Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([O:14][Si](C)(C)C)([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>ClCCl>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([OH:14])([C:12]([NH2:13])=[O:26])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved in dichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0° C. and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0° C. and 25% ammonium hydroxide solution was added carefully dropwise to pH ˜10-11. The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (EI) for C17H18N2O2: 283 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]([CH3:33])=O>>[CH3:30][C:31]1([CH3:33])[NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][C:3]=2[NH:18]1)=[CH:9][CH:10]=[CH:11][CH:12]=4
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)Nc2ccc3c(c2N1)C(=O)c1ccccc1C3=O
Reaction time: 48 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dry acetone (100 mL), and concentrated sulfuric acid (0.1 mL) is further added thereinto. After mixing and reacting in room temperature for 48 hours, the reacted mixture is transferred into a potassium carbonate column. The product is collected and recrystallized by methanol, so as to obtain the purple compound 20, and the production rate is 31%. In the purification steps of the Embodiment 21, regular extraction method will reduce the production rate, and thus the basic column is used to remove the acid in the rough extract, so as to increase the production rate.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and pyridin-3-ylboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.82 min, m/z=445.1 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.83 (dd, J=8.80, 4.40 Hz, 1H) 2.87 (d, J=11.49 Hz, 1H) 3.14-3.26 (m, 2H) 3.39-3.45 (m, 1H) 4.18 (d, J=2.45 Hz, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.50 (dd, J=7.70, 4.77 Hz, 1H) 7.78-7.90 (m, 3H) 8.03 (d, J=2.20 Hz, 1H) 8.55-8.61 (m, 1H) 8.65 (d, J=1.71 Hz, 1H) 8.77 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2ccncc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 4-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g 3-(pyridin-4-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.O[NH3+:28].O[NH3+]>O>[C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:11]([C:14]#[N:28])=[CH:10][CH:9]=1
Reactant: [NH3+]O
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
With stirring (20 rpm), a turbine dryer is charged at room temperature with 1007 parts by weight of anhydrous sodium sulfate, 222 parts by weight of biphenyl-4-carbaldehyde and 105 parts by weight of hydroxylammonium sulfate. Following evacuation to 13 mbar, the mixture is heated to 70° C. and stirred at this temperature for 3 hours. It is subsequently heated at 130° C., during which about 43 parts by weight of water are removed by distillation. After half an hour, the pressure is reduced to 4 mbar and the jacket temperature is raised successively to 170° C. over the course of 60-70 minutes, the product undergoing fractional distillation. 194 parts by weight of biphenyl-4-carbonitrile are obtained with an outstanding purity of ~98-99% (HPLC) and a melting point of 83°-85° C., along with 10 parts by weight of a less pure fraction.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:5]([N+]([O-])=O)[C:6]=1[Cl:7].Br[C:20]1[NH:21]C(C2C=CC(Cl)=C(Cl)C=2)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:5]([C:20]#[N:21])[C:6]=1[Cl:7]
Reactant: O=[N+]([O-])c1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl
Product: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl

Procedure:
In a similiar fashion one can prepare 2-bromo-3-chloro-5-(3,4-dichlorophenyl)-4-nitropyrrole by starting with 2-bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8]OC(OC)N(C)C.[Na].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18]>C(O)C.C1COCC1>[C:5]([C:4]1[CH:8]=[C:19]([C:17]#[N:18])[C:20](=[O:21])[NH:22][C:1]=1[CH3:2])(=[O:7])[CH3:6]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of acetylacetone (41 ml), N,N-dimethylformamide dimethylacetal (106.2 ml) and THF (200 ml) was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was added dropwise to a solution prepared by dissolving metal sodium (13.8 g) in ethanol (600 ml) and adding thereto cyanoacetamide (33.6 g), and the mixture was refluxed for one hour. The reaction mixture was ice-cooled, and the precipitated crystals were separated by filtration. The crystals were dissolved in water (1 liter) and then weakly acidified with 3N hydrochloric acid. The precipitated crystals were separated by filtration and recrystallized from DMF-methanol to give 5-acetyl-6-methyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile (60 g) as colorless crystals. M.p. 230° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:19][C:10]1[C:11]([OH:18])=[C:12]([C:15](=[O:17])[CH3:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Zinc dust (5.5 g) was added portionwise to a suspension of 1-(4-(benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone (5.5 g) in acetic acid (55 mL) over 15 min, whilst maintaining the internal temperature below 40° C. with an ice bath. The mixture was allowed to attain ambient temperature and stirred for a further 2 h. The mixture was filtered through Celite (caution gets hot, do not allow to dry), washed with acetic acid, and the filtrate poured onto ice/water (500 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid (4.8 g). 