Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:26])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(C)c(OCc3ccccc3)ccc2[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)c(OCc3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 5-benzyloxy-4-methyl-1H-indole-2-carboxylate (3.50 g, 11.3 mmol), 60% sodium hydride (0.45 g, 11.3 mmol) and N,N-dimethylformamide (70 ml) was stirred at room temperature for 30 minutes, and then methyl iodide (3.21 g, 22.6 mmol) was added dropwise thereto, followed by stirring at room temperature for another 2.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane=3/97) to obtain 3.53 g of ethyl 5-benzyloxy-1,4-dimethyl-1H-indole-2-carboxylate.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[N:10]([C:12]([CH3:15])=[N:13][N:14]=2)[N:11]=1.[CH3:19]O>>[Cl:5][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[N:10]([C:12]([CH3:15])=[N:13][N:14]=2)[N:11]=1
Reactant: CO
Reactant: Cc1nnc2c(C(=O)O)cc(Cl)nn12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)nn2c(C)nnc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
Thionyl chloride (2.0 mL) was added to a solution of product 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (4.0 g, 18.5 mmol) in MeOH dropwise under cooled ice-bath. The resulting mixture was stirred at 80° C. for 16 hours and then cooled to room temperature and concentrated in vacuum. The crude product was purified by flash column chromatography (silica-gel, PE: EA=3:1) to give product methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow solid (3.0 g, 71.8%). 1H NMR (300 MHz, CD3OD) δ: 7.92 (s, 1H), 4.07 (s, 3H), 2.79 (s, 3H). LRMS (M+H+) m/z: calcd 227; found 227.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH2:18]Br.[C-:21]#[N:22].[Na+]>CS(C)=O.O>[C:21]([CH2:18][C:5]1[C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:22]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 2-bromomethyl-5-isopropoxy-isophthalic acid dimethyl ester (Cpd C, 17.4 g, 50.5 mmol) in DMSO (200 mL) was added NaCN (3.71 g, 75.7 mmol) in H2O (20 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (500 mL), and extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine (1×300 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-40%, EtOAc/heptanes) to give Dimethyl 2-(cyanomethyl)-5-(propan-2-yloxy)benzene-1,3-dicarboxylate (Cpd D, 12.8 g, 87% yield) as a clear oil which solidified upon standing.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:26])[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])C.[OH-].[K+]>C1COCC1.C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:13]([CH3:14])([CH3:15])[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:8]=2)=[O:26])=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 65 °C

Procedure:
A mixture of 2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (357 mg, 0.785 mmol) and concentrated aqueous KOH (2 mL) in a mixture of THF (3 mL) and ethanol (5 mL) was heated at 65° C. for 2 h, cooled to RT and partitioned between ethyl acetate and 3 M HCl. The combined organic extract was dried and concentrated to give the title compound. m/z 428.1 (MH+).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[NH:17][CH2:18][CH2:19][N:20]=1>C(OCC)C>[CH:1]([N:14]=[C:16]1[NH:20][CH2:19][CH2:18][NH:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClC1=NCCN1
Solvent: CCOCC
Product: c1ccc(C(N=C2NCCN2)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2.26 g of benzhydrylamine and 30 ml of an ethyl ether solution containing 2.5 g of 2-chloro-2-imidazoline was allowed to stand at room temperature for 2 days. The reaction mixture was then treated in the same manner as in Synthesis Example 1 to give crystals of 2-benzhydryliminoimidazolidine. The crystals were dissolved in methanol and an equivalent amount of concentrated hydrochloric acid solution was added. The solution was distilled off in vacuo to give 3.2 g of 2-benzhydryliminoimidazolidine hydrochloride having a melting point of 207°-209° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:36](=[O:37])[C:35]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]4[C:33]3=[O:42])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A mixture of 3-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.00 g, 10.8 mmol) and sodium carbonate (1.20 g, 11.3 mmol) in acetonitrile (30 mL) and water (30 mL) under nitrogen was stirred at room temperature for 15 minutes. To the resulting solution was added N-ethoxycarbonyl phthalimide (2.36 g, 10.8 mmol). The resulting mixture was stirred at room temperature for 18 hours. Most of solvent was removed in vacuo. To the solution was added hydrochloric acid (6N) until the pH of solution <1 to give a suspension and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (2×10 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to afford 3-(3-cyclopentyloxy-4-methoxy-phenyl)-3-phthalimidopropanoic acid as a white solid (3.0 g, 68% yield): mp, 168.0–169.0° C.; 1H NMR (DMSO-d6) δ 1.55–1.88 (m, 8H, C5H8), 3.27 (dd, J=6.9, 16.5 Hz, 1H, CHH), 3.51 (dd, J=8.9, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 4.71–4.75 (m, 1H, CH), 5.61 (dd, J=6.9, 8.8 Hz, 1H, NCH), 6.87–6.95 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.81–7.91 (m, 4H, Ar), 12.4 (br s, 1H, OH); 13C NMR (DMSO-d6) δ 23.51, 32.14, 32.17, 36.07, 50.08, 55.52, 79.57, 112.15, 113.97, 119.39, 123.17, 131.09, 131.19, 134.66, 146.77, 149.16, 167.67, 171.72; Anal Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42. Found: C, 67.21; H, 5.46; N, 3.45.
