Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[CH:30]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:30][C:29]#[CH:28])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CC(C)N1CCN(c2ccc(O)cc2)CC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(N2CCN(CCC(=O)OC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a mixture of the compound from step 1 (278 mg, 1.0 mmol) and K2CO3 (152 mg, 1.1 mmol) in DMF (5 mL) was added 3-bromopropyne (130 mg, 1.1 mmol) dropwise at rt. The reaction mixture was stirred at rt overnight and then partitioned between water and ethyl acetate. The organic payers were combined and washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give a brown oil. The crude product was purified by silica gel flash chromatography (30% ethyl acetate in hexane) to furnish the title compound (120 mg, 38%) as a light yellow solid; MS; m/z 317 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=3)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:26]>CO>[NH2:26][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(OCC4CO4)c(C)c3)no2)s1
Reactant: N
Solvent: CO
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)s1

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazole (123 mg, 0.345 mmol) in 7 N NH3 in methanol (10 mL) is stirred at 45° C. for 16 h. The solvent is evaporated and the residue is separated by chromatography on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give 1-amino-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (35 mg) as a white solid; LC-MS: tR=0.84 min, [M+1]+=374.14.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: CCc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Yield: 50.6 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-ethylphenylboronic acid (62.3 mg, 0.42 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (5:1)) yielded 52 mg (49%) of 3-(4-ethylphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
5 g of 4-fluoro-3-trifluoromethylbenzoic acid and 9 ml SOCl2 were stirred in 50 ml of MeOH at 60° C. for 8 h. The volatile constituents were then removed in vacuo to result in 5.1 g of a colorless oil, which was employed further without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:18]([NH:20][NH2:21])=O>C(O)CCC>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:18]=[N:20][N:21]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NNC=O
Solvent: CCCCO
Product: FC(F)(F)c1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 4.50 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine, 2.09 g. of formylhydrazine and 100 ml. of n-butanol is stirred and refluxed for 3 days. The solvent is removed and the residue dissolved in methylene chloride, passed through magnesol and the solid from the filtrate recrystallized from methylene chloride/hexane to afford the product as white crystals, m.p. 160°-161° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][O-:31].[Na+]>CO.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([O:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: C[O-]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NCCN(C)C)c2nc3c(ccc4c(OC)cccc43)nc2c1

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and a 25% solution of sodium methoxide in methanol (4 mL) was heated to reflux for 6 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (42 mg).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:13][C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1.O>CC(N(C)C)=O>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:14]2[C:15]([C:17]#[N:18])=[N:16][C:11]([C:6]3[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:13]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(CNc2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Temperature: 22.5 °C

Procedure:
6-(1-Isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarbonitrile (14.61 g) was added to a suspension of NaH (60% in oil suspension) (1.36 g) in DMA (36.5 ml) and the mixture was stirred at 20-25° C. for an hour. After addition of 1-(chloromethyl)-4-methoxybenzene (4.82 ml), the mixture was stirred at the same temperature for 20 hours. To the reaction mixture was added water (183 ml) and a precipitate was collected by filtration. The precipitate was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was crystallized from a mixture of n-hexane and CHCl3 to give 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (16.58 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1(C=CCO)C=CC=CC=1.N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][C@@H:9]2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: OCC=Cc1ccccc1
Agent: N
Product: OC[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-bromophenyl) prop-2-en-1-ol (the product of Example 1A) for 3-phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][NH:26]C(=O)C)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1>Cl>[O:31]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][NH2:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)NCCOc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Agent: Cl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(OCCN)c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of N-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethyl)acetamide (15 mg, 0.03 mmol) and an aqueous solution of hydrochloric acid (10 mL, 37% W/W) was heated with stirring at 80° C. for 3 hours. The reaction mixture was purified by preparative HPLC and SPE to give 9.3 mg of the desired product (yield was 68.5%). MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 8.10-8.06 (d, J=7.6 Hz, 1 H), 7.93-7.88 (d, J=7.2 Hz, 1 H), 7.82-7.76 (d, J=8 Hz, 1 H), 7.73-7.68 (t, J=7.6 Hz, 1 H), 7.65-7.60 (d, J=6.8 Hz, 1 H), 7.60-7.53 (t, J=7.2 Hz, 1 H), 6.68 (s, 1 H), 5.41 (s, 2 H), 4.70-4.65 (m, 2 H), 4.65-4.45 (m, 2 H), 3.80-3.72 (t, J=2.8 Hz, 2 H), 3.62-3.58 (t, J=4.4 Hz, 2 H), 2.47 (s, 3 H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[S].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.Cl>C(O)C.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]2[S:10][C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:24][C:16]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: [S-2]
Reactant: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [S]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium sulfide nonahydrate (875 mg, 3.78 mmol) and sulfur (120 mg, 3.78 mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4-methylbenzamide (1 g, 3.44 mmol) in ethanol (20 mL) at 85° C. The solution was stirred at 85° C. for 3 h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v to afford 400 mg (43%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>C(#N)C>[CH2:3]([CH:4]1[CH2:15][CH:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]1[N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)CC=CN1CCCCC1
Reactant: C=CC(=O)OCC
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(C)C)C1N1CCCCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
1-(4-Methyl-1-pentenyl)piperidine (844 g) and acetonitrile (70 mL) were mixed. The ethyl acrylate (443 mL) and hydroquinone (447 mg) were added to the mixture. The resulting mixture was stirred at 95° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (994.08 g) as a crude product.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C(#N)C.O>[CH3:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNc1ccc(O)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: O
Product: CN(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Yield: 58.7 %

