Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[CH2:11](O)[CH3:12]>>[Cl:1][CH2:11][C:12]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1
Reactant: Nc1ccc(O)cc1O
Reactant: CCO
Reactant: Cl
Product: Oc1ccc2nc(CCl)oc2c1

Procedure:
1.78 g (11.3 mmol) of said ethyl chloromethylimidate hydrochloride, 1.22 g (7.55 mmol) of 4-aminoresorcinol hydrochloride, and 20 ml of ethanol were introduced into a two-necked flask provided with a Dimroth condenser, and the mixture was refluxed with heat in argon atmosphere for a whole day and night. After completion of the reaction and cooling, the crystal was filtered and washed with hexane, then the object was vacuum dried. There was obtained 0.40 g (2.33 mmol) of 2-chloromethyl-6-hydroxybenzoxazole, and the yield of the reaction was 30.9%.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH:9]1C(O)=O.NC1C=CC(C2[NH:25][C:26]3[CH:32]=[CH:31][C:30](N)=[CH:29][C:27]=3[N:28]=2)=CC=1>CN(C=O)C.N1C=CC=CC=1>[C:1](=[C:2]1[N:28]=[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]2=[N:25]1)=[O:5].[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH2:9]1.[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(C(=O)O)C1(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1(C)CC1(C)C
Product: O=C=C1N=c2ccccc2=N1
Temperature: 60 °C

Procedure:
Bis-(2,2,3,3-tetramethylcyclopropane) carbonyl benzimidazole was synthesized as follows: oxalyl chloride (1.07 ml, 2 M in CH2Cl2) was added to 2,2,3,3-tetramethylcyclopropane carboxylic acid (0.305 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed to react at RT for 1 hour. To the above solution was added 2-(4-aminophenyl)-6-amino benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The reaction was heated to 60° C. overnight. The reaction was cooled and the precipitate filtered and washed with NaHCO3 and hexanes. The resulting solid was purified by preparative HPLC to yield a solid that was >99% pure.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[C:8]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:20])[NH:13]2.[H][H].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1>CN(C=O)C>[Cl:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][N:13]2[C:14]3[C:9](=[C:8]([CH:4]4[O:5][CH2:6][CH2:7][O:3]4)[CH:17]=[CH:16][C:15]=3[O:18][CH3:19])[CH2:10][CH2:11][C:12]2=[O:20])=[CH:28][CH:29]=1
Reactant: COc1ccc(C2OCCO2)c2c1NC(=O)CC2
Reactant: [H][H]
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(Cl)nc1)C(=O)CC2
Temperature: 0 °C
Yield: 78.7 %

Procedure:
Sodium hydride (55% in oil) (2.1 g) was added in small portions under ice cooling to a DMF solution (70 ml) of 5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one (10 g), and stirring was carried out at room temperature until the generation of hydrogen stopped. The resulting mixture was cooled with ice again, and a DMF solution (30 ml) of 2-chloro-5-chloromethyl pyridine (9.74 g) was added dropwise. After stirring at room temperature for 4 hours, the reaction mixture was poured into ice water, and the produced insoluble matter was collected by filtration. The solid was washed with water and diethyl ether and dried to thereby obtain 11.84 g (yield: 79%) of 1-(6-chloropyridin-3-ylmethyl)-5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one as a light yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([Br:1])[N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: C=C[C@@H](Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
N-Bromosuccinimide (3.63 g) was added to a solution of (S)-tert-butyl (1-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (7.98 g) obtained in Step 3 in DMF (64 ml) at −15° C., and the mixture was stirred at −15° C. for 1 hour. A 10% aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction mixture, and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The resulting organic layer was washed with a saturated sodium chloride solution twice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound (6.30 g) as a light-brown solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-:12].[Na+]>OO>[CH:9]1[CH:10]=[C:2]([C:1]([OH:6])=[O:11])[C:3]([C:4]([O:12][O:12][C:4]([C:3]2[C:2]([C:1]([OH:6])=[O:11])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:5])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: O=C1OC(=O)c2ccccc21
Agent: OO
Agent: [Na+]
Product: O=C(O)c1ccccc1C(=O)OOC(=O)c1ccccc1C(=O)O
Reaction time: 0.42 h