Reaction SMILES: [Cl-].[CH3:2][Al+:3][CH3:4].[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Li]>CCCCCC>[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Al:3]([CH3:4])[CH3:2]
Reactant: [Li]Cc1ccccc1N(C)C
Reactant: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Product: CN(C)c1ccccc1C[Al](C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
10.0 ml (107.8 mmol) of dimethylaluminium chloride were added dropwise to a suspension, cooled to −30° C., of 15.21 g (107.8 mmol) of [2-(dimethylamino)benzyl]lithium in 250 ml of hexane in an inert nitrogen atmosphere. After slow warming to room temperature, the mixture was stirred for 14 hours in order to complete the reaction. Filtration through a D4 frit and removal of the solvent by distillation gave 11.95 g of [2-(dimethyl-amino)benzyl]dimethylaluminium (62.5 mmol/58%) as a colourless liquid by slow fractional distillation from the residue.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:31]([O:32][CH3:33])=[CH:30][C:8]2[NH:9][C:10](=[O:29])[C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)=[CH:14][C:12]=3[NH:13][C:7]=2[CH:6]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:6][C:7]2[NH:13][C:12]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)[CH:16]=[CH:17][C:11]=3[C:10](=[O:29])[NH:9][C:8]=2[CH:30]=1
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1OCCCl)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCN1CCCC1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of Example 497 (11 mg, 0.023 mmol), pyrrolidine (3.9 μL, 0.046 mmol), K2CO3 (6.5 mg, 0.046 mmol) and DMF (0.5 mL) was heated overnight at 50° C., cooled to room temperature, and filtered. The filtrate was purified by preparative HPLC to provide 6 mg (51%) of the desired product. MS (ESI) m/e 505 (M+H)+; 1H NMR (500 MHz, DMSO-d6) 9.72 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.78-7.80 (m, 2H), 7.53 (d, J=1.6 Hz, 1H), 7.29-7.35 (m, 3H), 6.78 (s, 1H), 6.73 (s, 1H), 4.18 (t, J=5.0 Hz, 2H), 4.03 (s, 3H), 3.71 (s, 3H), 3.44-3.68 (m, 4H), 3.11-3.17 (m, 2H), 2.00-2.07 (m, 2H), 1.95-1.93 (m, 2H).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH2:8][CH2:7][C:6]1=[O:21])(=[O:4])[CH3:3].[CH3:22][CH2:23][CH2:24][CH2:25][CH:26]([OH:31])[CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[C:2]([NH:5][CH2:14][CH2:13][CH2:12][C:11]([C:10]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=1[CH2:8][CH2:7][C:6]([O:31][CH:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH2:24][CH2:23][CH3:22])=[O:21])=[O:15])(=[O:4])[CH3:3]
Reactant: CCCCC(O)CCCC
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Solvent: ClCCl
Product: CCCCC(CCCC)OC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
15 ml of concentrated hydrochloric acid are added to a solution of 10.00 g (0.034 mol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 90 ml of 5-nonanol and 50 ml of methylene chloride and the mixture is stirred at room temperature for 18 hours. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetate gives 1-butylpentyl 2-(4-acetamido-butyryl)-5-chlorohydrocinnamate as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([F:29])[CH:23]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:16]#[N:17])=[C:24]([F:29])[CH:23]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Yield: 68.8 %

Procedure:
A mixture of 3.1 g (9.96 mmol) of 7-(3-Chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 1.6 g (10.96 mmol) of 4-chloro-2-fluoro-aniline, and 1.2 g (10 mmol) of pyridine hydrochloride in 31 ml of 2-ethoxyethanol was stirred at reflux for 1.5 hr. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried and solvent was removed. The residue was purified on a silica gel column eluting with chloroform-ether mixtures to give 2.88 g of the title compound as an off-white solid powder: mass spectrum (electrospray, m/e) M+H 419.7.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12]C)[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2ccc(OC)cc2s1
Agent: BrB(Br)Br
Product: CCc1cc2ccc(O)cc2s1
Yield: 81.8 %

Procedure:
This material was prepared from 2-ethyl-6-methoxybenzo[b]thiophene 134a (2.30 g, 12 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give a white solid (1.75 g, 82%). 1H NMR (DMSO-d6) δ 9.43 (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.16 (1H, d, J=2.2 Hz), 6.95 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.81 (2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5](F)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[C:17]1([C:13]2[CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[CH:5]=[CH:4][N:3]=3)[CH:16]=[CH:15][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: c1ccc(-c2cccc(Nc3ccnc(Nc4cccc(-c5ccccc5)c4)n3)c2)cc1

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobiphenyl were reacted to provide N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine. LCMS: purity: 98%; MS (m/e): 415 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: OCc1ccccn1
