Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:48]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>>[Cl:48][CH:31]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:47][CH:46]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[N:20][CH:19]=1)[C:32]([F:35])([F:34])[F:33]
Reactant: ClCCl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (0.172 g, 0.266 mmol) in dichloromethane (3.00 mL, 0.266 mmol) was added triethylamine (0.093 mL, 0.664 mmol) and methanesulfonyl chloride (0.042 mL, 0.531 mmol) at 0° C. and the mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with saturated NH4Cl and water at 0° C., and the separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were dried over Na2SO4, and concentrated and dried under vacuum to give the crude 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.177 g, 0.0266 mmol), which was used directly in the next step without further purification.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.O[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:28]([C:24]1[CH:23]=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[CH:17]=2)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: N#Cc1cccc(-c2cccc(O)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of 1.210 g (5.99 mmol) of diisopropyl azodicarboxylate is added dropwise to a solution, cooled to 0° C., under an argon atmosphere, of 0.974 g (4.99 mmol) of 3′-hydroxybiphenyl-3-carbonitrile, 1.205 g (5.99 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate and 1.570 g (5.99 mmol) of triphenylphosphine in 12 ml of tetrahydrofuran. The mixture is subsequently stirred at ambient temperature overnight. 15 g of silica are added and the mixture is evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with a 10:90 and then 15:85 mixture of ethyl acetate and cyclohexane, in order to obtain 1.538 g (4.06 mmol) of product in the form of a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:2]1
Reactant: CI
Reactant: N#CC1(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2(C#N)CC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
1-(1H-indole-3-yl)cyclopropanecarbonitrile (183 mg) was dissolved in N,N-dimethylformamide (2 mL) and sodium hydride (60% in oil, 45 mg) was added under ice cooling, followed by stirring for 5 minutes. To the reaction solution, methyl iodide (0.07 mL) was added, followed by stirring at room temperature for one hour. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (parallel separation purification system) to obtain the titled compound having the following physical properties (196 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:22][CH3:23])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(-c2ccc(OC)c(OC)c2)cc(=O)n1C
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.17 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to ambient temperature. To the mixture was added ethyl iodide (5 ml) with stirring, which was continued at ambient temperature for 3.5 hours. To the reaction mixture was added water, and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether and the resulting precipitates were collected by filtration to give 6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4(3H)-pyrimidinone (0.18 g) as by-product.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:8])[CH:7]=1.[CH3:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C.C(OCC)(=O)C>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][O:31][CH:26]([CH3:25])[CH2:27]3)[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=1
Reactant: CC1CNCCO1
Reactant: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nn2c(O)cc(N3CCOC(C)C3)nc2c1Cc1cccc(C(F)(F)F)c1C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 0.17 mmol), prepared as described in Example 1, step d, in ethanol (1.5 mL) was added 2-methylmorpholine (85 mg, 0.84 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 145° C. for one hour. The reaction mixture was diluted with ethyl acetate (15 mL), washed with 5% HCl solution (3 mL). Organic layer was dried, filtered, and concentrated to dryness. The crude was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 39%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, MeOD) δ ppm 1.17 (br. s., 2H) 1.19 (d, J=1.26 Hz, 1H) 2.13 (br. s., 3H) 2.47 (br. s., 3H) 2.66 (t, J=11.62 Hz, 1H) 2.68 (br. s., 1H) 2.94-3.06 (m, 1H) 3.63 (br. s., 3H) 4.01 (br. s., 2H) 7.11 (br. s., 1H) 7.23 (br. s., 1H) 7.51 (br. s., 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-])=O)=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.[OH-].[Na+].O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c([N+](=O)[O-])cc3F)CC2)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c(N)cc3F)CC2)CC1
Reaction time: 20 h

Procedure:
60a obtained in the previous step was dissolved in acetonitrile (4 mL) and treated with Na2S2O3 (0.42 g) in 1N NaOH (4 mL). After 20 h, the mixture was poured in water and extracted with EtOAc twice. The combined extracts were dried and concentrated to afford the crude 60b.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2F)CC1)c1ccccc1
Yield: 56.7 %

Procedure:
0.2 g (0.000956 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.17 g (57%) of 1-(2-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10]SC.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([S:10][CH3:9])=[CH:7][N:6]=1
Reactant: CSSC
Reactant: Clc1ncc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1cnc(Cl)nc1
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A solution of 1.00 g (5.17 mmol) of 5-bromo-2-chloropyrimidine and 551 μl (6.20 mmol) of dimethyl disulfide in 26 ml of tetrahydrofuran was cooled to −78° C. and 1.89 ml (5.17 mmol) of 2.73 N n-butyl lithium/n-hexane solution was added thereto, and the reaction solution was stirred for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 149 mg of the title compound as a white solid (yield: 18%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[S:17]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])(=[O:18])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A stirred solution of 13.9 g of tetrahydro-2-pyranylmethanol and 18.2 g of triethylamine in 250 ml of methylene chloride was cooled to -10° C. and 15.1 g of methansulfonyl chloride was added dropwise over 5 minutes while maintaining the temperature at -10° C. to 0° C. using a cooling bath. The bath was removed and the mixture was stirred for 1/2 hour while the temperature reached 16° C. The reaction mixture was washed successively with 150 ml of ice water, 150 ml of 10% hydrochloric acid solution, 150 ml of saturated sodium bicarbonate solution and 150 ml of saturated sodium chloride solution, then dried (MgSO4) and evaporated under vacuum at 50° C. to give 23.7 g of a yellow oil, which was Claisen distilled to yield 19.7 g of the desired product; b.p. 110° C. (0.2 mm).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:17]=1.Cl>CN(C)C=O>[Cl:15][C:16]1[N:17]=[C:18]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:19]=[C:20]([NH:14][S:11]([CH:10]=[CH:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:13])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