Procedure:
Diphthaloyl peroxide was prepared by adding finely powdered phthalic anhydride (7.2g) gradually over a period of five minutes to a solution of hydrogen peroxide (0.46% by weight, 90 cm3) maintained at a temperature of between 1° to 3° C by the use of a cooling jacket, and the pH of 9 plus or minus 0.2 by dropwise addition of sodium hydroxide sufficient to counteract the generation of acidity as the reaction proceeded. The solution was stirred constantly, so that the proportion of the finely powdered phthalic anhydride which did not go into solution, remained in suspension, and the temperature and pH were controlled for a further 25 minutes, by which time substantially all the hydrogen peroxide had been consumed. The suspension was filtered into sulphuric acid (10% by weight, 30 cm3) and substantially all the diphthaloyl peroxide precipitated out. The solid which had been filtered off was washed with water and then dried to recover phthalic anhydride (3.03g). The acidified filtrate was centrifuged and the precipitate, separated thereby, was washed with water (40 cm3) and dried giving diphthaloyl peroxide (3.l g). An iodometric assay of the crude product showed that it contained 89.1% of active material, and negligible amount of monoperoxyphthalic acid, giving a reaction yield of 59.4%, based on consumption of phthalic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7](C)=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24].[CH3:29]S(C)=O>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH2:29][NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][CH:7]=[N:6][C:5]=1[O:12][C:13]1[C:14]([CH3:21])=[CH:15][C:16]([Cl:20])=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CS(C)=O
Reactant: CCC(N)CC
Product: CCC(CC)NCc1ccnc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride, water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to give 140 mg of yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 43.6 %

Procedure:
Using a method similar to Example 334, and using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3S)-1-benzylpyrrolidin-3-yl amine (0.21 mL, 1.22 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.214 g (43%) of the title compound as a white foam (chromatography solvent: ethyl acetate→19:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2144; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3. Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t, 2H, J=6.8 Hz). 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: [C:1]([CH:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Mg].[Cl-].[NH4+].[O:25]1CCCC1>>[OH:25][C:2]1([CH:1]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NC(C(=O)c2ccccc2)CO1
Reactant: C1CCOC1
Reactant: BrC1CCCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: O=C1NC(C(c2ccccc2)C2(O)CCCCC2)CO1

Procedure:
5.0 g (0.0262 mole) of 4-benzoyl oxazolidin-2-one dissolved in 100 ml of absolute tetrahydrofuran are added dropwise while cooling with ice to a Grignard solution prepared from 12.8 ml (0.127 mole) of bromocyclohexane and 2.98 g (0.128 gram equivalent) of magnesium in 150 ml of absolute tetrahydrofuran. This solution is stirred for 2 hours at 60° C, subsequently hydrolysed with approximately 500 ml of a saturated ammonium chloride solution and repeatedly extracted with chloroform. The organic phases are combined, dried over Na2SO4 and concentrated in a rotary evaporator. The oil is taken up in ether. The crystals formed are filtered off under suction.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][C:23]([F:29])=[C:22]([N+:30]([O-:32])=[O:31])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (1.0 g, 4.21 mmol) in THF (20 mL) was dropwise added LHMDS solution (5.1 mL, 5.1 mmol, 1 M in THF) at −78° C. After stirring at −78° C. for 30 min, a solution of 2,3,4,6-tetrafluoronitrobenzene (0.823 g, 4.21 mmol) in THF (5 mL) was added drop wise into the reaction mixture, which was slowly warmed to room temperature and stirred for 16 h. After completion (as indicated by TLC), the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was triturated with hexane to yield 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (0.748 g). 1H-NMR (400 MHz, CDCl3): δ 6.71-6.76 (2H, m), 7.40 (1H, d, J=8.8), 7.46 (1H, d, J=10), 7.69 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CC1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC1COS(C)(=O)=O
Reaction time: 8 h
Yield: 99 %