Reactant: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine (prepared in the above Example 297(3)) 71 mg and 2-hydroxymethylpyridine 25 mg in tetrahydrofuran 3 ml is added potassium tert-butoxide 26 mg under ice cooling. The mixture is stirred for 30 minutes at the same temperature and diluted a 10% aqueous citric acid solution. The solution is extracted with ethyl acetate and the extract is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified and separated with silica gel chromatography (silica gel 5 g, solvent; chloroform:ethyl acetate=3:1) and crystallized from isopropyl ether to give 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxy)pyrazine as a pale yellow crystalline powder, 25 mg. mp 132–133° C., MS(m/z): 415(M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (250 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added cinnamoyl chloride (160 mg, 0.93 mmol) and triethylamine (TEA, 0.30 mL, 2.2 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was purified by preparative TLC (PTLC, 20% EtOAc/CH2Cl2) to provide 290 mg (85%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.32-7.20 (m, 10H), 7.17 (d, J=7.9 Hz, 1H), 6.74 (dd, J=6.8, 1.5 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.80-4.69 (m, 1H), 4.20-4.09 (m, 3H), 3.51-3.45 (m, 1H), 3.31-3.20 (m, 2H), 2.95-2.82 (m, 2H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.91-1.71 (m, 2H). MS: exact mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:32][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[O:31])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:35])=O>C(Cl)Cl>[Cl:35][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:32][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[O:31])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4ccc(CO)nc4cc3C2)c2cccnc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4ccc(CCl)nc4cc3C2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-2-(hydroxymethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (1.44 g, 3.22 mmol) in CH2Cl2 (10 mL) was added thionyl chloride (7.66 g, 64.3 mmol) and the resulting mixture was stirred at ambient temperature for 30 min, then concentrated in vacuo. The residue was concentrated in vacuo from toluene (2×10 mL) to give the title compound in sufficient purity for use in the next step. MS: m/z=466 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:17]=[CH:18][C:19]([O:21]C(C)(C)C)=[O:20])[NH:10][C:9]2=[O:33]>CO>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:17]=[CH:18][C:19]([OH:21])=[O:20])[NH:10][C:9]2=[O:33]
Reactant: CCCOc1ccc(C=CC(=O)OC(C)(C)C)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(C=CC(=O)O)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
2N Aqueous sodium hydroxide solution (2.8 ml) was added to a stirred solution of t-butyl 3-(8-methyl-quinazolin-4(3H)-on-2-yl)-4-n-propoxycinnamate (Example 10; 0.79 g, 0.0018 mol) in methanol (2.8 ml) and the resulting solution heated under reflux for 4 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in water (25 ml) and this solution washed with ethyl acetate (4×30 ml). The aqueous solution was acidified with 2N hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give the title compound, which crystallized from ethyl acetate to give a white solid (0.41 g, 60%), m.p. 256-257° C.
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[NH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1>O1CCOCC1.O>[CH3:31][C:30]1[C:25]2[N:26]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:24]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Reactant: Cc1cccnc1N
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(C#N)c(-c2cnc3c(C)cccn23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
10 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, pages 90-91) was dissolved in a mixed solvent of 150 mL of 1,4-dioxane and 30 mL of water and then 8.04 g of N-bromosuccinimide was added thereto under an ice-cold condition, and the mixture was stirred for 1.5 hours at room temperature. To the reaction solution, 4.89 g of 2-amino-3-picoline was added, and the mixture was further stirred for 2.5 hours. 200 mL of water was added to the reaction solution to extract with 2 L of a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer was washed with water, and dried over anhydrous magnesium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a small amount of chloroform and solidified with hexane to obtain 4.02 g of 4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [1-6] (hereinafter, referred to as the compound [1-6]) as a light brown solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)O)=[CH:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=3)=[N:14][CH:13]=2)=[CH:2]1
Reactant: OC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Into a round bottom flask was added compound 14 (200.0 mg, 0.50 mmol) and trifluoroacetic acid (5.0 mL, 0.065 mol) and triethylsilane (3.0 mL, 0.019 mol). The reaction was stirred at room temperature for 30 min, poured into aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified to give pure product 12 (Table 1 Cmpd 1-3) (120.0 mg, yield=62.8%) as a white solid (M+1=383).