Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:19](=[O:21])[CH3:20])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 8.0 g (42 mmol, 1.0 eq.) of (4-nitrophenyl)methanamine hydrochloride in 40 mL of methylene chloride and 28 mL (340 mmol, 8.0 eq.) of pyridine was added 16 mL (170 mmol, 4.0 eq.) of acetic anhydride. The mixture was stirred at room temperature for 16 h and diluted with 200 mL of methylene chloride. The organic solution was washed with sat. brine and dried (Na2SO4). The solvent was removed in vacuo to provide 8.0 g (41 mmol, 98%) of N-(4-nitrobenzyl)acetamide (I-21).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCNCC1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC(CC(=O)O)CC1

Procedure:
4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from Preparative Example 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml) (33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd-C at 55 psi at 25° C. for 68 hours. The catalyst was filtered off and washed with water. The combined filtrates were evaporated to dryness to give the title compound (MH+ 158).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2C(OC(C)(C)C)=O)[CH:13]=[CH:14][CH:15]=1.C(O)(C(F)(F)F)=O.[Cl:40]CCl>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[NH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3F)c2)CC[C@]12CCNC2=O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1NCC[C@]12CC[C@H](c1cccc(OCc3ccccc3F)c1)N2

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(3-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D46, 200 mg, 0.45 mmol) in dichloromethane (2 mL) cooled at 0° C., was added TFA (0.4 mL) dropwise and the ice-bath removed. After 1 h the solvent was evaporated under vacuum and the crude mixture purified by SCX column to give the title compound as the free base (154 mg, quant.); Rt (HPLC) 3.58 min. The free base (77 mg, 0.23 mmol) was dissolved in dichloromethane (2.5 mL), and o the resulting solution cooled at 0° C. HCl (0.29 mL of a 1M solution in diethyl ether, 0.29 mmol) was added dropwise. After 15 min the solvent was removed under reduced pressure and the resulting solid triturated with diethyl ether to give the title compound (68 mg, 80%); Rt (HPLC) 3.72 min. MS: (ES/+) m/z: 341 [MH+]; C20H21FN2O2 requires 340; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 10.13 (br. s., 1H), 8.94 (br. s., 1H), 8.39-8.53 (m, 1H); 7.57 (t, 1H), 7.41-7.47 (m, 1H); 7.38 (t, 1H), 7.31-7.35 (m, 1H); 7.22-7.30 (m, 2H); 7.17 (d, 1H), 7.10 (d, 1H), 5.13-5.18 (m, 2H); 4.72 (br. s, 1H), 3.34-3.41 (m, 2H); 2.25-2.68 (m, 5H), 2.12 (br. s, 1H).
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])=[CH:7][CH:6]=1)C.NC1C=CC([C:24]([O:26][CH2:27][CH3:28])=[O:25])=CC=1.C(#N)CC#N.O.[NH2:37][NH2:38]>>[CH2:27]([O:26][C:24](=[O:25])[C:7]1[CH:6]=[CH:5][CH:10]=[CH:9][C:8]=1[NH:11][N:12]=[C:13]1[C:14]([NH2:15])=[N:38][N:37]=[C:16]1[NH2:17])[CH3:28]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: NN
Reactant: CCOC(=O)c1ccc(NN=C(C#N)C#N)cc1
Solvent: O
Solvent: N#CCC#N
Product: CCOC(=O)c1ccccc1NN=C1C(N)=NN=C1N
Yield: 33 %

