Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>C1C=CC=CC=1.C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccccc1NC(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
In an atmosphere of dry air, 4-cyanobenzoic acid (1.5 g, 10 mmol) was dissolved in benzene (5 ml), and DMF (0.1 ml) and thionyl chloride (2.2 ml, 30 mmol) were added dropwise to the resulting solution at room temperature, followed by 30 minutes of heating under reflux. After removing the solvent by evaporation, the resulting residue was subjected to azeotropy using benzene (10 ml×2) to obtain a yellow solid which was subsequently dissolved in methylene chloride (10 ml) and mixed with o-anisidine (1.16 ml, 10 mmol) and 20% sodium hydroxide aqueous solution (4 ml) with cooling in an ice bath. After 20 minutes of stirring at the same temperature, the resulting mixture was extracted with methylene chloride and then washed with 1N hydrochloric acid, water and saturated brine in that order. After drying on anhydrous magnesium sulfate, the solvent was removed by evaporation, and the resulting light yellow solid was purified by recrystallization (methylene chloride-ether) to obtain 2.36 g (93.6%) of the title compound in the form of creamy-colored crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([NH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:41])[C:27]3[CH:32]=[CH:31][C:30]([O:33]CC4C=CC=CC=4)=[CH:29][CH:28]=3)[C:22]([OH:24])=[O:23])=[O:18])[CH2:12]2)=[O:10])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([NH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:41])[C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:22]([OH:24])=[O:23])=[O:18])[CH2:12]2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O)c1ccc(O)cc1
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-benzyloxybenzoyl)amino-β-alanine (190 mg, 0.34 mmol) and 10% Pd—C (50% wet) (60 mg) in methanol (7 mL) was hydrogenated at 1 atm of hydrogen. After 5 hours, the catalyst was removed by filtration, then the filtrate was evaporated in vacuo. The residue was purified by an ODS column chromatography using Daisogel-120SP (10% CH3CN/water)and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-hydroxybenzoyl)amino-β-alanine (153 mg, 0.32 mmol, 94.1%) as a white powder
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[C:31]([CH3:35])([CH3:34])[NH:30][C:29]1=[O:36]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[C:31]([CH3:35])([CH3:34])[C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:36])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3(C)C)cc2F)CC1
Yield: 10.4 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (20 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1.[Br:21]C1C=C2C(C)(C)C(C)=NC2=NC=1>>[Br:21][C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: CC1=Nc2ncc(Br)cc2C1(C)C
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Product: CC1=Nc2c(cc(Br)c[n+]2CCCS(=O)(=O)[O-])C1(C)C

Procedure:
Compound 6 was prepared analogously to compound 5 (Example 5), except that 5-bromo-2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine (50) was used as a starting material.
Reaction SMILES: [O-][Si]([O-])=O.[Ca+2:5].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]>[Si](O)(O)(O)O>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[Ca+2:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=[Si]([O-])[O-]
Agent: O[Si](O)(O)O
Agent: [Ca+2]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The method of claim 1 wherein the calcium metasilicate is acidified with citric acid to form calcium citrate in the silicic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:35][CH2:34][C:32]3[CH:31]=[CH:30][C:16]([O:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=4)=[C:15]([F:14])[CH:33]=3)[CH:3]=2)[CH2:9][CH:10]1[CH3:13]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(Oc4ccc(C#N)c(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[OH-].[Na+].ClC1C=CC=C(C(OO)=[O:25])C=1>CN(C)C=O.O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]([OH:25])=[CH:12][C:7]=1[CH3:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(O)cc1C
Reaction time: 2 h

