Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:29])([F:28])C([O-])=O.[Na+].C(OCC)(=O)C.O>CN1CCCC1=O.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:24]([F:29])([F:28])[F:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: O=C([O-])C(F)(F)F
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(F)(F)F)nc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a solution of 0.8 g (2.17 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 12 ml 1-methyl-2-pyrrolidone, 2.36 g (17.4 mmol) sodium trifluoroacetate was added. After a solution had formed, 1.65 g (8.7 mmol) copper iodide was added and the reaction mixture was heated to 180 deg C. for 2 h. The mixture was cooled to room temperature, ethyl acetate and water were added and the suspension was filtered through a bed of dicalite speed plus. The phases were separated, the aqueous layer was washed with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel (0.032–0.063 mm) with tert-butyl methyl ether:n-hexane (1:5) as eluant to afford the desired compound as a colorless oil (27.7%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CS(C)=O>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
2,6-Dimethylpiperazine(3.43 g, 30.00 mmol) was added to ethyl 4-fluorobenzoate (1.101 mL, 7.5 mmol), in DMSO (10 mL) warmed to 120° C. under nitrogen. The resulting solution was stirred at 120° C. for 20 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by silica column chromatography, eluting with 10% methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (1.490 g, 76%) as a colourless solid.
Reaction SMILES: [NH2:1]CC1C=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29])C1C=CC=CC=1.O>C1C=CC=CC=1.C(OCC)C>[F:35][C:34]([F:37])([F:36])[CH2:33][O:32][C:26]1[CH:25]=[CH:24][CH:23]=[CH:31][C:27]=1[C:28]([NH2:1])=[O:29]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: NC(=O)c1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.2 g (0.0299 mole) of 2-aminomethylpyridine and 12.1 g (0.114 mole) of sodium carbonate in 100 ml of benzene is added dropwise a solution of 9.8 g (0.0285 mole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 30 ml benzene. The mixture is stirred for about 16 hours at room temperature. Water and diethyl ether are added. The ether layer is separated, washed with water, then with saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, and the magnesium sulfate is removed by filtration. The filtrate is evaporated to provide a white solid, 5-benzyloxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxybenzamide. The infrared and nuclear magnetic resonance spectra of this product are consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1CCN
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Forty (40) grams of 4-bromobenzoic acid was dissolved in 200 ml of dry dimethylformamide. While the solution was cooled with ice with stirring, 23 g of triethylamine and 22 g of ethyl chloroformate were added. After a lapse of 30 minutes, 28 g of 1-amino-2-(2-methylphenyl)ethane was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 50° to 60° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from cyclohexane to afford 49 g of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 101.5° to 103.0° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C:10]1([CH3:23])[CH3:22])C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C:10]1([CH3:23])[CH3:22]
Reactant: CC1(C)Oc2ccc(F)cc2NC(=O)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccc(F)cc2NC(=O)[C@H]1N

Procedure:
The title compound was prepared by hydrogenation of (−)-(S)-7-dibenzylamino-2-fluoro-6,6-dimethyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 225.3 (M+H+, 100).
Reaction SMILES: [O:1]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:19])=[CH:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:19])[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCCC2

Procedure:
2.6 g. of 7-(6,7-epoxy-3,7-dimethyl-2-nonenyloxy)-chromane are dissolved in 26 ml. of ethyl acetate and hydrogenated in the presence of 130 mg. of platinum oxide until the theoretical amount of hydrogen has been made up. The mixture is then filtered off from the catalyst, evaporated and chromatographed on silica gel with hexane/ether (7:3). There is obtained pure 7-(6,7-epoxy-3,7-dimethyl-nonyloxy)-chromane, nD20 = 1.5159.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:22][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:25][CH2:24]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-difluoromethoxy-3-hydroxy-benzaldehyde (5.0 g, 27 mmol) and potassium carbonate (5.5 g, 40 mmol) in dimethylformamide (30 ml) under inert atmosphere at 60° C. was added bromoethylcyclopropane (5 g, 37 mmol). The mixture was stirred and heated at 65° C. After 1.5 hour, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2×25 ml) and water (25 ml). The organic layer was washed with water (25 ml), brine (25 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde as an oil (6.4 g, 100%). 1H NMR (CDCl3): δ 0.38-0.44 (m, 2H), 0.62-0.75 (m, 2H), 1.15-1.36 (m, 1H), 3.98 (d, J=4.5 Hz, 2H), 6.78 (t, JH-F=75 Hz, 1H), 7.30-7.50 (m, 3H), 9.96 (s, 1H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[N:21]2[N:22]=[N:23][N:24]=[C:20]2[C:19]2[N:25]=[C:26]([CH2:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH2:30][OH:31])[C:18]=2[C:17]=1[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:56]1[C:60](=[O:61])[C:59]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:58]2[C:57]1=[O:66]>CN(C=O)C>[CH3:15][C:16]1[N:21]2[N:22]=[N:23][N:24]=[C:20]2[C:19]2[N:25]=[C:26]([CH2:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH2:30][O:31][N:56]3[C:60](=[O:61])[C:59]4[C:58](=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:57]3=[O:66])[C:18]=2[C:17]=1[CH3:35]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Diisopropyl azodicarboxylate (372 μL, 1.89 mmol) was added to a stirred solution of 3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-α]pyridin-7-yl)propan-1-ol (500 mg, 1.72 mmol), triphenylphosphine (496 mg, 1.89 mmol), and N-hydroxyphthalimide (308 mg, 1.89 mmol) in DMF (17 mL) at room temperature. After 4 hours, the solvent was removed under reduced pressure to afford an oil that was triturated with ethyl acetate to generate a pink solid. The solid was isolated by filtration and washed with ethyl acetate to yield 630 mg of 2-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-α]pyridin-7-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a pink powder.
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1)([CH3:6])[C:3]([OH:5])=[O:4].Cl[CH:26]1[C:35]2C(=CC=CC=2)CC[CH2:27]1>>[CH3:6][C:2]([O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:35][CH2:26][CH2:27]2)[N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: ClC1CCCc2ccccc21
Reactant: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Product: CC(C)(OCc1nn(C2CCCc3ccccc32)c2ccccc12)C(=O)O

