Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]4[CH2:30][CH2:31][CH:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:33][CH2:34]4)=[O:28])[CH:21]=3)=[CH:42][CH:43]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (149 mg) and (+)-10-camphorsulfonic acid (152 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 97:3) to provide the title compound (88.2 mg, 40%) as white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:47]=[CH:46][C:20]([CH2:21][CH:22]([C:30]([NH:32][S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])=[O:31])[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[CH:22]([CH2:21][C:20]1[CH:46]=[CH:47][C:17]([NH:16][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:18][CH:19]=1)[C:30]([NH:32][S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:34])=[O:35])=[O:31])[CH3:29]
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)C(Cc1ccc(NC(=O)C2CCNCC2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 16 h

Procedure:
To a solution of the compound (250 mg) obtained in Example 17 in methylene chloride (10 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred for 16 hr. After concentration under reduced pressure, an ether/chloroform mixture was added, and the precipitate was collected by filtration to give the title compound (247 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:3]=1.[C:14]([O:17]C(=O)C)(=O)[CH3:15].[N+:21]([O-])([OH:23])=[O:22]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:14](=[O:17])[CH3:15])=[C:9]([N+:21]([O-:23])=[O:22])[CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2noc(C)n2)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
4-(5-Methyl-1,2,4-oxadiazol-3-yl)aniline (500 mg) was added to acetic anhydride (2.1 mL) over 10 min and the mixture was cooled down to 10° C. HNO3 (65% in water, 0.59 mL) was added slowly to keep the temperature of the reaction mixture below 15° C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10 min. The resulting mixture was basified with aq. NH4OH (25%) to pH=12 and extracted with DCM. The phases were separated and the org. phase was evaporated in vacuo. LC-MS (B): tR=0.75 min; [M]+: 262.05.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (S)-2-Amino-4-methyl-pentanoic acid amide (CAN 687-51-4) as starting materials and isolated (13.5 mg, 24%) as a white solid; MS (ESI, m/z): 374.0 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.Cl[C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:29][C:28]=2[O:38][CH3:39])=[CH:25][CH:26]=1.O>C1COCC1>[CH3:39][O:38][C:28]1[CH:29]=[C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[N:22][C:21]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)nn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.98 mL, 0.98 mmol) was added to tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.18 g, 0.98 mmol) in THF (3.3 mL) at 0° C. and the mixture was stirred for 10 min at 50° C. 3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (0.12 g, 0.40 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 h at RT. Water (0.1 mL) was added and the solvent was concentrated under reduced pressure to afford (0.18 g, 100%) of a brown solid.
Reaction SMILES: [C:1]([O:8][CH2:9]I)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][N:13]=[C:14]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:15]([NH:17][CH:18]1[C:35](=[O:36])[N:20]2[C:21]([C:32]([O-:34])=[O:33])=[C:22]([CH2:25][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)[C:15]([NH:17][CH:18]1[C:35](=[O:36])[N:20]2[C:21]([C:32]([O:34][CH2:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:33])=[C:22]([CH2:25][S:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:16]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Reactant: CCCCCC(=O)OCI
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCOC(=O)C1=C(CSc2nncs2)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of iodomethyl hexanoate (1.58 g.) in dimethylformamide (3 ml.) was added at a time under ice-cooling to a stirred solution of sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (3.0 g.) in dimethylformamide (15 ml.). The mixture was stirred for 10 minutes at the same temperature and poured into a mixture of water (50 ml.) and ethyl acetate (100 ml.). The aqueous layer was separated and extracted twice with ethyl acetate (50 ml.). The combined ethyl acetate layer was filtered and the filtrate was washed three times with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to a volume of 20 ml. to give precipitates, which were collected by filtration, washed with ethyl acetate (10 ml.) and dried to give hexanoyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.1 g.).
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[CH:15]=1)[CH:11]=[O:12]>CN(C=O)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][CH2:17][CH3:18])[CH:15]=1)[CH:11]=[O:12]
Reactant: CCCc1cc(C=O)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCc1cc(O)cc(C=O)c1

Procedure:
To a solution of sodium hydride (183 mg) and ethanethiol (0.6 ml) in DMF (15 ml) was added dropwise a solution of 3-methoxy-5-propyl-benzaldehyde (0.9 g). The reaction mixture was heated for 3 hours at 150°, quenched with NH4OAc buffer and extracted with ethyl ether. The ethyl ether layer was dried (Na2SO4) and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1(=[O:21])[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][NH:12]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:19][CH2:20][C:15]3([C:11](=[O:21])[N:12]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCC12CCNCC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC3(CCN(Cc4ccccc4)C3=O)CC2)nc1