Procedure:
A mixture of 2-chlorobenzimidazole (1.0 g), 4-(N-methylamino)phenol (1.13 g) and acetonitrile/water (1:1) was heated under reflux for a period of 5 hours. The mixture was concentrated, made basic with dilute ammonium hydroxide and the solid was collected. The product was recrystallised from ethanol to give 4-[N-methyl-N-(2-benzimidazolyl)amino]phenol (0.92 g) as colourless crystals, mp>260° C.
Reaction SMILES: [C:1]([CH:5]1CC2O[CH:6]1C=C2)(OC)=[O:2].[CH2:12]([NH2:30])[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][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.Cl>O>[CH2:12]([NH:30][C:1](=[O:2])[CH:5]=[CH2:6])[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][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution and 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added to 134.8 parts stearylamine. The reaction medium is heated to 60° C. and stirred for 15 hours at this temperature. 300 parts of chloroform are next added and the mixture neutralised with 4 parts concentrated hydrochloric acid. 100 parts of water are added, the organic phase is separated off, and the aqueous phase extracted with 50 parts chloroform. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. under a vacuum of 20 Torr. The residue is heated in a vacuum to 110° to 120° C. (bath temperature 140° C.). At the conclusion of the furane separation, the sedimentation temperature increases to 140° C. The mixture is cooled down, the product is dissolved in hot acetone, filtered, and allowed to recrystallise. 117 parts N-stearylacrylamide having a melting point of 75° to 77° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15](OC(=O)C(F)(F)F)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:29]([O:31]/[CH:32]=[CH:33]/[Sn](CCCC)(CCCC)CCCC)[CH3:30].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:32]([O:31]/[CH:29]=[CH:30]/[C:15]1[C:14]([C:23]([O:25][CH3:26])=[O:24])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:33]
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OC(=O)C(F)(F)F
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a stirred solution of methyl 1-(4-fluorobenzyl)-4-[(trifluoroacetyl)oxy]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin (E [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under a nitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). The resulting mixture was heated to 140° C. for 2 hours. It was quenched with water, and extracted with ethyl acetate three times. The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as brown glue (0.40 g, 35% yield). 1H NMR (MeOD) δ; 8.50 (s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J=6.8 Hz), 7.05 (t, 2H, J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz). LCMS (APCl, M+H+): 355.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]2=[O:15])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 84 %

Procedure:
A mixture of 3-(4-methoxyphenylamino)phthalic acid (0.52 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.30 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.58 g of the product, in 84% yield: mp 228-230° C.; 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.52-2.64 (m, 2H), 2.83-2.96 (m, 1H), 3.77 (s, 3H), 5.12 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 6.96-7.00 (m, 2H), 7.12-7.17 (m, 2H), 7.24-7.28 (m, 2H), 7.54 (t, J=7.9 Hz, 1H), 8.24 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.3, 110.6, 112.4, 114.7, 118.5, 125.3, 131.8, 132.4, 136.1, 144.3, 156.6, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C, 63.31; H, 4.47; N, 10.83.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[OH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[OH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: OCCN1CCNCC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCO)CC3)cc2)CC1
Yield: 82 %

