Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1([S:9]([C:12]2[C:13]([O:29][CH2:30][C:31](OCC)=[O:32])=[N:14][N:15]3[C:20]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][C:18]([CH3:28])=[N:17][C:16]=23)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.O1CCOCC1.C1COCC1>[C:3]1([S:9]([C:12]2[C:13]([O:29][CH2:30][CH2:31][OH:32])=[N:14][N:15]3[C:20]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:19][C:18]([CH3:28])=[N:17][C:16]=23)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1nn2c(N3CCN(C)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCN(C)CC2)n2nc(OCCO)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32382.8 %

Procedure:
A solution of 0.126 g of KOH in 5 ml of H2O was added to a solution of 0.61 mg of ethyl 2-[3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-2-yloxy]-acetate in 20 ml of dioxan/THF 1:1 and stirred at RT for 2.5 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with 30 ml of CH2Cl2,and the combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2,CH2Cl2/MeOH 9:1) of the residue and crystallization from EtOH yielded 0.18 g (18%) of 2-[3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-2-yloxy]-ethanol as colorless crystals. M.p. 177.5-178°.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:20])=[C:16]2[Cl:19])=[CH:11][C:10]=1[C:21]1[N:22]=[N:23][C:24]([N:27]([CH3:38])[CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)=[CH:25][CH:26]=1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:21]3[N:22]=[N:23][C:24]([N:27]([CH3:38])[CH:28]4[CH2:29][C:30]([CH3:36])([CH3:37])[NH:31][C:32]([CH3:35])([CH3:34])[CH2:33]4)=[CH:25][CH:26]=3)=[C:9]([OH:8])[CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: CN(c1ccc(-c2cc3ccc(O)c(Cl)c3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(c1ccc(-c2cc3ccc(O)c(Cl)c3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a mixture of 7-(benzyloxy)-1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (25 mg, 0.047 mmol) in DCM (1 mL) was added BBr3 (1 M solution in DCM, 0.25 mL, 0.25 mmol) slowly at −78° C. The mixture was stirred at −78° C. for 10 minutes, then warmed to RT and stirred for 1.5 h. The reaction was quenched with MeOH and concentrated. The residue was loaded onto a 1 g SCX column, washed with MeOH and eluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated to give the desired product as a light brown solid (10 mg, 48.2% yield). LCMS Rt=0.54 min [Method Q], MS (M+1)=441.3. 1H NMR (METHANOL-d4) δ 8.17-8.27 (m, 2H), 7.66 (d, J=9.1 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J=10.1 Hz, 1H), 7.00 (d, J=9.1 Hz, 1H), 5.13 (t, J=11.9 Hz, 1H), 3.02 (s, 3H), 1.71-1.79 (m, 2H), 1.59-1.68 (m, 2H), 1.44 (s, 6H), 1.28 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O.O>C(O)C>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=12
Reactant: O=CCCl
Reactant: COC(=O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccn2ccnc12

Procedure:
To a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol, 1.0 eq) in ethanol (250 mL) was added NaHCO3 (5.08 g) and chloroacetaldehyde in water (35 mL of 45% in water, 148 mmol, 4.5 eq). The reaction mixture was heated at reflux for 18 h. Solvent was removed and the residue was basified with Na2CO3 and then extracted with DCM. Organic layers were combined and evaporated to give a residue, which was purified by column to give the titled compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])=[O:4].[OH-].[Na+].Cl.O>CO.O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])=[O:4]
Reactant: CNC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Methyl 2-methylcarbamoyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.50 g, 3.55 mmol) obtained in Example 31 was dissolved in methanol-tetrahydrofuran (1:1, 40 ml) and 1N aqueous sodium hydroxide solution (20 ml) was added. The mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to acidify the reaction mixture, and water (50 ml) and ethyl acetate (100 ml) were added for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.40 g, yield 96%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH:42]([CH3:45])[CH2:43][OH:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH:42]([CH3:45])[CH2:43][OH:44])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-propanol using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 577 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:22]=3)[N:17]=[C:16]([CH3:33])[CH:15]=2)=[C:4]([CH2:34][CH3:35])[N:3]=1.[OH-].[K+].Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:22]=3)[N:17]=[C:16]([CH3:33])[CH:15]=2)=[C:4]([CH2:34][CH3:35])[N:3]=1
Reactant: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCOc3c(N)nc(N)nc3CC)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCc1nc(N)nc(N)c1OCCCOc1cc(C)nc2ccc(OCCCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A suspension of the ethyl ester obtained in step (c) (0.314 g, 0.65 mmol) and aqueous KOH solution (10 equiv) was stirred at 25° C. overnight. The solution was neutralized by addition of dilute HCl. The precipitate formed was separated by filtration and dried in an oven at 80° C. to give a light yellow solid (0.2487 g, 84%). 1H NMR (400 MHz, DMSO-d6): 0.91 (3H, t, J=7.5 Hz), 1.98 (2H, m), 2.29 (4H, m), 2.41 (2H, t, J=7.2 Hz), 2.56 (3H, s), 3.86 (2H, t, J=5.5 Hz), 4.05 (2H, t, J=5.9 Hz), 4.40 (2H, t, J=5.3 Hz), 5.67 (2H, s), 6.24 (2H, s) 6.94 (1H, s), 7.33 (2H, m), 7.75 (1H, d, J=9.1 Hz).
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH2:19][OH:20].CCCCC>C(O)C>[N:4]1[N:3]=[C:2]([S:1][CH2:18][CH2:19][OH:20])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Sc1nnc2ccccn12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCC
Product: OCCSc1nnc2ccccn12

