s, 12-H), 6.98 (1H, s, 8-H), 6.96 (1H, s, 4-H), 6.75 (1H, s, 4-H), 6.04 (2H, d, J 4.8 Hz, 10-H2), 4.40 (2H, d, J 11.2 Hz, 5-H2), 4.04 (1H, d, J 10.8 Hz, 7-HA), 4.01 (1H, d, J 10.8 Hz, 7-HB), 3.96 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.71 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.3, 61.2, 61.5, 67.6, 67.8, 101.6, 109.0, 109.9, 110.2, 126.8, 129.5, 131.3, 131.7, 143.0, 147.3, 147.7, 150.8, 153.3; νmax/cm−1 (thin film) 2967, 2932, 2866, 1600, 1484, 1460, 1414, 1324, 1239, 1146, 1107, 1045; m/z (ES) 301 (MH+—CH2O, 100%); Rf (hexane-ethyl acetate 4:1) 0.28.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]1[CH:26]=[CH:25][C:23]([OH:24])=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]1[CH:26]=[CH:25][C:23]([O:24][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:13]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 85 °C
Yield: 69.7 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.5 g, 3.02 mmol), ferulic acid ethyl ester (0.97 g, 4.37 mmol), anhydrous potassium carbonate (1.0 g, 7.25 mmol), and DMF (40 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stirring to react for 8 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.5), filtering to obtain filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain solid, 0.75 g (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-3-methoxyphenyl)acrylic acid ethyl ester, a yield is 69.7%, m.p. 111.5-111.9° C.