Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5]CN.[CH3:14][NH:15]CC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:31]=[C:32]1[NH:41][C:40]2[N:39]=[CH:38][C:37](/[CH:42]=[CH:43]/[C:44]([OH:46])=O)=[CH:36][C:35]=2[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][N:15]([CH3:14])[C:44](=[O:46])/[CH:43]=[CH:42]/[C:37]1[CH:38]=[N:39][C:40]2[NH:41][C:32](=[O:31])[CH2:33][CH2:34][C:35]=2[CH:36]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: COc1cccc(CCN)c1OC
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c1OC
Yield: 61 %

Procedure:
According to the procedure of Example 1 (a), except substituting (2,3-dimethoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.362 g, 61%) was prepared as an orange solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.64 (m, 1H), 8.36-8.32 (m, 1H), 8.09-8.02 (m, 1H), 7.52-7.47 (m, 1H), 7.31-7.22 (m, 1H), 7.08-6.95 (m, 2H), 6.69-6.64 (m, 1H), 4.78-4.62 (m, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.01-2.85 (m, 5H), 2.56-2.49 (m, 2H); MS (ESI) m/e 382 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14](O)=[O:15])=[O:10].[CH3:28][NH:29][CH3:30].O>ClCCl.CN(C)C=O>[CH3:28][N:29]([CH3:30])[C:14]([C:13]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([CH:12]=1)[C:9]([O:8][CH3:7])=[O:10])=[O:15]
Reactant: CNC
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)N(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.46 ml, 5.24 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 300 mg, 1.05 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of dimethylamine (716 mg, 5.24 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Water (40 ml) was added and the mixture was extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as colourless oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40](O)=[O:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40]([C:36]3[CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:39]=[CH:38][CH:37]=3)=[O:41])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C=CC=C(C(=O)Nc2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
30 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 2 mL of methylene chloride, to which 25 mg of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid, 21 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 13 mg of N,N-dimethylaminopyridine were added, and stirred overnight at room temperature. The reaction mixture was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol) to obtain 38 mg (78%) of the title compound as a light pink crystalline powder.
Reaction SMILES: CN1C(=O)N(C)CCC1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=1.CC([O-])(C)C.[K+]>O.CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=3)=[CH:23][CH:22]=2)=[CH:13][C:12]=1[C:29]([F:30])([F:31])[F:32]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=C(CCc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
To a mixture of DMPU (0.7 mL) and DMF (2.8 mL) was added N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(4-hydroxyphenyl)propanamide (600 mg, 1.75 mmol) and 4-chloro-N-methylpyridine-2-carboxamide (prepared as described in Bankston, D. et al. Organic Process Research and Development 2002, 6, 777-781; 328 mg, 1.92 mmol). To this solution was added KOt-Bu (590 mg, 5.25 mmol). The reaction mixture was stirred at 100° C. for 18 h and then cooled to rt, diluted with water and extracted with EtOAc and DCM. The combined organic solutions were washed with water and brine, dried over Na2SO4, filtered and concentrated to give a brown oil. Purification by column chromatography provided 100 mg of a colorless solid. 1H NMR (300 MHz, CD3OD) δ: 10.11 (br s, 0.34H), 8.41 (d, J=5.6 Hz, 1H), 8.07 (br d, J=2.2 Hz, 1H), 7.74 (br dd, J1=8.7 Hz, J2=2.1 Hz, 1H), 7.48-7.51 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 2H), 6.98 (dd, J1=5.6 Hz, J2=2.5 Hz, 1H), 3.34 (s, 0.84H), 3.04 (t, J=7.5 Hz), 2.92 (s, 3H), and 2.71 (t, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14]([OH:16])([CH3:18])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3-bromo-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione (0.04 g, 1.37 mmol, 1 equiv) in dry THF was added CH3MgBr (0.27 mL, 2.74 mmol, 2 equiv) dropwise at 0° C. The resulting mixture was stirred for 4 h at 0° C. The reaction was quenched with saturated NH4Cl, extracted with EtOAc, and dried over Na2SO4. The organic extract was concentrated under reduced pressure to give the desired product. MS (ESI): 309, 311 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[F:5])=[C:15]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2CN2CCCCC2)c1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Thionyl chloride (0.066 g, 0.56 mmol) was added to a solution of 66.64B (0.023 g, 0.070 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours. After removing solvent, 66.64C was obtained in 100% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:14]([CH:38]([OH:40])[CH3:39])[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:53][C:54](OC(C)=O)=[O:55]>CN(C1C=CN=CC=1)C.CCOCC>[C:54]([O:40][CH:38]([C:14]1[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][C:17]2[C:12]([C:13]=1[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)[CH3:39])(=[O:55])[CH3:53]
Reactant: CC(O)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution alcohol (300 mg) from Step 4 in Ac2O (2 mL) was added pyridine (300 mL) and DMAP (2 mg). After 2 hr, the reaction mixture was diluted with Et2O, washed with H2O, a solution of CuSO4, and the solvent evaporated to give the title product which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[N:11]#[C:12][Br:13]>CCO.O>[BrH:13].[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:12]([NH2:11])=[N:9][N:8]=2)[N:7]=1
Reactant: Cc1cc(Cl)nnc1NN
Reactant: N#CBr
Solvent: CCO
Solvent: O
Product: Br
Product: Cc1cc(Cl)nn2c(N)nnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(6-Chloro-4-methylpyridazin-3-yl)hydrazine (W3.002; 4.6 g) were initially charged in EtOH (330 ml) and water (70 ml) while stirring at RT. Thereafter, cyanogen bromide in a mixture of EtOH (170 ml) and water (30 ml) was slowly added dropwise at RT. After stirring at RT for 6 h, the mixture was left to stand overnight. Then the mixture was dried and the residue was purified using silica gel (40 g cartridge, DCM/methanol gradient of 0-10% in 30 min). 7.3 g of the title compound were obtained.
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:8]([NH:37][C@@H:34]2[CH2:35][CH2:36][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33]2)=[O:24])[CH2:15][CH2:14]1)([CH3:21])([CH3:22])[CH3:23]
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1