Procedure:
60 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine are dissolved in 500 ml of ethanol. 21 g of sodium carbonate and 29 ml of 2-bromoethanol are then added. The reaction mixture is heated under reflux for 9 hours, the mineral substances are filtered off, the filtrate is then concentrated in vacuo, the concentrate is taken up with water acidified with 0.5N hydrochloric acid and extraction is carried out with chloroform. The aqueous phase is then rendered basic with aqueous ammonia, saturated with sodium chloride and then extracted with chloroform. The chloroform phase obtained is dried over magnesium sulfate and then concentrated in vacuo. The crystals which then form are taken up with pentane, filtered off, washed with pentane and dried to give 69.2 g of 2-[1,2,4-triazolo(4,3-a)pyridin-3-ylmercapto]ethanol in the form of crystals melting at 84° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1.C(O)(=O)C.[C-:30]#[N:31].[K+]>O.ClCCl>[C:30]([C:2]1([CH3:1])[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][NH:3]1)#[N:31]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C1)OCO3
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C2=NNC(C)(C#N)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
In a 100 ml bomb tube made of stainless steel 10.12 g (30.0 millimoles) of 8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and 50 ml of glacial acetic acid are weighed in. To the suspension at 15–20° C. 5.90 g (90.6 millimoles) of potassium cyanide are added within 5 minutes under cooling with icecold water. The bomb tube is sealed. The reaction mixture is stirred at 70° C. for 24 hours, cooled, stirred with 350 ml of dichloro methane and 350 ml of water and the layers are separated. The aqueous phase is extracted with 150 ml of dichloro methane, the organic phases are washed with 50 ml of water, dried over magnesium sulfate and evaporated. The residue is is crystallized from 100 ml of ether, filtered and washed with ether. Thus 10.40 g of the desired compound are obtained, yield 95%, mp.: 148–151° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH2:18][CH2:19]O)=[CH:4][CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: OCCc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
2-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)ethanol (60 mg, 0.21 mmol) was dissolved in THF (4 ml). To the resulting mixture was added diisopropyl azodicarboxylate (42 mg, 0.21 mmol) and PPh3 (54 mg, 0.21 mmol). The resulting mixture was stirred at RT overnight. Preparative TLC gave 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, yield: 89%) MS (M+H)+: 273.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:16]=[CH:15]2.O>CC(N(C)C)=O>[NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:16]=[CH:15]3)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Reactant: OC1CCCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(OC4CCCNCC4)c(C)cc3c2=O)cc1
Yield: 41 %