1H NMR (300 MHz, DMSO-d6) δ 7.53 (m, 2H), 7.48-7.33 (m, 3H), 7.28 (d, J=9.0 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 5.29 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:1]([O:11][C:12]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(C(=O)O)c(O)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC2CCN(S(C)(=O)=O)CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.12 mL) and acetic anhydride (0.065 mL) were sequentially added to a methylene chloride (1.8 mL) suspension of the obtained 2-hydroxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoic acid (0.18 g), followed by stirring at room temperature for 1 hour. Under ice-cooling, pyridine (0.023 mL) and acetic anhydride (0.016 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.18 g of 2-acetoxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoic acid as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][CH:21]=[CH:20]2.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([NH:31][C:11](=[O:13])[C:10]2[CH:15]=[CH:16][C:7]([CH3:6])=[C:8]([C:17]3[CH:26]=[C:25]4[C:24](=[CH:19][CH:18]=3)[C:23](=[O:27])[NH:22][CH:21]=[CH:20]4)[CH:9]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride (2M, 0.4 mL) in THF was added dropwise to a stirred solution of 4-methyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzoic acid, methyl ester (Intermediate 3) (76 mg) and cyclopropylamine (0.15 mL) in THF (2 mL). The mixture was stirred for 10 min., quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo and the residue was purified by HPLC to give the title compound as a solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)[CH:11]=2)O)=[CH:4][CH:3]=1.O=S(Cl)[Cl:31]>C1C=CC=CC=1>[Cl:31][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)c1cc(-c2cccc(C(O)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)c1cc(-c2cccc(C(Cl)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reaction time: 0.75 h

Procedure:
To a solution of (4-chloro-phenyl)-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol from Step 1 (1.0 g, 2.58 mmol) in benzene (7 mL) at 0° C. was added SOCl2 (0.375 mL, 5.2 mmol) dropwise. After 45 min. at 0-10° C., the resulting reaction mixture was filtered through silica gel and celite and then concentrated.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:13]([C:14](O)=[O:15])[C:8]=2[C:7]([CH3:21])=[N:6]1)([CH3:4])[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH:12]=[C:13]([C:14]([NH:22][CH2:23][C:24]3[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])=[O:15])[C:8]=2[C:7]([CH3:21])=[N:6]1)([CH3:3])[CH3:4]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)(C)C)c2nc(C(C)(C)C)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C(C)(C)C)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.242 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.5 mg, 0.363 mmol), N-methylmorpholine (0.106 mL, 0.968 mmol), 1-hydroxy-7-azabenzotriazole (65.9 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol). The final product was collected as 91 mg (87%). LCMS E-S (M+H)=424.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.74 (s, 9H), 2.12 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 4.35 (d, J=4.80 Hz, 2H), 5.88 (s, 1H), 7.15 (s, 1H), 8.61 (t, J=4.93 Hz, 1H), 11.52 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:22]=1>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=3[O:19][CH3:20])=[CH:36][CH:35]=2)[CH:22]=1
Reactant: Oc1ccc(-c2ccc3c(c2)oc2ccccc23)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(-c2ccc3c(c2)oc2ccccc23)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Dibenzofuran-3-yl-phenol following the Standard Procedure J. MS (ES) for C32H30O7 [M+NH4]+:544, [M+Na]+: 549.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[N:19]([CH3:27])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([NH2:16])=[N:18][N:19]2[CH3:27])=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cn1nc(N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Temperature: 25 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.60 g, 11.7 mmol), 3-amino-1-methyl-1H-indazol-6-ol (Step a, 2.72 g, 16.7 mmol) and cesium carbonate (Aldrich, 16.3 g, 50.1 mmol) in DMSO (16.7 mL, Aldrich) were stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was extracted with DCM. The organic phase was washed with water, dried with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-100% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution as the eluant afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 351.1 (M+1). Mass Calc'd for C19H18N4O3: 350.38.