Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH:11]=[O:12])[CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[C:4]([CH:3]=1)[CH:11]=[O:12]
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1-n1cccn1
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a solution of 4-chloro-2-formylphenylboronic acid (200 mg, 1.09 mmol) in DMF (10 mL) are added pyrazole (88 mg, 1.3 mmol), Cu(OAc)2 (295 mg, 1.6 mmol), pyridine (171 mg, 2.2 mmol) and molecular sieve (200 mg) at room temperature. The mixture is stirred for 48 hours with open cap. The mixture is filtered through a short pad of diatomaceous earth (2 g) rinsing with MeOH (10 mL). The combined filtrate is extracted with H2O (15 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% EtOAc in heptane to afford 5-chloro-2-pyrazol-1-yl-benzaldehyde (50 mg, 22%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[N+:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[C-:9].[CH:15](=O)[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>Cl(O)(=O)(=O)=O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:8][C:9]1[N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]2=[N:1][C:15]=1[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cnccn1
Reactant: O=Cc1ccco1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CNc1c(-c2ccco2)nc2cnccn12

Procedure:
Compound (5) was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml methyl isocyanoacetate solution (0.2 M, MC), 0.500 ml furfural solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17](Br)[N:16]=1.[CH3:24][N:25](C)[CH:26]=[O:27]>CCCCCC>[C:24]1([NH:25][C:26]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[O:27])[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)nc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
3.34 g (0.187×1.1 mol) of 3-(trifluoromethyl) phenol was dissolved in about 30 ml of dimethyl formamide (hereinafter referred to merely as “DMF”). The solution was further mixed with 0.78 g (ca. 60% in mineral oil; 0.0187×1.04 mol) of NaH and then with 5.00 g (0.0187 mol) of 2,6-dibromo-4-methoxy pyridine. After stirring at about 120° C. for about 2 hours, the resultant mixture was allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), and the obtained eluate was subjected to recrystallization using hexane, thereby obtaining an aimed product.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.ClC1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.Cl>ClCCl>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[C:5]1[CH:28]=[CH:27][C:23]([CH3:24])=[CH:22][CH:21]=1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
Ethyl acetoacetate (51.25 g, 390 mmol) was added dropwise to the stirred suspension of anhydrous magnesium chloride (37.54 g, 390 mmol) in dried dichloromethane (200 ml) over a period of 1 hour under argon atmosphere at 0° C. followed by pyridine (62.5 g, 788 mmol). After 15 minutes, 4-chlorobenzoylchloride (68.95 g, 394 mmol) was added dropwise and stirring was continued for 15 minutes at 0° C. and further stirred for 1.5 hours at 30° C. The resulting reaction mixture was neutralized with hydrochloric acid (6N, 235 ml) at 0–5° C., filtered and washed with water. The filtrate was extracted with diethylether (3×100 ml). The ether extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The obtained oil was taken in ammonium chloride (21 g in 200 ml water) solution containing ammonia (2 ml) and stirred at 30° C. for 20 minutes. The resulting solution was extracted with ethyl acetate (3×200 ml). Ethyl acetate extract was dried over anhydrous sodium sulphate, concentrated to yield the crude product, which was purified by column chromatography to yield the title compound as viscous oil (43 g, 48.2%). 1H-NMR (DMSO-d6): δ 1.15–1.18 (t, 3H), 4.08–4.13 (q, 2H), 4.20 (s, 2H), 7.61–7.64 (d, 2H), 7.94–7.97 (d, 2H). MS m/z: 227.1 (M+). Preparation 3 Synthesis of ethyl(4-methylthio)benzoylacetate
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH2:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(N(CC)CC)C>CN(C)C=O>[ClH:1].[CH2:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: CCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Product: Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
1-Chloro-3-(4-methoxyphenyl)isoquinoline (405 mg) and 4-ethylpiperidine (168 mg) were dissolved in N,N-dimethylformamide (5 ml), followed by the addition of triethylamine (251 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system). Then the resulting product was converted into a hydrochloride in a conventional manner, and then recrystallized from ethanol/isopropyl ether, to give the hydrochloride of the title compound as a colorless crystals (87 mg, yield; 13%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[C:24]([CH3:36])([CH3:35])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CC#N.CCOC(C)=O>[CH3:35][C:24]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)([CH3:36])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: CC(C)(Br)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C(=O)OCc1ccccc1)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (554 mgs, 2.4 mmol) in CH3CN (5 mL) and K2CO3 (1.1 g, 8.0 mmol) was added benzyl 2-bromo-2-methylpropanoate (512 mgs, 2.0 mmol). The reaction mixture was heated to 80° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, stirred and filtered. The filtrate was then concentrated and purified by flash chromatography on silica gel with elution using 3% MeOH/CH2Cl2 to give Benzyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propanoate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]#[C:16][CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Cl:13][CH2:14][C:15]#[C:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCC#CCCl)cc2N1
Yield: 66.1 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (930 mg, 6 mmol), 1,4-dichlorobut-2-yne (326 mg, 2 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-(4-chlorobut-2-ynyloxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 50) (330 mg, 66%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:21])([CH3:20])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1.N1C=CC=CC=1>CCOCC>[C:1]([NH:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:20])([CH3:21])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(NC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (0.39 g., 5 mmole) was added to a stirred solution of 0.78 g. (2.2 mmole) of 10-amino-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine in 10 ml. of dry pyridine, cooled in an ice bath. After stirring at room temperature for 18 hours, the mixture was poured into 100 ml. of ice water and exracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florisil column (60-100 mesh) and eluted with chloroform and then graded chloroform-methanol mixtures to give the pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]#[N:15].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[NH:22][N:21]=[N:20][N:15]=1
Reactant: N#CC1CC12C(=O)Nc1ccc(Br)cc12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccc(Br)cc2C12CC2c1nnn[nH]1
Temperature: 5 °C
Yield: 68.6 %

