Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[Cl:22])=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc2nccn2cc1Br
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 76.8 %

Procedure:
In a sealed tube, a mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (505 mg, 1.98 mmol), 2,4-dichlorobenzeneboronic acid (416 mg, 2.18 mmol), Pd(PPh3)4 (114 mg, 0.10 mmol) and Na2CO3 (2.0 M solution in water, 3.5 mL) in DME (5 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, poured into AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (488 mg, 1.52 mmol, 77%). MS: 321 [M+1]+; HPLC: AtRet=1.43; TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenyl)butanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 3 hours. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.031 g, 27% yield over 2 steps): 1H NMR (CD3OD) 8.75 (br s, 1H), 8.25 (br s, 1H), 8.1 (br s, 1H), 7.7–7.6 (m, 3H), 7.5 (t, 1H), 2.4 (t, 2H), 1.72 (sextet, 2H), 1.0 (t, 3H); ES-MS (m/z) 362 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([NH:23][C:24](=[O:26])[CH:25]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[C:27]([N:23]1[N:5]2[CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]2=[CH:25][C:24]1=[O:26])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2[nH]c(=O)cc2N1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2c(cc(=O)n2C(=O)c2ccccc2)N1
Reaction time: 0.5 h

Procedure:
A suspension of 1,2,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester (36 mg; 0.1 mmole) in dichloromethane (2 ml) and pyridine (1 ml) under argon was treated with benzoyl chloride (28 mg; 0.2 mmole). The reaction was allowed to stir for 30 minutes and then diluted with ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, water, sodium bicarbonate and brine. It was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (40% acetone in hexanes) and the product was crystallized from absolute ethanol to provide a solid, melting point 201°-203° C.
Reaction SMILES: FC1C=C(C=CC=1)CC1C2C(=CC=C(CCCNS(CCC)(=O)=O)C=2)CCC1NC(=O)[O-].CI.C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]1[CH:43]=[C:44]([CH:75]=[CH:76][CH:77]=1)[CH2:45][CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([CH2:56][CH2:57][CH2:58][N:59]([CH3:66])[S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61])[CH:54]=2)[CH2:49][CH2:48][CH:47]1[NH:67]C(=O)OC(C)(C)C.[ClH:78]>C(#N)C.C(OCC)(=O)C.C(O)(C)C>[ClH:78].[NH2:67][CH:47]1[CH:46]([CH2:45][C:44]2[CH:75]=[CH:76][CH:77]=[C:42]([F:41])[CH:43]=2)[C:55]2[CH:54]=[C:53]([CH2:56][CH2:57][CH2:58][N:59]([CH3:66])[S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61])[CH:52]=[CH:51][C:50]=2[CH2:49][CH2:48]1
Reactant: CCCS(=O)(=O)N(C)CCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(=O)OC(C)(C)C)CC2
Agent: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(=O)[O-])CC2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: CC#N
Solvent: CI
Product: CCCS(=O)(=O)N(C)CCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(N)CC2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
tert-Butyl (1-(3-fluorobenzyl)-7-(3-(propylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (cf. 209 and 201a, 65 mg, 0.125 mmol) was dissolved in acetonitrile (800 μL) and methyl iodide (24 μL, 0.376 mmol) and cesium carbonate (0.102 g, 0.313 mmol) was added. The reaction mixture was heated for 24 hours in a sealed vessel to 80° C. The reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was successively washed with water and saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was purified by preparative thin-layer chromatography (silica gel, dichloromethane, methanol). The obtained tert-butyl 1-(3-fluorobenzyl)-7-(3-(N-methylpropylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (65 mg, 0.122 mmol) was dissolved in 4 M hydrochloric acid in isopropanol and stirred at room temperature for 4 hours. The solvent was removed in vacuo. Diethyl ether was added and the precipitate removed by filtration and dried. Yield: 22 mg (0.047 mmol, 38%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8](/[C:15](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:30]3[CH2:32][CH2:31]3)=[CH:25][CH:24]=2)=[CH:16]\[C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18]2)[CH:9]=[CH:10][C:11]=1[O:12]CC.O>CCCCCC.