Procedure:
4-Methoxy-3-methylphenol was prepared according to the procedures described in Higgins et al., “An Assessment of the Reaction Energetics for Cytochrome P450-Mediated Reactions,” Arch. Biochem. Biophys. (2001); 385: 220-30. Specifically, phosphorus oxychloride (5.1 ml, 0.057 mol) was added dropwise to a solution of o-methylanisole (5.33 ml, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 hours, cooled, and then added to 100 ml of water. To the solution, 10% NaOH was added and the solution was extracted with 4×100 ml of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate, and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The purified oil (1.78 g, 28%) was dissolved in dichloromethane (100 ml) and then 3.03 g (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 hours, cooled, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressured. The dark oil that remained was dissolved in 7 ml of methanol and 5.5 ml of 10% aqueous potassium hydroxide solution was added. The solution was stirred for ˜2 hours, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give 4-methoxy-3-methyl-phenol as long white needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.O1CCCC1.C(O)C.[N:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]=[S:33]>C(OCC)(=O)C>[Cl:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:7][C:2]=1[NH:1][C:32]([NH:31][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[S:33]
Reactant: CCOC(=O)CN=C=S
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CNC(=S)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.0 g, 8.89 mmol) in a tetrahydrofuran/ethanol solution (1:1) is treated with ethyl isothiocyanatoacetate (1.93 g, 13.34 mmol), refluxed for 9 hours, stirred at room temperature overnight, and concentrated in vacuo to obtain an orange-brown gum. Flash column chromatography of the gum using silica gel and 25% to 30% ethyl acetate in hexanes solutions gives the title product as a white foam (2.24 g, 52% yield, mp 95-103° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.21 g of an iron powder, 3 ml of acetic acid and 0.3 ml of water was added a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 9-42] in 1.2 ml of acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 1 hour, then, the reaction solution was filtrated through Celite, and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel chromatography to obtain 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine (as a mixture of two diastereomerical isomers).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:3]=[CH2:4].[CH:27]([OH:29])=[O:28]>>[CH:27]([O:29][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:28]
Reactant: O=CO
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)CCCC(C)C
Product: CC(=CCOC=O)CCCC(C)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 9 h

Procedure:
275 g (0.75 mole) of 3,7,11,15,19-pentamethyl-1-eicosen-3-ol (formula II, with n=3) and 390 g (7.6 moles) of 90 percent strength by weight formic acid were reacted at 60° C. by a method similar to that of Example 1; the reaction time was 9 hours. 545 g of 85.8 percent strength by weight formic acid were recovered. The crude 3,7,11,15,19-pentamethyl-2-eicosen-1-yl formate was distilled through a Claisen head. The yield was 221 g (corresponding to 74.7% to 74.7% of theory); boiling point 176°-178° C./0.1 mbar; nD25 =1.4582.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:7]=1[C:8]([O:10]CC)=[O:9].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of ethyl 2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and ethanol (0.68 mL) was added 1N aqueous sodium hydroxide solution (0.68 mL), and the mixture was stirred at room temperature for 16 hrs. 1N Hydrochloric acid (0.68 mL) and water (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (76 mg) as white powder crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][O:12][C:13]3[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=[C:15]([CH2:23][CH3:24])[CH:14]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[NH:42][N:41]=[N:40][N:39]=1.Cl>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][O:12][C:13]3[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=[C:15]([CH2:23][CH3:24])[CH:14]=3)[CH:9]=2)[NH:4][C:3]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[NH:42][N:41]=[N:40][N:39]=1
Reactant: CCc1cc(OCc2ccc3c(c2)c(Br)c(-c2ccccc2-c2nnn[nH]2)n3C(=O)OC(C)(C)C)c2c(n1)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(OCc2ccc3[nH]c(-c4ccccc4-c4nnn[nH]4)c(Br)c3c2)c2c(n1)CCCC2
Temperature: 60 °C

Procedure:
1,1-Dimethylethyl 3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole-1-carboxylate (A) (100 mg) in a mixture of ethanol (15 ml) and 2M aqueous sodium hydroxide solution (5 ml) is heated at 60° C. for 3 hours. The mixture is cooled and acidified with 2M hydrochloric acid to pH 5 to 6. The mixture is then extracted with dichloromethane and the combined extracts are dried (MgSO4) and evaporated to give 3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:44]=[CH:43][O:42][C:41]=2[CH3:45])O1>>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([C:40]1[CH:44]=[CH:43][O:42][C:41]=1[CH3:45])[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(-c4ccoc4C)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 191 from methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate and 4,4,5,5-tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane and was isolated as a pale yellow solid (10 mg, 49%) after reverse phase chromatography: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.58-8.46 (m, 1 H), 7.62-7.53 (m, 1 H), 7.46-7.33 (m, 2 H), 7.32-7.24 (m, 1 H), 7.24-7.05 (m, 2 H), 6.62 (t, J=1.9 Hz, 1 H), 5.37 (s, 1 H), 3.71 (d, J=1.2 Hz, 3 H), 2.51 (d, J=2.3 Hz, 3 H), 2.37 (d, J=1.2 Hz, 3 H), 2.33 (d, J=2.0 Hz, 3 H), 1.09 (d, J=4.5 Hz, 9 H); LC/MS (m/z) ES+=474 (M+1).
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21](C)=[CH:20]C=2O)=[CH:15][CH:14]=1)(=O)C1C=CC=CC=1.[C:29]([O:32][C@@H:33]1[O:50][C@H:49]([CH2:51][O:52]C(=O)C)[C@@H:44]([O:45]C(=O)C)[C@H:39]([O:40]C(=O)C)[C@H:34]1[O:35]C(=O)C)(=O)[CH3:30].C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:32]([C:29]1[CH:30]=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:24])[C:18]=1[CH2:17][C:16]1[CH:27]=[CH:28][C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[CH:14][CH:15]=1)[C@@H:33]1[O:50][C@H:49]([CH2:51][OH:52])[C@@H:44]([OH:45])[C@H:39]([OH:40])[C@H:34]1[OH:35]
Reactant: Cc1cc(C)c(Cc2ccc(CCCOC(=O)c3ccccc3)cc2)c(O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Cc2ccc(CCCO)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.7 %