Sodium hydride (60%) (480 mg) was added to a solution of 1.00 g of 2-phenylethenesulfonamide in 10 ml of dimethylformamide with ice cooling followed by stirring at room temperature for 15 minutes. To this reaction solution was added 1.91 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine with stirring. The reaction mixture was stirred at room temperature for 2.5 hours and poured into a mixture of 1N hydrochloric acid and ice. The resulting crystals were collected by filtration and pulverized in hot ethanol. After allowing to cool, the crystals were collected by filtration to give 1.91 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.C[CH2:14][N:15](CC)[CH2:16]C.CNC.C1COCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH3:16])[CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) and Et3N (1.5 mL, 11 mmol) in dichloromethane (10 mL) was added a solution of dimethylamine 2.0 M in THF (2.2 mL, 4.4 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was washed with 10 mL of 1N aqueous HCl and 10 mL of brine. Organics were dried over Na2SO4 and evaporated to dryness. Crude product was purified by chromatography on silica gel (eluting with 0-25% ethyl acetate in hexanes) to afford 4-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (780 mg, 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.4 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.7 mg, 2.4%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CN([C:17]([O:21][N:22]1N=NC2C=CC=N[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CONC>CN(C=O)C>[CH3:17][O:21][N:22]([CH3:23])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:13]
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol. 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and O,N-Dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then the solvent was concentrated. The residue was purified via flash column (PE/EA=2/1, v/v) to afford N-methoxy-N-methylquinoxaline-6-carboxamide as a yellow solid (5.1 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34](O)=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:57][S:54]([CH:51]4[CH2:53][CH2:52]4)(=[O:56])=[O:55])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
A solution of 50 (151 mg, 0.257 mmol) and carbonyldiimidazole (162 mg, 0.437 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (58 mg, 0.482 mmol) and DBU (76 mg, 0.502 mmol) were added. The resulting solution was stirred at 50° C. for 12 h, then cooled to room temperature. The reaction mixture was quenched with water and extracted with AcOEtethyl acetate, dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2/EtOAc, 95:5). The solid obtained was triturated in water, filtered, dried under high vacuum, triturated in diethylether and dried again under high vacuum to give 138 mg (77%) of the title product 51 as a white powder: m/z=691 (M+H)+; 1H-NMR (CDCl3): 10.70 (br s, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.97 (d, J=6.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 6.70 (bs, 1H), 5.88 (bs, 1H), 5.74 (dd, J=17.3 Hz, 8.3 Hz, 1H), 5.16 (t, J=10.4 Hz, 1H), 4.74 (dd, J=9.4 Hz, 7.3 Hz, 1H), 4.11-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.89 (m, 1H), 2.83 (s, 3H), 2.58-2.35 (m, 3H), 2.29-2.13 (m, 1H), 2.11-1.92 (m, 2H), 1.75-0.76 (m, 9H).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([O:26][CH:27]1[CH2:30][NH:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([O:26][CH:27]1[CH2:28][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:30]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc(COC2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-(benzyloxy)azetidine hydrochloride (58 mg, 0.29 mmol; which may be prepared as described in Step 2), DIPEA (96 μL, 0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by precipitation in MeOH/H2O and then triturated in acetone/diethyl ether to give the title compound as a beige solid (33 mg, 38%).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:27][CH3:28])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of 0.237 part of 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylic acid and 0.83 part of pulverized potassium carbonate in 6 parts by volume of dry dimethylformamide is stirred under heating at 100° C for 1 hour. To the mixture is then added 0.3 part by volume of diethyl sulfate. The mixture is stirred under heating at 100° C for 1 hour and filtered to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure and the residue is extracted with chloroform. Evaporation of the solvent from the extract gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142° C.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:30]OCCOC.[N+](=C)=[N-]>C(O)(=O)C.CCOCC>[CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([O:27][CH3:30])=[O:26])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)O)c1
Reactant: COCCOC
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 400 mg. of N-decyl-3-(3-[cis-3-carboxypropenamido]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2ccc(Cl)cc2Cl)ccc1Oc1cncc(Cl)c1
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of the aniline produced in Example 1 (100 mg, 0.34 mmol) in CH2Cl2 (2 mL) was added pyridine (81 μL, 1 mmol) and 2,4-dichlorobenzoyl chloride (140 mg, 0.68 mmol). The mixture was stirred for 90 min. The product was purified by column chromatography on silica gel (gradient elution: 30:1 hexane/ethyl acetate to 7:1 hexane/ethyl acetate) followed by recrystallization from Ch2Cl2/hexanes to yield 126 mg (79%) of the title compound. mp 125-127° C.