Procedure:
A suspension containing 5′-bromo-2-cyano-spiro[cyclopropane-1,3′-[3H]indol]-2′(1′H)-one (263 mg, 1 mmol) and trimethyltin azide(384 mg, 2 mmol) in xylene (20 mL) was stirred and heated to reflux for 16 hours. After cooling the solution to 5° C., a white precipitate was obtained that gave 210 mg (yield: 69%) of the title compound. MS: m/z 206 [M+1]+; 1H NMR (DMSO-d6): δ 10.7 (br, 1H), 7.14 (m, 1H), 7.0 (m, 2H), 6.70 (d, 1H), 2.90 (m, 1H), 2.24 (m, 1H). 1.98 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:32](Br)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>C1C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCN1
Solvent: c1ccccc1
Product: O=C(CC1CN(Cc2ccccc2)CCC1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27674 %

Procedure:
To a solution of 1-benzylpiperidin-4-one (10.0 g, 0.0529 mmol) and morpholine (6.9 g, 0.079 mol) in dry benzene was added a catalytic amount of PTSA (450 mg, 0.00262 mol). A round bottom flask was attached with a Dean Stark assembly then the reaction mixture was heat at reflux under nitrogen for 17 to 18 h. The reaction mixture was concentrated under a nitrogen atmosphere, then the crude mixture was diluted with dry benzene and cooled to 0° C. and a solution of phenacyl bromide (12.63 g, 0.0634 mol) in benzene was added. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with water and stirred at RT for 1 h, then extracted with EtOAc (300×3 mL), dried over Na2SO4 and concentrated to afford the crude product which was purified by flash chromatography (eluent: 10% EtOAc/hexanes) to afford 1-benzyl-3-(2-oxo-2-phenylethyl)-piperidin-4-one (4.5 g, 45.0%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][Cl:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:28])[CH2:22][N:23]3[CH2:27]CC[CH2:24]3)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1.Cl.ClCCN(CCCl)C1C=CC(NC(=O)NC2C=C(NC(=O)CCl)C=CC=2)=CC=1.N1CCCC1>C1COCC1>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][Cl:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:28])[CH2:22][N:23]([CH3:27])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1
Reactant: O=C(CN1CCCC1)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Agent: Cl
Agent: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1

Procedure:
By following the same procedure as that for BO-2189, N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)-phenyl)-2-(pyrrolidin-1-yl)acetamide (BO-2151) hydrochloride was prepared from N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-chloroacetamide (2.2 g, 5.0 mmol) and pyrrolidine (1.6 g, 20 mmol) in THF (50 mL), 1.6 g (69%), mp 66-68° C. 1H NMR (DMSO-d6) δ: 1.90-1.93 (2H, m, CH2), 1.98-2.01 (2H, m, CH2), 3.11-3.15 (2H, m, CH2), 3.61-3.64 (2H, m, CH2), 3.66-3.72 (8H, m, CH2), 6.72-6.74 (2H, d, J=7.8 Hz, Ar—H), 7.19-7.22 (2H, d, J=7.6 Hz, Ar—H), 7.29-7.32 (3H, m, Ar—H), 7.78 (1H, s, Ar—H), 9.04 (1H, brs, NH), 9.31 (1H, brs, NH), 10.35 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 22.82, 41.05, 52.88, 54.04, 55.72, 108.81, 112.53, 113.50, 120.03, 129.05, 138.43, 140.72, 152.87, 163.35. HRMS [ES+]: calcd for C23H29Cl2N5O2, 478.4147 [M+H]+. found 478.1777. HPLC 98.6%.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH3:20][O:21][CH2:22][C:23]([O:25][C:26]1[C:27]([F:42])=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29]([CH3:35])=[C:30]([C:33]#[N:34])[C:31]=1[NH2:32])=O>C(OCC)(=O)C>[F:42][C:27]1[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH3:35])[C:30]([C:33]#[N:34])=[C:31]2[C:26]=1[O:25][C:23]([CH2:22][O:21][CH3:20])=[N:32]2
Reactant: COCC(=O)Oc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
p-Toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added to a toluene (30 ml) solution of 4-amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl methoxyacetate (I-58) (214 mg, 0.68 mmol), followed by stirring for 3 hours and a half with heating under reflux. After cooling to room temperature, the reaction liquid was diluted with ethyl acetate, washed with saturated sodium bicarbonate water and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (4:1) was concentrated under reduced pressure to obtain the entitled compound (160 mg, 79%) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>O1CCCC1.ClCCl>[CH2:26]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCc1cccs1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 17.4 %

