Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH:17]O>[C].[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: OO
Reactant: Cc1ccnc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(-c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 17 h

Procedure:
A mixture of 4-methyl-2-(4-nitrophenyl)pyridine (25.8 g), acetic acid (130 ml) and 30% hydrogen peroxide (27.5 ml) is agitated at 75°-85° C. for 17 hours. To the mixture is added 10% palladium-carbon in order to decompose excess amount of hydrogen peroxide, and then the palladium-carbon is removed by filtration. The filtrate is concentrated, and the concentrated solution is made alkaline with potassium carbonate and extracted with ethyl acetate. The extract is washed with water and dried, and ethyl acetate is distilled off to give 4-methyl-2-(4-nitrophenyl)pyridine N-oxide (26.6 g). M.P. 158°-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccccc2OCCOC2CCCCO2)cc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-benzyloxyphenol (3.00 g, 15.0 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil) (719 mg, 18.0 mmol) under ice-cooling, and the mixture was stirred at 30 min. 2-(2-Bromoethoxy)tetrahydropyran (2.72 ml, 18.0 mmol) was added to the reaction mixture and the mixture was stirred at 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g). The obtained compound was used for Step 2 without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15]I>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([NH:1][CH3:15])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CI
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Product: CNc1cc(OC)cc(OC)c1C(N)=O
Temperature: 110 °C
Yield: 5 %

Procedure:
2-Amino-4,6-dimethoxybenzamide (0.5 g, 2.55 mmol) and methyl iodide (0.17 mL, 2.81 mmol) were mixed in a closed bomb and heated at 110° C. for 14 h. The compound was washed with a dichloromethane-methanol mixture. After removing the solvent, the crude was purified by silica gel column chromatography (40 g) employing 1-5% methanol in dichloromethane to give 2,4-dimethoxy-6-methylamino-benzamide (0.027 g, 50.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:56])OC2C=CC=CC=2)=[CH:43][CH:42]=1)(=[O:40])[NH2:39]>CN(C=O)C>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:48]([NH:47][C:44]4[CH:43]=[CH:42][C:41]([C:38]([NH2:39])=[O:40])=[CH:46][CH:45]=4)=[O:56])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n2)cc1
Temperature: 90 °C
Yield: 5.3 %

Procedure:
To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine (4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]Br.CCOCC>C1COCC1>[CH2:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:10](=[O:11])[CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a 250 mL round bottom flask containing (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (10.49 g, 23.0 mmol) was added THF (200 mL), and the flask was cooled to 0° C. Methylmagnesium bromide (3.16 M in ether, 12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 2 hours, additional methylmagnesium bromide, 3.16 in ether (12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 1 hour, the mixture was poured into ammonium chloride-ice (200 mL), washed with brine (100 mL), dried over sodium sulfate, and stored at −20° C. for 15 hours. Plate-like crystals formed the next morning. The mixture was decanted from sodium sulfate and evaporated to provide a yellow oil that crystallized in the freezer over the weekend. The solid was triturated with hexane and chilled at −20° C. before filtration. The product was obtained as a white crystalline solid. The yellow filtrate was adsorbed onto silica gel and purified by chromatography through a Redi-Sep® pre-packed silica gel column (330 g), eluting with a gradient of 0% to 70% EtOAc in hexane to provide additional product as an oil that crystallized under hi vacuum. The two lots were combined to provide (S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-one (8.09 g, 85.6% yield) as a white solid. LCMS (ES+) m/z=412.3 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.13 (s, 3H) 2.93 (dd, J=13.30, 3.52 Hz, 2H) 3.21 (dd, J=13.30, 9.39 Hz, 1H) 3.50-3.60 (m, 3H) 3.82 (d, J=13.69 Hz, 2H) 7.19-7.30 (m, 4H) 7.30-7.35 (m, 8H) 7.46 (d, J=8.02 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: COCc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
18.3 g of 2-methoxymethyl-4-nitrophenol (1) (0.1 mol), 8.3 g (0.06 mol) of potassium carbonate and 40 ml of dimethylformamide were heated on a boiling water bath, and 12.1 ml (0.105 mol) of benzyl chloride were added over 10 minutes. After heating for 1 hour on the boiling water bath, the mixture was poured onto 150 g of ice. The yellow-brown crystals formed were filtered off, reslurried in ice-cold water and washed with petroleum ether. The wet product was recrystallized from 75 ml of isopropanol to give, after drying, 21 g of expected product with a melting point of 108° C. The results of the elementary analyses were as follows:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 62.7 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.080 g, 0.334 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.090 g; 0.368 mmol), HATU (0.127 g; 0.334 mmol) and N,N-diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (5 mL), was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and a solution of sodium hydrogen sulfate. The organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.090 g (62%) of the title compound as a pink solid.
Reaction SMILES: [C:1]12([C:8]3[CH:13]=[C:12](Cl)[N:11]=[N:10][C:9]=3[Cl:15])[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[C:1]12([C:8]3[C:9]([Cl:15])=[N:10][N:11]4[C:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:24][N:25]=[C:12]4[CH:13]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Clc1cc(C23CCC(CC2)C3)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2