Procedure:
This compound was prepared using 121 mg (0.5 mmol) of 4-(N′-dicyanomethylene-hydrazino)benzoic acid ethyl ester, which was derived from ethyl 4-aminobenzoate (165 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 45 mg (33%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][OH:23])[C:16]=1[CH3:24]>O.O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([OH:23])[C:3]([NH:2][CH3:1])=[O:4])[C:16]=1[CH3:24]
Reactant: COC(=O)c1ccccc1Nc1cccc(CNO)c1C
Reactant: CN=C=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)N(O)Cc1cccc(Nc2ccccc2C(=O)OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Methyl isocyanate (0.33 g, 5.8 mmol) is added dropwise to 2-[[3-(N-hydroxyamino)methyl-2-methylphenyl]amino]benzoic acid methyl ester (1.5 g, 5.2 mmol) in 33% water/dioxane (60 mL) with ice bath cooling. The reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (50 mL) and dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by recrystallization first from ether and then from ethyl acetate to give 2-[[3-[[hydroxy[(methylamino)carbonyl]amino]methyl]2-methylphenyl]amino]benzoic acid methyl ester (0.68 g, 38%). mp=173-175° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH3:30])[CH:24]=[C:23]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:22]=1[C:41](=[O:43])[CH3:42]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH3:30])[CH:24]=[C:23]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:22]=1[C:41](=[O:43])[CH2:42][C:8](=[O:10])[C:7]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1c(OCOC)cc(OCOC)cc1Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of sodium tert-butoxide (31.5 g, 328 mmol) and diethyl oxalate (60.5 mL, 3 eq.) in THF (250 mL) was slowly added dropwise a solution of 1-[2,4-bis(methoxymethoxy)-6-(4-nitrophenoxy)phenyl]ethanone (56 g, 149 mmol) in THF (350 mL) at −5° C. After stirring for 1 hour at this temperature, the resulting solution was stirred for further 3 hours at room temperature. The solution was then taken up in 10% citric acid solution (2000 mL) and thoroughly extracted with ethyl acetate. After washing with brine and drying over Na2SO4, the solvent was removed to provide a yellowish residue that was taken up in light petrol ether to remove the excess of diethyl oxalate to afford the quite pure title compound (58 g, 81% yield).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C@H:17]2[O:19][C@@H:18]2[C:20](O)=[O:21])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:24]1C(=O)C[CH2:26][C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.C(N)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([NH:24][C:20]([C@@H:18]1[C@@H:17]([C:15](=[O:16])[NH:14][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:19]1)=[O:21])[CH3:26]
Reactant: O=C(O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylic acid (1.80 g, 6.05 mmol.) and N-hydroxysuccinimide (696 mg, 6.05 mmol) in methylene chloride (10 mL) was added a solution of N,N'-dicyclohexylcarbodiimide (1.25 g, 6.05 mmol.) in methylene chloride (7 mL) under chilling with ice. The mixture was stirred for 30 minutes at room temperature. To the mixture was then added under chilling with ice a solution of ethylamine hydrochloride (493 mg, 6.05 mmol.) and triethylamine (0.84 mL, 6.05 mmol) in methylene chloride (7 mL). The resulting mixture was stirred overnight at 5° C. The solvent was distilled off under reduced pressure, and N,N'-dicyclohexylurea (DC-Urea) was removed by filtration after addition of ethyl acetate (10 mL). The solution was washed successively with water, 0.5N hydrochloric acid, an aqueous sodium hydrogen carbonate saturated solution, and an aqueous sodium chloride saturated solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=1/0 to 50/1), to give the desired compound as a white crystalline powdery product (928 mg, yield: 47%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCCl>[CH2:14]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=CCc1ccc(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 84.9 %

