Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]([F:43])([F:42])[F:41])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][C:16]=3[F:35])[C:10]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:9]2)[CH:7]=1.[C:44](Br)(=[O:47])[CH2:45][CH3:46].C(Cl)Cl>CN(C1C=CN=CC=1)C.CO>[CH2:36]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:17][C:16]=2[F:35])[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:44](=[O:47])[CH2:45][CH3:46])[CH:3]=[CH:4][C:5]=2[C:40]([F:42])([F:41])[F:43])[N:9]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
The title compound was prepared by reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with propionyl bromide (3 equivalents) in the presence of DMAP (1.1 equiv) following the method of Example 69. Chromatographic purification of the crude product on silica gel (elution with 0.8% MeOH in CH2Cl2) afforded a nearly quantitative yield of off-white, stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 682 (M+Li)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 94.5 %

Procedure:
Hydrogenation of 1-(4-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)2.2.2-trifluoro-ethanone (2.0 g, 6.66 mmol) under a H2 atmosphere (40 psi) and 10% Pd/C (200 mg) in MeOH over 1.5 hours, filtration through Celite and concentration affords a yellow oil (1.7 g). (TLC 50% EtOAc/hexanes Rf0.27). 1H NMR (400 MHz, CDCl3) δ6.99 (m, 1H), 6.64 (br s, 1H), 6.57 (m, 1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.17-3.07 (m, 3H), 2.35 (m, 1H), 1.90 (d, J=10.8 Hz, 1H). GCMS m/e 270 (M+).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1>>[NH:2]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Cc1ccnc(Cl)c1
Reactant: NN
Solvent: O
Product: Cc1ccnc(NN)c1
Temperature: 25 °C

Procedure:
In a 25 mL recovery flask, hydrazine hydrate (5 g) was added, and then 2-chloro-4-methylpyridine (1.0 g, 7.84 mmol) was slowly added thereto at room temperature while stirring. After refluxing for three hours, the reaction mixture was cooled and extracted with chloroform twice. The organic phase was washed with saturated brine once and dried over, anhydrous magnesium sulfate. Then, the solvent was distilled off to give 2-hydrazino-4-methylpyridine (crude product).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[CH:12][CH:13]=1.[OH-].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)ccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
To a stirred solution of 66.32A (1.00 g, 3.5 mmol) in THF (70.0 mL) and MeOH (70.0 mL) at 0° C. was slowly added potassium hydroxide (1.9 mL, 3.8 mmol) to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then concentrated in vacuo, acidified with 1N HCl, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and to give a white solid 66.32B (0.90 g, 95% yield).
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:21]#[C:22][NH2:23].[Na].C>C1COCC1>[C:1]([NH:23][C:22]#[N:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: N#CN
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)NC#N
Reaction time: 63 h
Yield: 92.4 %

Procedure:
Stearoyl chloride (3.03 g, 0.010 mol) in 50 ml of freshly distilled dry THF was added drop-wise to a suspension of sodium cyanamide (1.92 g, 0.030 mol) in 100 ml of freshly distilled dry THF with vigorous stirring. The reaction was allowed to proceed at 25° C. for 63 hours. The solids which formed were collected by filtration and the solid cake was suspended in 200 ml of distilled water. The resulting soapy suspension (pH 10.5) was acidified to pH 1.5 with 10% HCl, filtered, and air-dried to give 2.85 g (92.4% yield) of crude 7. This was dissolved in THF and the solution decolorized with activated charcoal. The filtrate was concentrated until the solution became turbid. Addition of petroleum ether gave 2.29 g (crop 1) of white waxy 7. The filtrate was concentrated and petroleum ether added to give 0.28 g (crop 2) of additional product giving a total yield of 83.3%, mp 74°-75 ° C. TLC: Rf =0.69 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching (weak) and no color reaction with ferricyanide spray reagent; IR (Nujol, cm-1) 3210 (NH), 2250 (C≡N), 1735 (C=O); NMR (Silanor C, δ from TMS) 2.3-2.6 (t, --CH2 --CH2 --C=O), 1.0-1.8 (fused s, (CH2)14), 0.8-0.9 (t, CH3 --CH2 --); Anal. Calcd for C19H36N2O: C, 73.97; H, 11.76; N, 9.08. Found: C, 73.88; H, 11.50; N, 9.09.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C:5]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:6]#[N:7])[C:8]#[N:9]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1Cl
Yield: 35.9 %

Procedure:
Using 0.51 g of (2-chloro-4-fluorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(2-chloro-4-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (44)).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: OCC1CCNCC1
Reactant: Clc1nccnc1OC1CCCN(c2ccc3ccccc3n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: OCC1CCN(c2nccnc2OC2CCCN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (racemix mixture) (see PREPARATION P2.3; 0.1 g, 0.29 mmol) and piperidin-4-ylmethanol (0.033 g, 0.29 mmol) and K2CO3 (0.08, 0.58 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.020 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 420 calc. for C24H29N5O2 419.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:39](=[CH:40][C:41]=3[C:42]3[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:44][CH:43]=3)[N:38](COCC[Si](C)(C)C)[N:37]=[C:36]4[NH:64][C:65](=[O:69])[CH2:66][CH2:67][CH3:68])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:39](=[CH:40][C:41]=3[C:42]3[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)=[CH:44][CH:43]=3)[NH:38][N:37]=[C:36]4[NH:64][C:65](=[O:69])[CH2:66][CH2:67][CH3:68])=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12