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH2:51]>CC(C)=O.C(Cl)(Cl)Cl>[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH:51][C:43](=[O:44])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][CH:34]=1)[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Triethylamine (5.7 ml.), then isobutylchloroformate (5.3 ml.), were added with stirring to a solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (16.68 g.) in acetone (175 ml.) maintained at -20° C. The solution was stirred for 10 minutes at -20° C., then D-alanine methyl ester hydrochloride (6.4 g.) and triethylamine (5.7 ml.) in chloroform (65 ml.) were added. Stirring was continued one hour at this temperature, then four hours at room temperature. The mixture was filtered and the filtrate was stripped of volatiles. The residue and the filtration solid were combined and distributed between water (200 ml.) and ethyl acetate (250 ml.). Part of the product was collected by filtration and washed with aqueous hydrochloric acid, water, saturated sodium bicarbonate and water. The ethyl acetate layer was washed with cold aqueous hydrochloric acid (0.5N), water, saturated aqueous sodium bicarbonate, water again and saturated aqueous sodium chloride and stripped of volatiles, yielding another part of the product. The two parts were combined and recrystallized from absolute ethanol, affording (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-D-alanine methyl ester (15.28 g.; m.r. 161°-163° C.; [α]D25 -11.7°, c=2, dimethylformamide)
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C-:12]#[N:13].[Li+].[CH3:15][Si:16](C#N)([CH3:18])[CH3:17]>C1COCC1>[C:12]([C:1]1([O:11][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)#[N:13]
Reactant: C[Si](C)(C)C#N
Reactant: [C-]#N
Reactant: O=C1CCCc2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1(C#N)CCCc2ccccc21

Procedure:
To a solution of 1,2,3,4-tetrahydronaphthalene-1-one (20 g, 140 mmol) in THF (150 mL) was added 6 mL of a 0.5M solution of lithium cyanide (3 mmol, 0.02 equivalent). The reaction mixture was stirred for ~2 minutes and then trimethylsilyl cyanide (25 g, 250 mmol, 1.8 equivalent) was added in one portion. The reaction mixture was stirred for 4.5 hours. Solvents and excess trimethylsilyl cyanide were removed under reduced pressure to give the title compound as a yellow oil. The oil was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:16])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC>C(Cl)Cl.CCOCC.[O-2].[O-2].[Mn+4]>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:27][CH3:28])[CH:11]=2)=[O:16])[CH:18]=1
Reactant: COc1cc(C(O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCC
Product: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 6.2 g of α-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in 200 ml of methylene chloride is treated with 62 g of manganese dioxide and stirred at the reflux temperature 2 hours. After cooling the precipitate is filtered under suction and washed with methylene chloride. The filtrate is evaporated and the oil obtained is dissolved in hot ether, whereupon the solution is treated with a small amount of pentane. The separated crystals are filtered under suction. There is obtained 4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone in the form of colorless crystals of m.p. 110°-111°.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:2].[CH3:16][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:16]
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc2cc(C=O)oc2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C(C)O)oc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Methyl 2-formyl-1-benzofuran-6-carboxylate (750 mg, 3.67 mmol) is dissolved in anhydrous THF (30 ml) in a dry flask under nitrogen and cooled to 0° C. Methyl magnesium bromide (2.6 ml, 3.67 mmol) is added via syringe, and the reaction is stirred overnight, allowing the ice bath to expire. The reaction is quenched with 5% HCl (70 ml) and extracted with CH2Cl2 (3×25 ml). The combined organics are dried (MgSO4), filtered, and concentrated to a yellow oil. The crude material is chromatographed over 100 g slurry-packed silica gel, eluting with 35% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 412 mg (51%) of methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate as a yellow oil that solidified upon standing. MS for C12H12O4, (EI) m/z: 220 (M)+.
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([CH3:24])[CH:23]=1)[N:20]=[CH:19][C:18]([C:25]([NH2:27])=[O:26])=[C:17]2[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.[Br:37]C1C=C(S)C=CC=1>>[Br:37][C:8]1[CH:7]=[C:12]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH3:24])[CH:23]=2)[N:20]=[CH:19][C:18]([C:25]([NH2:27])=[O:26])=[C:17]3[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(SCCCCCCCCCCCO)cc23)c1
Reactant: Sc1cccc(Br)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 58, using 3-bromothiophenol in place of 11-mercapto-1-undecanol. ES/MS calcd. for C24H21BrN3O2S+ 494.1. Found m/z=494.1 (M+H)+.