Procedure:
A solution of (4-tert-butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) in MeOH is heated using microwave radiation at 100° C. for 30 minutes. The resulting solution is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water 0.1% HCl) to afford the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccsc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccsc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (1.02 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(3-thienyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.33 g, 55%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].O>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccn1
Yield: 57.7 %

Procedure:
2-(Chloromethyl)pyridine hydrochloride (303 mg) was suspended in N,N-dimethylformamide (3 ml), potassium carbonate (256 mg) was added thereto, and the mixture was stirred. Then, to the suspension was added a solution of (3,3,3-trifluoropropyl)malononitrile (300 mg) in N,N-dimethylformamide (3 ml), and further thereto was added potassium carbonate (256 mg), followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 270 mg of 2-((2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C(OCC)C.ClCCl.C(N(CC)CC)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCOCCO
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCOCCNc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4,7-dichloroquinoline (5.0 g, 25.0 mmol) and of 2-(2-aminoethoxy)ethanol (10.51 g, 100.0 mmol) is heated at 135° C. for 5 h, with magnetic stirring. After cooling, the reaction medium is taken up in 200 ml of diethyl ether and the stirring is maintained overnight at ambient temperature. The solid residue formed is isolated, and then dissolved in a mixture of 500 ml of dichloromethane/triethylamine (9/1, v/v) and filtered through sintered glass containing a bed of silica (SiO2 60 AAC 70-200 μm). The product is then eluted from the silica with ethanol (2 l). The ethanolic phases are combined and evaporated. 50 ml of dichloromethane are added to the residue and the organic phase is washed with twice 50 ml of water. The organic phase is recovered, dried over Na2SO4, and then evaporated in a rotary evaporator. After drying under vacuum, the compound 21 is obtained in the form of a beige powder: 5.03 g (yield=75%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:30](=[O:41])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1)[C:30]([C:10]1[N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])[CH:16]=[CH:17][C:12]=2[N:11]=1)=[O:41]
Reactant: COc1cc(OC)cc(C(=O)N(C)OC)c1
Reactant: O=C(O)c1ccccc1-c1ccc2ncn(CCc3ccccc3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc(OC)cc(C(=O)c2nc3ccc(-c4ccccc4C(=O)O)cc3n2CCc2ccccc2)c1

Procedure:
2-[1-(2-phenylethyl)-1H-benzimidazole-6-yl]benzoic acid and N,3,5-trimethoxy-N-methylbenzamide were subjected to a reaction in the presence of lithium diisopropylamide to give the compound having the following physical data.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3c(C)cccc32)CC1
Yield: 73 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11,3) (0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083 g, 0.50 mmol), and K2CO3 (0.069 g, 0.50 mmol) in MeCN and shaken at 50°. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR (CD3OD) d 7.15 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.4 Hz), 4.00 (t, J=7.2 Hz, CH2), 3.10 (d, J=12.1 Hz, 2H), 2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH3), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.31-1.24 (m, 9H), 0.90 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) d 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.36.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[CH:28][C:29]=2[F:34])=[S:47])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 80%).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=1)=[O:19])=[CH:7]2.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:33][N:32]=[N:31][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=1)=[O:19])=[CH:7]2
Reactant: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1cn(C)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1)C(=O)c1cn(C)c2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
A mixture of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.0 g, 2.0 mmol), prepared in the previous step, sodium azide (0.32 g, 6.0 mmol) and ammonium chloride (0.39 g, 6.0 mmol) in 15 mL of DMF was stirred under nitrogen at 100° C. for 6 h. The reaction was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 1 N NaOH. The organic layer was separated and the aqueous layer extracted five times with ethyl acetate. The aqueous layer was then acidified with 1N HCl. After 2 h a white solid had precipitated from solution. The solid was collected by filtration and dried under reduced pressure to give the title compound (0.8460 g, 84%) as an off-white solid, mp 227-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Br:17])[CH:3]=1.[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>O1CCCC1>[Br:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Br)C1=O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Br)C1=O
Yield: 93.4 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 2.0 grams (0.0067 mole) of 2-[(4-amino-2-bromophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.0 gram (0.0067 mole) of phthalic anhydride in 50 ml of tetrahydrofuran. The reaction mixture was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethyl acetate-hexane to yield 2.8 grams of 2-[[2-bromo-4-[(2-carboxyphenyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone, m.p. 177° C., dec.