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8](/[C:15](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:30]3[CH2:32][CH2:31]3)=[CH:25][CH:24]=2)=[CH:16]\[C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18]2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CCOc1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C1CC[C@H](/C=C(\c2ccc(O)c(Cl)c2)c2ccc(C3CC3)c(=O)[nH]2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 M solution of boron tribromide in hexane (0.8 mL) was added to a solution of 6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylpyridin-2(1H)-one obtained in Example 4-10 (110 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→90:10) to give the title compound as a colorless amorphous (17.5 mg).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(#N)C.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:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[F:39])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccccc3F)ccc2c1
Yield: 72.5 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.68 g, 3.05 mmol) in 30 mL of acetonitrile and add 2-fluorobenzene boronic acid (0.85 g, 6.10 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.43 g, 0.61 mmol) and sonicate briefly. Next add cesium fluoride (4.17 g, 27.45 mmol) and heat to 75° C. for 1 hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2 N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to isolate 1.10 g of the title compound (72%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[Br:1][C:9]1[C:5]([O:4][CH3:3])=[N:6][NH:7][CH:8]=1
Reactant: COc1cc[nH]n1
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1n[nH]cc1Br
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (0.405 ml) in dichloromethane (8 ml) at 0-5° C. was added dropwise to a mixture of 3-methoxypyrazole (775 mg) and sodium carbonate (1.67 mg) in dichloromethane (16 ml) under argon over a period of 10 minutes. The resulting suspension was stirred at 0-5° C. for 30 minutes. Aqueous sodium thiosulfate (2.37 ml, 0.1N) at 0-5° C. was added to the stirred suspension and the resulting mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and quenched with water. The phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated to afford a brown oil. Hydrogen chloride (4N in dioxane) (1.975 ml) was added to this brown oil. The mixture was diluted in dioxane and triturated. The resulting precipitate was collected by filtration, washed with dioxane and diethyl ether and dried to a constant weight to afford 4-bromo-3-methoxy-1H-pyrazole, hydrochloride salt (1 g) as a solid, which was used without further purification. NMR Spectrum: (DMSOd6) 3.82 (s, 3H), 7.78 (s, 1H), 7.99 (bs, 2H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][S:24][CH2:23][CH2:22][NH:21]1)=[O:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]([O:37][C@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:37][C@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([N:21]1[CH2:22][CH2:23][S:24][CH2:25][C@H:20]1[C:18](=[O:19])[NH:17][CH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[O:40])(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1
Reactant: CC(=O)O[C@@H](C(=O)Cl)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)N1CCSC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of (R)-tert-Butyl-4-chloro-2-{(thiomorpholine-3-carboxamido)-methyl}-benzyl-carbamate (0.56 g, 1.40 mmol) in CH2Cl2 (25 mL) was added triethyl amine (0.59 mL, 4.2 mmol) and solution of (2R)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl acetate (0.496 g, 2.8 mmol) in CH2Cl2 (5 mL) dropwise at −10° C. and the resulting mixture was allowed to warm up to room temperature over 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile/water) to obtain the title compound (0.42 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:10]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.CCCCCC.[C:30](=[O:32])=[O:31].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([F:17])[C:12]([C:30]([OH:32])=[O:31])=[C:13]([F:16])[C:14]=1[F:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
31.8 g of the compound (6) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 93 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 12.9 g (41 mmol) of 4-heptyloxy-2,3,5,6-tetrafluorobenzoic acid (7).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl>CCO.C(OCC)(=O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:30][C:31]=1[S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(methylsulfonyl)-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide (0.7 g, 1.164 mmol) in 1:1 EtOH/Ethyl acetate (10 mL) was added tin(II) chloride (1.324 g, 6.98 mmol). The reaction was heated at 70° C. for 3 h. Solvent was evaporated and the reaction was partitioned between EtOAc and water. The resulting semi viscous mass was filtered (6 h) and the solid obtained (0.5 g, 75%) was progressed as is to the next step. LCMS (m/z, ES+)=572 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:19])[CH:3]=1.[C:20]1([C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N+]=[N-])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>CN(C=O)C>[C:20]1([CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:1][C:2]2[C:7]3[CH:8]=[CH:9][C:10]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)=[C:11]([CH3:12])[C:6]=3[O:5][C:4](=[O:19])[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1c(C2CCCCO2)ccc2c(O)cc(=O)oc12