Procedure:
The product was prepared according to the procedure described in Example 6b), using as starting material 2-methyl-2-[(1-benzyl-1H-indazol-3-yl)methoxy]propanoic acid as starting material and 1-chloro-1,2,3,4-tetrahydronaphthalene as reagent.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyanobenzyl bromide and tert-butyl glycinate. It was isolated as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 3.79 (s, 2H), 3.19 (s, 2H), 2.60 (br s, 1H), 1.41 (s, 9H). HPLC (Method A) Rt 2.17 min (Purity: 97.2%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[Cl:19][C:20]1[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][N:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([CH3:8])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Yield: 26.8 %

Procedure:
Triethylamine (31.8 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine-4-carbonyl chloride (20 g) and methylene chloride (1 liter) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was triturated under methylene chloride and the resultant solid was isolated and dried under vacuum at 40° C. There was thus obtained a second crop (8.13 g) of 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49 (m, 1H), 8.64 (m, 1H), 10.85 (s, 1H); Mass Spectrum: M+H+ 292 and 294.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:17](=[O:56])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:57]([OH:60])[CH2:58][CH3:59])[CH:15]=2)[N:10]=1)[CH2:6][CH2:7][CH3:8]>C1COCC1>[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:35]=[N:34][N:33]=3)=[CH:24][CH:25]=2)[C:17](=[O:56])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:57]([O:60][CH3:1])[CH2:58][CH3:59])[CH:15]=2)[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCCCc1nc2ccc(C(O)CC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(CC)OC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.556 ml of methyl iodide in 5.0 ml of THF is added 0.071 g of 60% sodium hydride followed by 0.657 g of 2-butyl-6-(1-hydroxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]4(3H)-quinazolinone. The reaction is stirred for 16 hours at room temperature, then quenched with saturated NH4Cl solution and extracted with ether. The organics are dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:5 ethyl acetate/hexanes to provide 0.59 g of the desired product as a white solid. FAB MASS SPEC 751(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][CH2:17][O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: COc1ccc2c(OCCBr)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
A mixture of 6-chloropyridazin-3(2 H)-one (3000 mg, 22983 μmol), K2CO3 (5000 mg, 36178 μmol), and 4-(2-bromoethoxy)-7-methoxyquinoline (6110 mg, 21656 μmol) in DMF (25 mL) was stirred at room temperature for 1.5 h. H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL). The organic layer was washed with H2O (50 mL), dried over Na2SO4, and concentrated to an orange oil. The oil was diluted with ether (40 mL) and the mixture was concentrated to slurry. Hexane (20 mL) was added and the mixture was agitated at 60° C. for 50 min and cooled to room temperature. The mixture was filtered, washed with ether to give a light tan solid (3.2 g). The filtrate was concentrated and partitioned between H2O (20 mL) and EtOAc (50 mL). The organic layer was washed with H2O and concentrated. The residue was triturated with acetone-hexane (1:2) to give a second crop of product (1.5 g). MS (ESI pos. ion) calc'd for C16H14ClN3O3: 331.1; found 332.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.93 (s, 3 H) 4.55 (t, J=5.28 Hz, 2 H) 4.67 (t, J=5.38 Hz, 2 H) 6.64 (s, 1 H) 6.94 (d, J=9.59 Hz, 1 H) 7.14 (dd, J=9.10, 2.45 Hz, 1 H) 7.18 (d, J=9.78 Hz, 1 H) 7.34 (d, J=2.54 Hz, 1 H) 8.05 (d, J=9.19 Hz, 1 H) 8.65 (d, J=5.28 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)[CH3:2].Cl.[C:25]([S:44][CH2:45][CH2:46][NH2:47])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH:47][CH2:46][CH2:45][S:44][C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:15])=[CH:9]2)[CH3:2]
Reactant: CCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
To a mixture of 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.43 g), 2-(tritylthio)ethylamine hydrochloride (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g), triethylamine (0.20 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.28 g) at 0° C., and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.89 g, quantitative) as colorless crystals. melting point 58-61° C.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:33](C(OC(C)(C)C)=O)[C:14]2=[N:15][C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:18]=[C:13]2[CH2:12][CH2:11]1)C.[OH-].[Na+].CO.Cl>CCO.O>[C:22]1([CH3:25])[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]3[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])[NH:33][C:14]3=[N:15][C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCCCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(CCCCCC(=O)O)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl 6-(6-ethoxy-6-oxohexyl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 4) (83 mg, 0.149 mmol) in EtOH (2 ml) was treated with 2M NaOH (0.223 ml, 0.446 mmol) and stirred at RT for 16 hours. MeOH (1 ml) and 2M HCl (0.372 ml, 0.744 mmol) were added and stirring continued at RT for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (30 ml). The mixture was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. The crude product was dissolved in EtOH (1 ml) and treated with 2M NaOH (0.223 ml, 0.446 mmol). After stirring at RT overnight, the mixture was diluted with water (30 ml) and the pH was adjusted to pH1 using 1 M HCl. The aqueous portion was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford an enantiomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:6][C:7]([O:10][CH2:13][CH:15]2[O:17][CH2:16]2)=[CH:8][CH:9]=1)[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC2CO2)cc1O