Procedure:
To a reaction solution of ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (4-1) (577 mg; 4.0 mmol) with Et3N (1.1 mL; 8.0 mmol) and DMAP (49 mg; 0.4 mmol) in 12 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.4 mL; 4.8 mmol). The resulting mixture of brown color suspension was stirred at 0° C. to room temperature under N2 for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2Cl2 (200 mL) and saturated NaHCO3 solution (50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane:EtOAc/1:1. The filtrate was concentrated by vacuum to give 880 mg of ethyl 2-{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate as a yellow oil (99% yield). 1H NMR (400 MHz, chloroform-D) δ ppm 0.91-1.02 (m, 1H) 1.26 (q, J=6.99 Hz, 3H) 1.29-1.36 (m, 1H) 1.63-1.74 (m, 1H) 1.79-1.92 (m, 1H) 3.02 (s, 3H) 3.99-4.24 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:5]([CH2:4][CH2:3][CH2:2][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: O=S(=O)(CCCCl)c1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A solution of 17.8 g (0.07 mole) of 1-chloro-3-(p-chlorophenylsulfonyl)propane and 15.2 g (0.082 mole) of potassium phthalimide in 300 ml of dimethylformamide was stirred at 90°-110° C. for 2 hr and then quenched in water. The mixture was extracted with methylene chloride and the methylene chloride layer dried over magnesium sulfate. Diethylether and hexane were added and the solution stored at 0° C. overnight. The crystalline product was recrystallized from methylene chloride diethyl ether to give a white crystalline product, m.p. 187.5°-188.5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 40, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (336 mg) as a foamy white solid. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.42 (s, 3H) 2.46 (td, J=5.84, 0.80 Hz, 2H) 2.58 (td, J=5.78, 1.13 Hz, 2H) 3.52-3.63 (m, 2H) 3.63-3.72 (m, 2H) 6.45 (s, 1H) 6.65 (dt, J=8.21, 0.69 Hz, 1H) 6.90-6.97 (m, 2H) 6.99 (dt, J=7.16, 0.48 Hz, 1H) 7.04-7.11 (m, J=8.10, 1.21, 0.84, 0.63 Hz, 1H) 7.36 (dd, J=8.86, 7.71 Hz, 1H) 7.59 (dd, J=9.11, 4.65 Hz, 1H) 7.68 (dd, J=8.08, 7.52 Hz, 1H) 8.12 (d, J=8.87 Hz, 1H) 8.79 (d, J=3.90 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]#N)[CH:27]=3)[C:22]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].[OH-:46].[Na+].[CH3:48][OH:49]>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([C:36]([O:49][CH3:48])=[O:46])[CH:27]=3)[C:22]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CO
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C#N)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: [OH-]
Agent: [Na+]
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(=O)OC)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,4S)-4-{(3-Cyano-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (315 mg) is dissolved in methanol (9 ml), and thereto is added 1N aqueous NaOH solution (1 ml). The mixture is stirred at room temperature for 1 day, and partitioned by adding 1N HCl and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→3:7→0:1) to give (2R,4S)-2-ethyl-6-methoxy-4-{(3-methoxycarbonyl-5-trifluoromethylbenzyl)-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (54 mg). MS (m/z): 659 [M+H]+.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[CH:26]=[C:25]([C:35]([O:37]C)=[O:36])[C:24]4=[O:39])[CH2:17][CH2:16]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[OH-].[Na+]>O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[CH:26]=[C:25]([C:35]([OH:37])=[O:36])[C:24]4=[O:39])[CH2:19][CH2:20]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(=O)O)c(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To 1 mL of a methanol solution containing 0.20 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, 0.5 mL of 20% aqueous sodium hydroxide solution was added and stirred for 1 hour. 3 mL of water was added, removed methanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]#[N:31])[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=3)[CH2:8][CH:7]1[C:24]([OH:26])=[O:25].[N:32]1C=NC=N[CH:33]=1.CC(O)=O>CCO>[NH2:31][C:30]1[C:29]2[C:2](=[CH:3][C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]4[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=5)[CH2:8][CH:7]3[C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[N:1]=[CH:33][N:32]=1
Reactant: N#Cc1ccc(CN2C(=O)CN(Cc3cc4cc(Cl)ccc4[nH]3)CC2C(=O)O)cc1N
Reactant: c1ncncn1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2cc(CN3C(=O)CN(Cc4cc5cc(Cl)ccc5[nH]4)CC3C(=O)O)ccc12
Temperature: 25 °C
Yield: 9.3 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acid (200 mg, 0.30 mmol), 1,3,5-triazine (244 mg, 3.00 mmol), and glacial HOAc (180 mg, 3.00 mmol) in absolute EtOH (20 mL) is maintained at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and the solid is collected on a Buchner funnel and washed with EtOH followed by diethyl ether. Oven-drying in vacuo provided 13 mg (76%) of the title compound as an off-white solid. 1H NMR (300 MHz, d6-DMSO) δ2.63 (m, 1H), 3.06 (d, J=16.4 Hz, 1H), 3.24-3.42 (m, 4H), 3.68 (ABq, ΔAB=34.5 Hz, JAB=14.1 Hz, 2H), 3.96 (m, 1H), 4.63 (ABq, ΔAB=400 Hz, JAB=15.8 Hz, 2H), 6.27 (s, 1H), 6.99 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.40 (s, 1H), 7.46 (s, 1H), 7.69 (br s, 2H), 8.10 (d, J=8.5 Hz, 1H), 8.32 (s, 1H), 11.20 (s, 1H) ppm; MS (ion spray): m/z 465 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]12[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH:22]C(=O)O[C:18]2=[O:19].C1(C)C=CC=CC=1>CCOCC>[C:18]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12]1)(=[O:19])[C:17]1[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH2:22]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: OCCN1CCN(c2cccc(Cl)c2)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 70 %