Procedure:
Intermediate B-17 was prepared by the general procedure for intermediate B-15, by using 2-chloro-5-nitropyridine, 2,8-diazaspiro[4,5]decan-1-one, and benzyl bromide as starting materials. MS (M+1): 337.3
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:56](Br)[CH:57]=[CH2:58]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([CH2:28][O:29][CH2:58][CH:57]=[CH2:56])[O:27]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H]1O[C@@H](c2cc(Cc3ccc(OCC)cc3)c(Cl)cc2OCC=C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of primary alcohol (21, 1.5 g, 2.04 mmol) from Step 1 in N,N-dimethylformamide (10 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in mineral oil, 123 mg, 3.06 mmol), and the mixture was stirred for 30 min at the same temperature. Then allyl bromide (0.26 mL, 3.06 mmol) was added dropwise, and the mixture was stirred with gradual warming to ambient temperature over 5 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (10 mL). The mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (22, 1.12 g, 1.44 mmol, 71%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-:13]#[N:14].[Na+].O>CN(C=O)C>[C:13]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2×500 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield methyl 3-(cyanomethyl)benzoate 1 (17 g, 89%). 1H-NMR (400 MHz, CDCl3) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
Reaction SMILES: [H-].[Na+].C[Si](C)(C)N[Si](C)(C)C.[O:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14](=O)[CH2:13]1.[OH2:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:24]([O:23][C:27](=[O:22])[CH2:26][C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[O:12][CH:13]=1)[CH3:25]
Reactant: O=C1COc2ncccc21
Reactant: O
Reactant: C1CCOC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1coc2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.325 g (8.14 mmol) of sodium hydride (50% suspension in mineral oil) in 8 ml of anhydrous tetrahydrofuran was added 0.1 ml of 1,1,1,3,3,3-hexamethyldisilazane and 1.81 g (8.14 mmol) of triethyl phosphonoacetate (Aldrich) in 4 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 1 h, cooled at 0° C. and there was added 1 g (7.4 mmol) of furo[2,3-b]pyridin-3-one (prepared according to J. Het. Chem. 1986, 23, 1465-1469). After being stirred at room temperature for 24 h, water was added, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with ethyl acetate/cyclohexane in the proportions 40/60 to give 0.73 g of pure product.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.C(N(CC)CC)C.[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.CO>[C:20]1([C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
L-Serine (2.10 g, 20.0 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in methylene chloride (20 mL) (Wako Pure Chemical Industries, Ltd.), and then trimethylsilyl chloride (8.9 mL) (Shin-Etsu Chemical Co., Ltd.) was added thereto, followed by reflux for 20 minutes. The mixture was returned to room temperature, and then triethylamine (10 mL) (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by reflux for 45 minutes. The mixture was ice-cooled, and then triethylamine (2.8 mL) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (5.61 g, 20.1 mmol) (Wako Pure Chemical Industries, Ltd.) were added thereto, followed by stirring at room temperature for 5 hours. An excessive amount of methanol (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=99:1 as an eluent), to thereby obtain the title compound (0.36 g, 5% yield).
Reaction SMILES: BrCCCCC(O)=[O:7].C(O)C1C=CC=CC=1.[CH:17]([N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24])([CH3:19])[CH3:18]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:18][CH:17]([CH3:19])[N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24].[NH2:20][C:21]([NH2:22])=[O:7]
Reactant: O=C(O)CCCCBr
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: NC(N)=O
Temperature: 25 °C

Procedure:
A solution of 5-bromopentanoic acid (1.00 g, 5.52 mmol) and benzyl alcohol (0.286 mL, 2.76 mmol) in methylene chloride (14 mL) was treated sequentially with N,N′-diisopropylcarbodiimide (0.523 g, 4.14 mmol) and 4-dimethylaminopyridine (43.9 mg, 0.359 mmol). The solution was allowed to stir at room temperature. A precipitate formed within 1 minute of the addition of the 4-dimethylaminopyridine. After −65 h, the reaction mixture was filtered, the solid was washed with CH2Cl2 and the filtrate was washed with 20 mL portions of 1N HCl, sat NaHCO3 and brine and dried over Na2SO4. The solution was filtered and concentrated to yield a nearly colorless liquid along with a solid (DIC urea). The material was taken up in 1/1 MTBE/heptane to yield a solution with a white precipitate. The mixture was filtered and concentrated and the crude material was purified by flash chromatography (75 g silica gel; 5-10% MTBE/hept) to yield the title compound (0.69 g, 92%) as a colorless liquid. HPLC purity>95% (ret. time, 4.73 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([O:27][CH3:28])=[CH:21][C:20]=1[OH:29])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:22]1[CH:23]=[C:24]([O:25][CH3:26])[C:19]([C:17](=[O:18])[CH3:16])=[C:20]([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:21]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc(OC)c(C(C)=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), 2-hydroxy-4,6-dimethoxyacetophenone (196 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (25 mg, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31]OS(C)(=O)=O)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:37]([C:44]12[CH2:51][CH2:50][N:47]([CH2:48][CH2:49]1)[CH2:46][CH2:45]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C>[OH2:13].[Cl-:1].[CH2:37]([C:44]12[CH2:45][CH2:46][N+:47]([CH2:31][CH2:30][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=4)[CH2:10]3)([CH2:50][CH2:51]1)[CH2:48][CH2:49]2)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: c1ccc(CC23CCN(CC2)CC3)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC(CC[N+]23CCC(Cc4ccccc4)(CC2)CC3)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 80 °C
Yield: 151.2 %

Procedure:
A mixture of 1.4 g of the compound obtained in step B of EXAMPLE 21 and 0.6 g of 4-benzylquinuclidine in 3 ml of DMF is heated at 80° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water, with 300 ml of 10% HCl solution and with 300 ml of saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.35 g of the expected product after crystallization from AcOEt. M.p.=172°-175° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:52][O:53][C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)=[O:55]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:52][O:53][C:54](=[O:55])[C:56]1[CH:57]=[CH:58][CH:59]=[C:60]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH:61]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
4-Chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (317 mg, 1.00 mmol), palladium acetate (11 mg, 5 mol %), S-Phos (41 mg, 10 mol %) and 3-methoxycarbonylphenylboronic acid (637 mg) were dissolved in dimethylformamide (10 ml). Then, argon substitution was carried out three times under ultrasonic irradiation in reduced pressure. The reaction mixture was stirred at 100° C. for 2 hours, and the reaction mixture was allowed to cool to room temperature, and then poured onto water (100 ml). The reaction mixture was extracted twice with ethyl acetate/tetrahydrofuran (4/1, 100 ml), and the combined organic layers were washed with brine, followed by drying over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0 to 50/1), to obtain a colorless solid (374 mg, 90%).