Procedure:
By refluxing 34 g of 2,4-dihydroxybenzoic acid methyl ester with 185 g of epichlorohydrin and 35 g of potassium carbonate for 2 to 3 hours, and chromatographing the crude product on 100 g of silica gel (elution with toluene), 4-(2,3-epoxypropoxy)salicylic acid methyl ester having a melting point of 53°-55° is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH2:6])[CH3:2].[CH2:26]([CH:36]1[CH2:41][C:40](=[O:42])[O:39][C:37]1=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:6][C:40](=[O:42])[CH2:41][CH:36]([C:37]([OH:39])=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:2]
Reactant: CCCCCCCCCCC1CC(=O)OC1=O
Reactant: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)OCC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CC(CCCCCCCCCC)C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
Nε-Lauroyl-L-lysine ethyl ester (29.9 g) was dissolved in dehydrated dichloromethane (650 ml), n-decyl succinic anhydride (21.2 g) was added, and the mixture was stirred at room temperature for 24 hr. The obtained white turbid solution was heated and cooled in a freezer to give crystals. The mixture was filtered, dried, and recrystallized to give Nε-lauroyl-Nα-(3-carboxytridecanoyl)-L-lysine ethyl ester (43 g, yield 85%). 4 g thereof was dissolved in distilled ethanol (100 ml), and 4M aqueous NaOH solution (1.68 ml) was added with stirring. The mixture was stirred at room temperature for 3 hr, filtered, dried under reduced pressure, and recrystallized. yield 4.1 g, 97%.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:23])([F:22])[F:21])=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][C:9](=[O:24])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:21])([F:22])[F:23])=[C:14]([NH2:17])[CH:15]=3)[NH:10][C:9](=[O:24])[C:8]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2C1CCCCC1
Yield: 100 %

Procedure:
8 g (22.4 mmol) of 1-cyclohexyl-6-trifluoromethyl-7-nitro-2,3(1H,4H)-quinoxalinedione dissolved in 200 ml of tetrahydrofuran were hydrogenated under a pressure of about 1 bar of hydrogen in the presence of 1 g of palladium/active carbon (10% by weight Pd) at room temperature. The reaction mixture was filtered. Conventional workup of the filtrate gave a 100% yield of the abovementioned compound.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2C#N)CC1
Temperature: 80 °C
Yield: 44.9 %

Procedure:
To a solution of 4-amino-2-fluoro-5-nitrobenzonitrile (132 mg, 0.730 mmol) and tert-butyl piperazine-1-carboxylate (136 mg, 0.730 mmol) in DMF (3 ml) was added triethylamine (0.102 ml, 0.730 mmol). The mixture was heated to 80° C. in a Microwave reactor for 50 min., cooled to r.t., purified by prep-HPLC to afford tert-butyl 4-(5-amino-2-cyano-4-nitrophenyl)piperazine-1-carboxylate (120 mg, 0.328 mmol, 44.9% yield). 1H-NMR (CD3OD, 500 MHz): δ 8.42 (1H, s), 6.45 (1H, s), 3.65-3.61 (4H, m), 3.28-3.25 (4H, m), 1.51 (9H, s). m/e (M+H): 348.3.