Procedure:
To 1-chloro-4-methyl-2-nitrobenzene (2.00 g, 11.7 mmol), allyltributylstannane (5.79 g, 17.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.818 g, 1.17 mmol) in two 25-mL reaction vials was added 1,2-dichloroethane (20 mL). The vials were capped and heated at 120° C. for 45 minutes in a Biotage Initiator® microwave reactor with an external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was loaded onto a Celite® cartridge. The crude material was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent. The combined acetonitrile/water fractions were concentrated, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and dried in a vacuum oven to provide the title compound as a yellow liquid (1.76 g, 84%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.9 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 5.96 (ddt, J=16.6, 10.1, 6.4 Hz, 1H), 5.08 (ddq, J=18.5, 17.0, 1.5 Hz, 2H), 3.64 (d, J=6.4 Hz, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 149.09, 137.62, 135.35, 133.81, 131.81, 131.72, 124.94, 116.81, 36.62, 20.72; EIMS m/z 176 ([M]+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.CN(C=O)C>[CH2:17]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.005 g of 2-amino-3-phenylpropanol and 3 g of ethylene carbonate in 50 ml of toluene in a round bottom flask with a Dean-Stark trap was refluxed for 48 hours and the reaction was followed by tlc. At the end of the reaction the solution was washed with water and brine and concentrated to dryness to give 5.86 g of light yellow oil. The racemic 4-benzyloxazolidin- 2-one was dissolved in 20 ml of THF and was added to 1.98 g of 60% NaH in 40 ml of THF and 10 ml of DMF. After the initial reaction had subsided the reaction mixture was refluxed for 2 hours. After cooling to r.t. 5.44 g of 1-bromobutane in 20 ml of THF was added and the reaction mixture was refluxed overnight. It was then poured into ice-water and extracted twice with ethyl acetate. Combined organic extracts were washed three times with water, followed by brine. After drying, the solution was concentrated to give 7.625 g of crude oil. This was kugelrohr distilled (155°-160° C./0.3 mm) to give 6.54 g (84.7% overall yield) of product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.CC(N(C)C)=O>CCOC(C)=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][CH2:21][CH2:20][NH:19][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)=[N:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)cc1-c1ccccc1
Yield: 70 %

Procedure:
The crude material above, ethyl 6-chloro-4-phenylpyridine-3-carboxylate (140 mg, 0.56 mmol) was mixed with (2-aminoethyl)(5-nitro(2-pyridyl))amine (408 mg, 2.24 mmol), Hünig's base (390 ul), and DMA (2 ml) for 48 hours at 70-75° C. with stirring under argon. The reaction was followed by TLC and HPLC. When judged complete, the reaction was diluted with EtOAc (100 ml) and washed with sat. aq. NaHCO3 (5×30 ml), brine (30 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The yellow solid was purified by column chromatography using 5% MeOH in CH2Cl2 as the cluent. The product was dried overnight in vacuo giving ethyl 6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)-4-phenylpyridine-3-carboxylate in 70% yield.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Mg]Br)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH3:4])[CH:7]=2)[OH:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately 3 mL of a solution of 3,4-bromoveratrole (3.5 g, 15.9 mmol) in THF (10 mL) was added to a mixture of magnesium turnings (0.4 g, 15.9 mmol) in THF (5 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,4-bromoveratrole solution was added dropwise to the solution under mild reflux. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,4-dimethoxyphenyl)magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (2.4 g, 13.3 mmol) in THF (10 mL) at 0° C. After complete addition, the solution was allowed to stir at room temperature for 1 h. The mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (40 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed and residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol as an oil (2.6 g, 63%): 1H NMR (CDCl3) δ 7.89 (d, J=2 Hz, 1H), 7.54-7.49 (dd, J=2, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.88-6.81 (m, 3H), 5.78 (d, J =3 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (d, J=3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[OH:22][N:20]1[C:4]2[CH:3]=[CH:2][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:12][C:13](=[O:14])[C:15]1=[O:16]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2ccccc12
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ccccc3ccc2n(O)c1=O
Yield: 64.4 %

Procedure:
A solution of 0.5 g (1.36 mmol) 4-bromo-1-ethoxalylamino-2-nitronaphthalene in 30 ml tetrahydrofuran was added 10 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 50 mg 5% Pd-C as a catalyst. The precipitated product was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid and recrystallization (dimethylformamide-water) of the precipitated product gave 0.2 g (65%) 4-hydroxy-benzo[f]quinoxaline-2,3(1H,4H)-dione. M.p. 270° C. decomp. 1H-N (1H, broad s), 8.6 (1H, m), 7.7 (5H, m). MS (m/e): 228 (M+, 90%).
Reaction SMILES: C(OC=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:13][NH:14][NH2:15].[CH2:16](O)C>>[NH2:12][C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CNN
Reactant: CCO
Product: CCOC(=O)c1cnn(C)c1N
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of ethyl (ethoxymethylene)cyanoacetate (68 g, 0.4 mol) and methylhydrazine (18.5 g, 0.4 mol) in 200 mL absolute ethanol was refluxed for 1.5 h, then cooled to RT and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether to give 54 g of crude ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate in 75.4% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-:20].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CO
Product: COc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 140 °C
Reaction time: 16 h