Procedure:
By the same procedure as described in the example 19, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 1-(2-hydroxyethyl)piperazine. Then, the product was recrystallized using isopropanol and ether to give the desired compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[N:20][CH:21]=3)=[O:15])[C@H:11]([C:27]([F:30])([F:29])[F:28])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][O:33]2>>[CH:24]1([CH2:23][O:22][C:19]2[N:18]=[CH:17][C:16]([C:14](=[O:15])[CH2:13][N:12]3[C:4]4=[N:3][C:2]([N:36]5[CH2:37][C@@H:32]6[CH2:38][C@H:35]5[CH2:34][O:33]6)=[CH:7][C:6](=[O:8])[N:5]4[CH2:9][CH2:10][C@H:11]3[C:27]([F:29])([F:28])[F:30])=[CH:21][N:20]=2)[CH2:25][CH2:26]1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1
Agent: Cl
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1

Procedure:
160 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 58.66 mg (0.43 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 125 mg of (8S)-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([NH:18][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])[CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(N)ccn1
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)Nc2ccccc2)ccn1
Yield: 33.4 %

Procedure:
203 mg (1.5 mmol) of phenyl isothiocyanate was added to a solution of 186 mg (1.5 mmol) of 2-methoxy-4-aminopyridine in 15 ml of dry acetone. The mixture was then refluxed for 33 hrs. After cooling, solvent was evaporated off by distillation and the residue was chromatographed in a conventional manner using silica gel (solvent, CHCl3 :acetone=10:1 volume). Fractions were collected and solvent removed by distillation. The residue was recrystallized from ether to give the desired product having a melting point of 138°-141° C. in an amount of 130 mg (yield 33.4%).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO>CN(C)C=O>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]2[NH:20][C:14]3[C:15]([C:17](=[O:19])[C:26]=2[CH:25]=1)=[CH:16][C:8]1[NH:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][C:5]=2[C:10](=[O:11])[C:9]=1[CH:13]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 150 °C

Procedure:
A solution was prepared by mixing 2.0 g of 2,5-di-(p-toluidino)-terephthalic acid, 0.1 g of p-toluenesulfonic acid, 15 mL of ethylene glycol, and 20 mL of dimethylformamide. A fused silica glass capillary (equivalent diameter, 0.20 mm; and length, 4.0 m) was provided as a reactor, and was fixed in such a manner that a portion of 2.5 m length out of the whole capillary was immersed in an oil bath. The oil bath was heated to 150° C., and this solution was fed into the reactor at a flow velocity of 1.1 mL/hr (retention time: 5 minutes) with a syringe pump. A pigment having a vivid magenta color was obtained from the discharge port of the capillary.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>ClCCl>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][C:5]1[O:6][CH2:2][CH2:3][N:4]=1
Reactant: COc1ccccc1CN
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: COc1ccccc1CNC1=NCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Commercially available 2-chloroethylisocyanate (3.10 mL, 36.45 mmol) was added slowly to a solution of 2-methoxybenzylamine (5.00 mL, 36.45 mmol) in dichloromethane (60 mL) at room temperature. The resulting reaction mixture was stirred for 30 minutes and the intermediate product thus formed was filtered and washed with hexane, and then suspended in water (150 mL). This suspension was heated to reflux and stirred at refluxing for 2 hours, then cooled to room temperature. The reaction mixture was extracted with ethyl acetate, and the aqueous phase was basified with ammonium hydroxide to pH=14. The basified aqueous phase was then extracted with ethyl ether (50 mL) 3 times and the combined organic phases were dried with magnesium sulfate. Concentration gave 5.10 g of N-(2-methoxybenzyl)-4,5-dihydrooxazol-2-amine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ=3.80 (t, 2H, J=10.1 Hz), 3.85 (s, 3H), 4.26 (t, 2H, J=10.1 Hz), 4.38 (s, 2H), 6.83-6.95 (m, 2H), 7.20-7.32 (m, 2H).