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(C2CCCCO2)ccc2c(OC(c3ccccc3)c3ccccc3)cc(=O)oc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
55 g of 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yl)-2H-1-benzopyran-2-one is introduced into 250 ml of anhydrous dimethylformamide heated to 40° C., and a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF is added dropwise. The addition is made over 3 hours while maintaining the temperature at 40° C. Several portions of 3 g of diphenyldiazomethane are added again and agitation is carried out for one hour at 40° C. The reaction medium is poured into 2 l of sulphuric ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, with a solution of soda (0.1 M), with water and with salt water followed by evaporation to dryness. The residue is agitated in an isopropyl ether-hexane mixture (1-2) followed by separation. The insoluble part is dried. 20.5 g of sought product is obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.C[Sn](C)(C)[C:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH:35]=1>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C([Sn](C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and tert-butyl 4-(trimethylstannyl)-3,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE 69)by a procedure analogous to that described in EXAMPLE HHH1, Step A. Mass spectrum (ESI) 582 (M+1).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[C].[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccccc1NC(=O)c1ccc(OCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCc1ccccc1NC(=O)c1ccc(OCCCOc2ccccc2)cc1
Yield: 79.6 %

Procedure:
To a solution of 250 mg of ethyl o-[p-(3-phenoxypropoxy)benzamido]cinnamate obtained in Example 34 in 10 ml of methanol and 20 ml of ethyl acetate was added 10% palladium-carbon. Catalytic reduction was performed until absorption of hydrogen was discontinued. The catalyst was filtered off and the residue was recrystallized from isopropyl alcohol to obtain 200 mg of ethyl 3-[o-[p-(3-phenoxypropoxy)benzamido]phenyl]propionate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc2ncncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cncnc4cc3C)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
6-Hydroxy-7-methyl-quinazoline (38 mg), 4-chloro-6,7-dimethoxyquinoline (159 mg), and 4-dimethylaminopyridine (87 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 150° C. overnight. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (71 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
To a stirred solution of methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 5.62 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 20 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-chloro-4-(N′-phenylureido) phenylacetic acid (1.58 g, 92%) as pale brown solid. 1H-NMR (DMSO-d6) δ 3.55 (s, 2H), 6.99 (t, J=7.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H1), 7.29 (t, J=7.6 Hz, 2H), 7.36 (s, 1H), 7.46 (d, J=8:0 Hz, 2H), 8.07 (d, J=8.3 Hz, 1H), 8.28 (s, 1H), 9.37 (s, 1H), 12.37 (br, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1>O1CCCC1>[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:47](=[O:48])[NH:46][C:43]1[CH:44]=[CH:45][C:40]([C:39]([F:38])([F:50])[F:49])=[CH:41][CH:42]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of L-phenylalanine benzyl ester p-toluenesulfonic acid salt (1.71 g) and triethylamine (405 mg) in dry tetrahydrofuran (30 ml), which was cooled to 0° C., was added 4-trifluoromethylphenyl isocyanate (748 mg). The mixture was stirred at the same temperature for 30 minutes. After evaporation of the solvent, the residue was washed with 5% hydrochloric acid, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-trifluoromethylphenylcarbamoyl)-L-phenylalanine benzyl ester (1.62 g) as white crystals.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-methoxyphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=241.9 [M+H]+.