Procedure:
A solution of 58 mg (0.51 mmol) azepan-4-ol in 5 ml dimethylacetamide was stirred with 45 mg (1.52 mmol) 80 percent sodium hydride for 45 minutes at room temperature. Then 150 mg (0.51 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 3 days during which additional amounts of azepan-4-ol and sodium hydride were added until complete conversion of the 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one was obtained. The reaction mixture was slowly added to 10 ml water and after 1 h of stirring the product was isolated by filtration and dried overnight in vacuum. 82 mg of 6-(azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:9]
Reactant: COc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (506 mg, 2.12 mmol) in 10 mL of CH2Cl2 containing oxalyl chloride (2.4 mmol) was added 2 drops of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred 1.5 hr prior to removal of the volatiles using a rotary evaporator. After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 8 ml of CS2, the stirred mixture was cooled to 4° prior to adding anisole (240 mg, 2.12 mmol) followed by AlCl3 (566 mg, 4.25 mmol). The reaction, after warming to 20° over 1 hr, was stirred for 20 hr prior to quenching with 1N HCl. Subsequently, the suspension was diluted with 50 ml H2O and stirred until all solids were in solution. The mixture was extracted 3× with EtOAc. The combined organic extracts were washed 1× with 1N HCl, H2O, aq NaHCO3, and brine prior to drying over Na2SO4. After removal of the volatiles, the residue was chromatographed on silica gel using 15% EtOAc/hexane to elute 450 mg of 5-bromo-2-chloro-4′-methoxybenzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 42.4 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.100 g, 0.232 mmol) was dissolved in methylene chloride (2.5 ml) and after adding thereto in sequence copper acetate (0.042 g, 0.232 mmol), 3-pyridylboronic acid (0.076 g, 0.464 mmol), Molecular Sieves 4A (0.100 g), triethylamine (0.059 g, 0.580 mmol) and pyridine (0.046 g, 0.580 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.050 g, 0.0984 mmol, 42%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:19]=2[N:18]=[CH:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:25]([OH:26])[C:23]2[CH:22]=[CH:21][C:20]3[N:16]([CH3:15])[CH:17]=[N:18][C:19]=3[CH:24]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2ccc3c(c2)ncn3C)c2ccc(Cl)cc21

Procedure:
3.5 g of 1-acetyl-6-chloro-2-indolinone, 3.4 g of 1-methylbenzimidazole-5-carboxylic acid, 6.1 g of TBTU, 2.9 g of HOBT-hydrate and 8.7 ml ethyldiisopropylamine are stirred in 100 ml DMF for 15 hours at ambient temperature. The mixture is combined with water and extracted with ethyl acetate, while the crude product is partially precipitated. The residue obtained by distilling off the solvent is taken up in dichloromethane and a little methanol and extracted with water. The organic phase is evaporated down, the residue stirred successively with ethyl acetate and diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[CH2:13]([C:12]1[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[NH:1][N:15]=1)[CH3:14]
Reactant: O=N[O-]
Reactant: CCCc1ccc(C(=O)OC)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
To a solution of methyl 3-amino-4-propylbenzoate (5.07 g) in acetic acid (150 ml) was dropwise added a solution of sodium nitrite (2.07 g) in water (5 ml) for 5 min. After stirring for 20 min, the reaction mixture was concentrated, and then toluene and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The separated toluene layer was dried over sodium sulfate and concentrated. The residue was allowed to stand and partially solidified. The solid was washed with hexane and dried to give the object compound (2.44 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][CH:3]=1.O=S(Cl)[Cl:16]>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: O=C(Cl)c1ccc2c(Cl)c[nH]c2c1

Procedure:
3-Chloro-1H-indole-6-carboxylic acid (200 mg) was mixed with 3 mL of SOCl2. The mixture was refluxed for 1 h and evaporated to dryness. Benzene (2 mL) was added and evaporated twice in order to eliminate residual SOCl2. The dark oil was triturated in ether/CH2Cl2 to yield 3-chloro-1H-indole-6-carbonyl chloride as a dark solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:27]([O:33][CH3:34])(=[O:32])[CH2:28][C:29]([CH3:31])=[O:30].[H-].[Na+].C([Li])CCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:31][C:29](=[O:30])[CH2:28][C:27]([O:33][CH3:34])=[O:32])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (0.100 g), methyl acetoacetate (0.028 ml), sodium hydride (0.031 g, washed with dry THF(3×3 ml)) and n-butyl lithium (1.4M in, hexanes, 0.26 ml) by the process as described for the preparation of Intermediate (10a) to afford a dark orange oil which was purified by FCC eluting with System A (2:3, 1:1) to afford the title compound (0.054 g) as an orange solid, Rf (System A 2:3) 0.18;
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[S:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[S:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(NC2=NCCS2)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC4=NCCS4)cc3)ccc2c1
Reaction time: 2 h
Yield: 43.2 %

Procedure:
15 Milliliters of 20% hydrous pyridine was added to 1.5 g of 4-[(4,5-dihydrothiazol-2-yl)amino]benzoic acid.hydrochloride, 1.62 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.43 g of DCC and 70.8 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to a mixed liquid of 200 ml of acetone and 200 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 10 ml of methanol and 0.97 ml of concentrated hydrochloric acid, and the solution was added dropwise to a mixed liquid of 150 ml of acetone and 50 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 651 mg of the desired product.