Procedure:
16.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.9 g of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 100 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and is then allowed to return to room temperature and 100 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 25 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×20 cm 3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 700 mg of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals melting at 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,2-dibromoethane (0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 72 mg (yield 72%) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([S:14]([OH:17])(=O)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na]>>[CH2:7]([S:14]([Cl:2])(=[O:17])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCS(=O)(=O)O
Agent: [Na]
Product: CCCCCCCS(=O)(=O)Cl
Reaction time: 8 h

Procedure:
To phosphorous pentachloride (3.3 g, 16 mmol) was added solid heptanesulfonic acid, sodium salt monohydrate (1.75 g, 8 mmol) and the mixture was left to stir overnight under nitrogen. Phosphorous oxychloride was removed by distillation at 150° C. for 3 h. The residue was distilled under reduced pressure (ca. 5 mm Hg) at 135° C. to give ca. 1 g of material which was allowed to cool to room temperature. The precipitated free acid was removed by filtration to afford the title compound as an oil (500 mg, 31%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 100 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (0.9 g) in CH2Cl2 (25 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.332 g), and methanesulfonyl chloride (0.365 g). After two hours the reaction mixture was washed with water (3×20 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].P(=O)(O)(O)[OH:31]>C1COCC1>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][C@@H:10]([CH3:26])[C:9]([OH:27])=[O:31])=[CH:19][CH:18]=1
Reactant: O=P(O)(O)O
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2-a, R1=BOC) was dissolved in 50 ml of a mixture of THF and a 2 M lithium hydroxide solution (ratio 1:1). After 1 hour at room temperature, phosphoric acid was added to neutralise the excess of lithium hydroxide. The slurry was concentrated under vacuum to remove most of the solvent and extracted with iso-propyl acetate. The organic phase was then washed with water, partially concentrated under vacuum and brought to crystallisation upon addition of heptane. The crystalline solid obtained was collected and dried under vacuum to yield about 3.6 g of [(2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid] (3-a, R1=BOC, R2=R3=H). Mpt 146-147° C.; δH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19). Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([N:32]3[C:36](=[O:37])[CH:35]=[CH:34][C:33]3=[O:38])=[CH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[N+:39]([O-:41])=[O:40]>>[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([N:32]3[C:36](=[O:37])[CH2:35][CH:34]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:33]3=[O:38])=[CH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[N+:39]([O-:41])=[O:40]
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: Nc1nc(NCCNc2ncc(N3C(=O)CC(N4CCOCC4)C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
Large excess of morpholine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain 1-[2({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-morpholin-4-ylpyrrolidine-2,5-dione.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=1>C(O)C.O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]2[CH:7]=[C:2]3[N:1]([CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Cc1ccccn1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc3ccccn3c2)cc1
Yield: 83.4 %

Procedure:
10 g of 2-picoline and 25 g of 4-methoxyphenacyl bromide in 35 ml of ethanol were refluxed for 18 hours. The reaction solution was concentrated under reduced pressure to give a solid, which was dissolved in 350 ml of water. After the aqueous solution was extracted with three 35 ml portions of ether, 35 g of sodium bicarbonate was added to the aqueous solution and was refluxed two hours. The cooled reaction mixture was filtered to give 20 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2c(c1)NCCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To 7-bromo-1,2,3,4-tetrahydroquinoline (1E) (1.0 g, 4.7 mmol) in DCM (30 mL) was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12 mmol), and pyridine (1.0 mL, 10.0 mmol). The reaction was allowed to stir at rt for 24 hours while monitoring by LCMS. To the reaction mixture was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12.0 mmol), and pyridine (1.0 mL, 10 mmol). The reaction was allowed to stir at rt for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 1.09 g (91%) of the desired product 1-(7-bromo-3,4-dihydroquinolin-1(2H)-yl)ethanone (1F): LC/MS (APCI): m/z 255.7 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1ccnc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccnc3cccnc23)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A mixture comprising 150 mg (0.911 mmole) of 4-chloro-1,5-naphthyridine and 1.00 g of 4-fluorophenol was heated at 160° C. After one hour, the mixture was cooled and dissolved in ethyl acetate and 2N sodium hydroxide. The organic layer was washed twice with base to remove excess 4-fluorophenol. The organic layer was then dried with magnesium sulfate and concentrated, producing an oil that slowly crystallized. This product was recrystallized in heptane, giving 103 mg of the title product. MP 122°-124° C. Yield 47%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:31][C:32](=[NH:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:32]([NH:44][O:25][C:24]([C:23]1[CH:22]=[C:21]([CH:29]=[CH:28][CH:27]=1)[CH2:20][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])(=[NH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1cccc(C(=O)O)c1
Reactant: CCCCCCCCCCCC(=N)NO
Product: CCCCCCCCCCCC(=N)NOC(=O)c1cccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 3-({(tert-butoxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and N-hydroxydodecanimidamide gave the title compound as a pale yellow oil (99%). 1H NMR (CDCl3, 300 MHz) δ 7.91 (m, 2H), 7.59 (m, 2H), 7.36 (m, 4H), 4.78 (br s, 2H), 4.48 (br s, 2H), 4.41 (br s, 2H), 2.34 (m, 2H), 1.65 (m, 2H), 1.50 (s, 9H), 1.26 (br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Rt: 7.34 min (HPLC purity: 95.6%).