Procedure:
Lit. Org. Lett. 2002, 4(6), 973-976. To a stirred suspension of 1.84 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 7 ml methanol were added 0.18 mmol copper(I) iodide, 3.69 mmol cesium carbonate and 0.37 mmol 1,20-phenanthroline and the reaction mixture was stirred at 140° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light red solid. MS (m/e): 230.2 ({37Cl}[M+H− Me2C═CH2]+, 42%), 228.2 ({35Cl}[M+H− Me2C═CH2]+, 100%).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1.[Cl:10][C:11]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[N:2][NH:1][C:5]=2[CH2:6]1)=[O:14]
Reactant: c1n[nH]c2c1CCNC2
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (1.01 g, 5.15 mmol) in DMF (17 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (2.31 g, 10.30 mmol), Hunig's base (3.55 mL, 20.60 mmol) and HATU (2.31 g, 10.30 mmol). The solution was allowed to stir for 30 min at rt then poured into ice water (300 mL). The resulting solid was collected by suction filtration and allowed to air dry. The solid was purified by chromatography on silica gel (0-100% ethyl acetatehexanes). The product fractions were concentrated to a white solid which was dissolved in ethanol (20 mL) and 1M NaOH (20 mL) and stirred at 80° C. for 1 h. Water (50 mL) and CH2Cl2 (50 mL) were added. The layers were separated and the water layer was extracted two times with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to an oil (1.37 g, 81%). MS (ESI) mass calcd. C14H11ClF3N3O, 329.1. m/z found, 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.79-7.73 (m, 1H), 7.52-7.41 (m, 2H), 7.37 (br s, 1H), 5.11 (d, J=16.6 Hz, 0.5H), 4.85 (d, J=16.6 Hz, 0.5H), 4.46 (d, J=15.9 Hz, 0.5H), 4.36 (d, J=15.9 Hz, 0.5H), 4.22-4.18 (m, 0.5H), 3.94-3.88 (m, 0.5H), 3.49-3.44 (m, 1H), 2.85-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.62-2.54 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:11])[C:9]=1[Cl:10])[C:5]#[N:6].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][OH:24]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:11][CH2:22][CH2:23][OH:24])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N)c(Cl)c(NCCO)c1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 3,5-diamino-4-chlorobenzonitrile (200 mg, 1.193 mmol) in DMF (2 mL) was added Hunig's base (2.501 mL, 14.32 mmol) followed by 2-bromoethanol (0.506 mL, 7.16 mmol). The resulting solution was heated at 100° C. for 10 h. LC-MS indicated ca. 30% conversion. It was passed through a pad of celite, rinsed with EtOAc. After concentration, purification via silica gel chromatography (0-70% EtOAc in Hexanes, 24 g) gave 3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg) as an orange oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[C:13]([CH:25]=1)[C:14]([NH:16][CH2:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][CH:19]=1)=[O:15])C1C=CC=CC=1.C(O)C>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[C:13]([CH:25]=1)[C:14]([NH:16][CH2:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(NCc1cccc(=O)[nH]1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: O=C(NCc1cccc(=O)[nH]1)c1cc(O)ccc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 60 ml of ethanol, 40 ml of methanol and 0.043 g of 10% palladium on charcoal was hydrogenated on a Parr apparatus at about 20° C. for about 16 hours. Filtration followed by evaporation of the filtrate provided a residue which was triturated with acetonitrile. The solid was separated by filtration and washed with acetonitrile to provide 6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.