Procedure:
7.2 g of thiophene was dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this solution, 56 ml of n-butyllithium solution (1.6 mol/l hexane solution) was added dropwise and stirred for 3.5 hours. To this solution, 25 g of hexadecylbromide was added dropwise and stirred at room temperature for 5.5 hours. 100 ml of water and 100 ml of dichloromethane were added to the resulting solution to separate the organic layer. The organic layer was washed with 300 ml of water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane) to obtain 4.4 g of 2-n-hexadecylthiophene represented by the following formula.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][C:46]1[O:47][CH:48]=[CH:49][CH:50]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[O:47][CH:48]=[CH:49][CH:50]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: ClCc1ccco1
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccco4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-(chloromethyl)furan (T. Reichstein et al., Ber., 63 749-754 (1930)) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:29]([CH3:30])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 103 %

Procedure:
A mixture of the compound (1.0 g) obtained in Example 263, dimethylamine hydrochloride (485 mg), triethylamine (0.8 ml) and dimethylformamide (10 ml) was heated at 80° C. for 5.5 h. The reaction mixture was distilled under reduced pressure and water and 2 N HCl were added to the residue; after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.1 g of the titled compound quantitatively.
Reaction SMILES: N[C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC(Cl)C.N([O:21][C:22]([CH3:25])(C)C)=O.CCCCC.C[O:32]CCOC>>[C:22]([O:21][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:32])[CH3:25]
Reactant: COCCOC
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)C(C)Oc1ncccc1N
Solvent: CC(Cl)Cl
Solvent: CCCCC
Product: COC(=O)C(C)Oc1ncccc1OC(C)=O
Reaction time: 0.17 h

Procedure:
First, 1.5 ml of a boron trifluoride diethyl ether complex was added dropwise to a mixture of 1.1 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine, 1 ml of 1,2-dimethoxyethane, and 1 ml of dichloroethane at −10° C. After stirring at the same temperature for 10 minutes, a solution of 0.8 ml of t-butyl nitrite in 1 ml of 1,2-dimethoxyethane was added dropwise to the reaction mixture at −5° C. or lower. After stirring at the same temperature for 30 minutes, n-pentane was poured into the mixture. The lower one of the two layers separated was dissolved in acetic anhydride, and the solution was stirred at 70° C. for 1 hour. After the solvent was distilled out, the residue was subjected to silica gel chromatography to give 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39](O)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:38][C:39]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:13]=2)=[O:40])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:29]
Reactant: CCOC(=O)c1ccc(NCC2CCCN2)cn1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
To a stirred mixture of ethyl 5-[(2-pyrrolidinyl)methylamino]pyridine-2-carboxylate (230 mg, 0.923 mmol), 3-methoxy-4-[-N′-(2-methylphenyl)ureido]phenylacetic acid (290 mg, 0.923 mmol), 4-DMAP (145 mg, 1.15 mmol) in DMF (7 ml) was added EDC.HCl (225 mg, 1.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (30 ml) column chromatography with CHCl3—EtOH (98:2, v/v) as eluent to give ethyl 5-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]pyridine-2-carboxylate (400 mg, 80%) as fine needles. IR (KBr) n 3325, 1709, 1618, 1585, 1531 cm−1; 1H-NMR (CDCl3) δ1.39 (t, J=7, 3 H), 1.73-2.07 (series of m, 4 H), 2.28 (s, 3 H), 3.12 and 3.49 (each m, each 1 H), 3.60 (s, 2 H), 4.39 (br q, J=7 Hz, 2 H), 4.53 (m, 1 H), 6.07 (br s, 1 H), 6.23 (br s, 1 H), 6.75-6.77 (series of s and m, 2 H), 6.82 (dd, J=3.0 and 8.5 Hz, 1 H), 7.09-7.22 (series of m, 3 H), 7.49 (d, J=8.0 Hz, 1 H), 7.90 (d, J=8.5 Hz, 1 H), 7.98 (d, J=2.6 Hz, 1 H), 8.06 (d, J=8.8 Hz, 1 H); MS (FAB) m/z 546 (M++1); Anal. Calcd. for C30H35N5O5.1.5×H2O: C, 52.92; H, 6.69; N, 12.23. Found: C, 63.11; H, 6.48; N, 11.96.