Procedure:
To a solution of 2-[4-(3-benzoyloxypropyl)benzyl]-3,5-dimethylphenol (0.72 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (2.3 g) in toluene (7 mL) and dichloromethane (3 mL) was added boron trifluoride diethyl ether complex (0.73 mL), and the mixture was stirred at room temperature for 10 hours. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and tetrahydrofuran (4 mL), sodium methoxide (28% methanol solution, 0.19 mL) was added to the solution, and the mixture was stirred at 30° C. for 7.5 hours. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10 mL), sodium methoxide (28% methanol solution, 0.075 mL) was added to the solution, and the mixture was stirred at 30° C. for 14 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to give 2-[4-(3-hydroxypropyl)-benzyl]-3,5-dimethylphenyl β-D-glucopyranoside (0.58 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:33]([NH:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:33]([NH:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OCC)cc3)c2c1
Solvent: CCO
Product: CCCCCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 72 from ethyl 4'-[(2-n-butyl-6-(N-(cyclohexylamino-carbonyl)-n-octylamino)-benzimidazol-1-yl)-methyl)bi-phenyl-2-carboxylate in ethanol/2N sodium hydroxide solution.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1.[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:26]([C:29]1[CH:34]=[C:33]([C:8]2[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:9]=2)[CH:32]=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 110 °C
Yield: 59.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.31 g) ethanol (1 ml), 3-nitrobenzeneboronic acid (0.24 g) and tetrakis(triphenylphosphine)palladium(0) (30 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give (2R)-1-(3'-nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol as a yellow oil (0.210 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a hygroscopic gum (0.150 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][CH:11]([CH3:20])[C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:14](=[O:15])[CH2:13][C:12](=[O:19])[CH:11]([CH3:20])[CH3:10]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)CC(=O)C(C)C
Product: Cc1ccc(C)c(NC(=O)CC(=O)C(C)C)c1
Temperature: 160 °C

Procedure:
A mixture of 2,5-dimethylaniline (7.70 g, 63.54 mmol) and ethyl 4-methyl-3-oxopentanoate (10.00 g, 1.0 eq) were refluxed at 160° C. overnight. After the reaction mixture was cooled to room temperature, it was triturated with hexane. The resulting precipitate was filtered and dried under high vacuum to yield the desired N-(2,5-dimethylphenyl)-4-methyl-3-oxopentanamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.18 (d, J=7.03 Hz, 6 H) 2.30 (d, J=7.62 Hz, 6 H) 2.66-2.85 (m, 1 H) 3.64 (s, 2 H) 6.87 (d, J=8.50 Hz, 1 H) 7.06 (d, J=7.62 Hz, 1 H) 7.77 (s, 1 H) 9.13 (br. s., 1 H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[C:5]([CH2:14][C:15]([OH:17])=[O:16])[C:4]1=[O:18])[CH3:2].Cl.[CH3:20]O>>[CH3:20][O:16][C:15](=[O:17])[CH2:14][C:5]1[C:4](=[O:18])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2
Reactant: CO
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(O)cc21
Agent: Cl
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A suspension of (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid (2.9 g, 12 mmol) in methanol (30 mL) was treated with 12 N aqueous HCl (3 mL, 36 mmol) and the mixture heated to reflux. After 5 h, the resulting solution was cooled to room temperature, filtered and left standing overnight. The resulting solid was vacuum filtered, washed with ice-cold methanol and air-dried to give the title compound (1.8 g, 58% yield) as white needles.