Procedure:
7.2 G. (0.03 mol) of 2-(4-m-chlorophenyl-piperazino)-ethanol and 6.55 g. (0.04 mol) of isatoic anhydride in 125 ml. of toluene are refluxed for 3 hours. The hot toluene solution is filtered and the toluene is evaporated from the filtrate to give a residue which is taken up in ether in order to remove a small amount of unreacted isatoic anhydride, the solution is filtered and the ether is driven off. The remaining product is triturated in petroleum ether, filtered off and recrystallised twice from isopropyl alcohol to give 7.6 g. (yield = 70%) of 2-(4-m-chlorophenylpiperazino)-ethyl anthranilate, which melts at 76°C.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.CC1C=C(C)C=C(C)N=1>C(Cl)Cl.[Cu-]=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])=[CH:13][CH:12]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:4]2[C:5](=[O:6])[C:7]([CH3:8])=[CH:9][NH:1][C:2]2=[O:3])=[CH:13][CH:12]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: Fc1ccc(I)cc1
Agent: O=[Cu-]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1c[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Product: Cc1cn(-c2ccc(F)cc2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
A mixture of thymine (5 g, 39.6 mmol), 1-fluoro-4-iodobenzene (9.68 g, 5 mL, 43.6 mmol), copper(I) oxide (6.24 g, 43.6 mmol) and 2,4,6-trimethylpyridine (200 mL) was heated 12 hours at reflux with stirring and under an argon atmosphere. The reaction mixture then was cooled to 25° C., diluted with methylene chloride (300 mL), washed with 5% sulfuric acid (5×300 mL) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give 1-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (1.85 g, 9.2 mmol), m.p. 212°-214° C., and 3-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (2.39 g, 10.2 mmol), m.p. 229°-231° C.