Procedure:
A mixture of 4-(bicyclo[2.2.1]hept-1-yl)-3,6-dichloropyridazine (1 g, 4.1 mM), benzoic hydrazide (0.84 g, 6.2 mM) and triethylamine hydrochloride (0.85 g, 6.2 mM) in p-xylene (80 ml) was heated at reflux for 18 hours, after which time more benzoic hydrazide (0.28 g, 2 mM) and triethylamine hydrochloride (0.28 g, 2 mM) were added and the reaction heated at reflux for a further 3 hours. The mixture was allowed to cool, then placed directly onto silica gel for purification by column chromatography using ethyl acetate/hexane mixtures as the eluent. This yielded the title compound (0.38 g, lower Rf of the two isomeric products). 1H NMR (250 MHz, CDCl3) δ1.55-2.06 (8H, m), 2.22 (2H, m), 2.44 (1H, m), 7.25 (3H, m), 8.13 (1H, s), 8.45 (2H, m); MS (ES+) m/e 244 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light yellow solid (0.28 g, 42%), MS (ISP) m/z=307.3 [(M+H)+], mp 157° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-chloro-phenylboronic acid (0.34 g, 2.17 mmol).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC
Temperature: 0 °C

Procedure:
300 g of veratrole was added dropwise over a period of 30 minutes to a suspension of 300 g of aluminum chloride in 300 ml of methylene chloride, taking care that the internal temperature did not exceed 30° C. Then, 450 g of biphenyl-4-carboxylic acid chloride were added in portions over a period of 30 minutes, while stirring and cooling (internal temperature 20°-25° C.). The resulting mixture was stirred for 4 hours at room temperature and was then poured into a mixture of 2 kg of ice/500 ml of concentrated hydrochloric acid. After the organic phase had been separated, the aqueous phase was extracted twice more with methylene chloride.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:27]1([C:7]2[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:16]3[NH:24][C:23]4[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=4[CH:17]=3)[N:8]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1N1CCC1
Yield: 60.7 %

Procedure:
This compound (18 mg, 61% yield) as a yellow solid was prepared according to the procedures described for Example 346, using 2-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (345) (28 mg, 0.076 mmol), azetidine (25.5 pt, 0.37 mmol, Matrix Scientific, Columbia, S.C.), and DIEA (26.4 μL, 0.15 mmol) in DMSO (0.75 mL) at 50° C. for 1 h. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H) 2.30 (quin, J=7.58 Hz, 2H) 2.85 (t, J=6.85 Hz, 2H) 3.43 (td, J=6.85, 2.35 Hz, 2H) 4.22 (t, J=7.63 Hz, 4H) 5.68 (s, 1H) 6.95 (s, 1H) 6.95 (s, 1H) 7.23 (t, J=7.82 Hz, 1H) 7.35 (dd, J=8.02, 1.37 Hz, 1H) 7.60 (dd, J=7.43, 1.37 Hz, 1H) 12.01 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2].[C:19](#[N:22])[CH:20]=[CH2:21].O>CN(C=O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:20][C:19]#[N:22])[C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: C=CC#N
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 52 °C
Yield: 101.4 %

Procedure:
At room temperature, to a mixture of 5′-nitrospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one(1.75 g, 6.99 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.110 mL, 0.699 mmol, 0.1 mole %) in DMF (31 mL) was added acrylonitrile (0.921 mL, 14.0 mmol, 2 eq) drop-wise. and the mixture was heated at 52° C. for 2 hr. The reaction was cooled to room temperature and poured into H2O (160 mL). The reaction mixture was extracted with Et2O. The combined organic extracts were washed with brine and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.15 g, 100% ). NMR (300 Mz, DMSO-d6): consistent
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].[C:30]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][N:42]([C:45](O)=O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)(O)=O>>[CH2:1]([N:3]([CH2:30][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:37][CH:38]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: O=C(O)c1ccc(C2CCN(C(=O)O)CC2)cc1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid text-butyl ester (60 mg) according to an analogous synthetic method to Example 337 described below, the title compound (35 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14]O)[CH:4]=[CH:3][CH:2]=1.[Cl-:16].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:16][CH2:14][CH2:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: OCCCOc1cccc2cccnc12
Reactant: [Cl-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: ClCCCOc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thinoyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chlorofrom and extracted with the potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, and was collected by filtration. The solid was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) of white, crystalline solid, m.p. 69°-71° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19]C)[C:7]=2[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.B(Br)(Br)Br>O>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]3)=[C:8]([OH:19])[C:7]=2[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c2c(cc(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)OC(C)(C)CC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2O)O1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under argon, 3.10 g (6.94 mmol) of 7-cyclopentyl-5-methoxy-2,2-dimethyl-6-[4-(trifluoro-methyl)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 8A) are dissolved in 30 ml of abs. dichloromethane. The mixture is cooled to −78° C., 6.25 ml (6.25 mmol) of boron tribromide (1 M in dichloromethane) are added and the yellowish solution is stirred at −78° C. After 1.5 h, another 6.25 ml (6.25 mmol) of boron tribromide (1 M in dichloromethane) are added, and stirring of the mixture is continued at −78° C. After 30 min, another 1.39 ml (1.39 mmol) of boron tribromide (1 M in dichloromethane) are added. After 30 min, 100 ml of water are added and the mixture is stirred for 30 min and allowed to warm to room temperature. The mixture is then extracted repeatedly with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 25:1). This gives 1.85 g (62% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3Br)ccc2=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
Solvent: O
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3ccccc3OC)ccc2=O)c1
Temperature: 98 °C
Reaction time: 30 h
Yield: 30.2 %

Procedure:
A mixture of ethyl (3-{3-[5-(2-bromophenyl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (235 mg), (2-methoxyphenyl)boronic acid (114 mg), Na2CO3(159 mg), Pd(PPh3)4 (29 mg) in toluene (8 mL) and water (4 mL) was stirred under N2 gas atmosphere at 98° C. for 30 hours and cooled to ambient temperature. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The aqueous layer of the reaction mixture was acidified with 1M HCl aqueous solution and extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The filtrate and the residue of the first extract was combined and evaporated in vacuo. The residue was dissolved in EtOH (20 mL). To the solution was added concentrated H2SO4 (1.5 mL) at ambient temperature and refluxed for 1 hour. The reaction mixture was cooled to ambient temperature, neutralized with saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=60:40) to afford ethyl (3-{3-[5-(2′-methoxybiphenyl-2-yl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (75 mg) as a colorless oil.