Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:16]([NH:19][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(C)(C)N)o2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(C)(C)NC(=O)OCc3ccccc3)o2)CC1
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
To a solution of crude {1-[5-(1-amino-1-methyl-ethyl)-furan-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (451 mg, 1.61 mmol) in a mixture of THF (8.0 mL) and water (1.6 mL), was added Li2CO3 (297 mg, 4.02 mmol) followed by benzyl chloroformate (0.57 mL, 4.0 mmol). This was stirred for 2.5 h then diluted with water (50 mL) and extracted EtOAc (3×50 mL). The combined organic layers were dried with Na2SO4 and concentrated to give a red residue. The residue was purified by flash chromatography (silica, 20->40% EtOAc/hexanes) to give 324 mg of the title compound as a yellow oil, m/z 437.64 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:26])[CH:3]=1.[NH3:27]>CO>[CH3:26][C:4]1[CH:3]=[C:2]([NH2:27])[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:7]12.[CH3:23][N:24](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:17]=[C:16]1[N:6]2[CH2:5][CH2:4][C:3]3[C:2]([C:23]#[N:24])=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[CH:12][C:13]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:14][CH2:15]1
Reactant: CN(C)C=O
Reactant: O=C1CN=C(c2cccs2)C=C2c3cccc(Br)c3CCN12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c1CCN1C(=O)CN=C(c3cccs3)C=C21
Temperature: 170 °C
Reaction time: 0.27 h

Procedure:
A microwave flask was charged with 9-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 29) (145 mg, 0.39 mmol), Zn(CN)2 (191 mg, 1.63 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol) in DMF (4 mL) was heated to 170° C. for 18 h. The reaction was allowed to cool to RT, taken up in AcOEt and washed with H2O. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexane to hexan/AcOEt 1:1) and prep. HPLC (column: RP-C18 sunfire, 5 μm, 100×300 mm; solvent A: H2O+0.1% TFA; solvent B CH3CN; gradient (% B): 10-30% in 16 min; 50 mL/min). The product obtained was passed onto a SPE cartridge to release the free base, and the residue obtained was triturated in heptane/AcOEt to give the title compound (8 mg) as a yellow solid. UPLC-MS: MS 320.2 (M+H+); UPLC rt 0.87 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 3.07 (t, J=5.55 Hz, 2 H); 3.87 (br. s., 2 H); 4.29 (br. s., 2 H); 7.11 (t, J=4.14 Hz, 1 H); 7.51 (s, 1 H); 7.56 (t, J=7.87 Hz, 1 H); 7.66 (d, J=4.24 Hz, 2 H); 7.93 (d, J=7.47 Hz, 1 H); 8.42 (d, J=8.07 Hz, 1 H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([O:20][P:21](C#N)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].C(N(CC)CC)C>ClCCl.O>[CH2:18]([O:20][P:21]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[CH:12][CH:13]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:19]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.2 g (5 mmol) of N-Boc tyramine, 0.9 g (5.5 mmol) of diethylcyanophosphonate and 1.4 ml (10 mmol) of triethylamine are placed in solution in 5 ml of dichloromethane at 0° C. under an argon atmosphere. The reaction mixture is stirred for 30 minutes at 0° C. followed by diluting with 25 ml of water and extracting with twice 30 ml of dichloromethane. The organic phases are combined followed by washing with 50 ml of water then 25 ml of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate, followed by filtering and concentrating under vacuum. The expected product is obtained in the form of a clear oil with a yield of 92% (1.73 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[F:16].[CH3:18][OH:19]>>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([O:19][CH3:18])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[F:16]
Reactant: CO
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F

Procedure:
To a mixture 0.30 g (7.55 mmole) of sodium hydride (60% in mineral oil) and 30 mL of methanol was added 1.49 g (6.86 mmole) of 2,5-difluoro-4-nitro-benzoic acid methyl ester. The mixture was heated at reflux for 18 hours and then quenched by the addition of water, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-hexanes (1:1) to give 0.92 g of 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.Cl.[O-:23][C:24]#[N:25].[Na+]>>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:24]([NH2:25])=[O:23]
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 5-amino-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) in ice water (20 ml) are added 5N HCl (2 ml, 10 mmol) under stirring. Then the mixture was heated to 70°14 80° C., sodium cyanate (0.715 g, 11 mmol) was added portionwise and the stirring was continued for further 4 h at this temperature. After cooling the raw product was extracted with CHCl3, the organic layer washed to neutrality with saline solution, dried and evaporated in vacuo. The residue was chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 50% yield.
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N+:11]=1[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.O>C(O)C.C(OCC)C>[CH2:30]([O:29][C:27]([C:26](=[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[CH3:17])[C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CN(C)C1=[N+](C)CCCCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C1CCCCCN1C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add (drop by drop at 90° in a stream of nitrogen to let the alcohol escape) a solution of 4.6 g of sodium in 100 ml of ethyl alcohol to a mixture of 53.2 g of the title compound of Example 1 and 29.8 g of ethyl 4-chlorophenylacetate. Stir it for a further 4 hours at 90° and then cool it to ambient temperature. Mix the cooled reaction mixture with 100 ml of water and 100 ml of diethyl ether, collect the organic phase and dry the latter over sodium sulfate. Concentrate the dried organic phase and then distil off any excess ethyl 4-chlorophenylacetate under a high vacuum to obtain a crude yield [15.5 g (34% of theory)] of the title compound as yellow oil.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[C:11]2[C:16](=[C:17](Br)[C:18]=1[O:19][CH3:20])[CH2:15][N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@:13]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:12]2>CO.[Pd]>[C:25]([O:24][C:22]([N:14]1[C@@:13]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[CH:9][CH:10]=2)[CH2:15]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1c(Br)cc2c(c1Br)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Reaction time: 1.5 h

Procedure:
Triethylamine (303 mg, 3 mmol) and 10% Pd—C (20 mg) were added to Compound 2.7 (500 mg, 1.05 mmol) in MeOH (5 mL) and the mixture was hydrogenated on a Parr shaker at 40 PSI for 90 min. The mixture was filtered through Celite and concentrated. The product was used in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1Cl)[C:5]([NH:7][CH2:8][C:9]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)=[O:6].C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])C1C=CC(C(Cl)=O)=CC=1>C1COCC1>[F:33][C:34]([F:45])([F:44])[C:24]1[CH:23]=[CH:22][C:4]([C:5]([NH:7][CH2:8][C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[O:6])=[CH:3][CH:2]=1
Reactant: CN(C)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1(CNC(=O)c2ccc(C(F)(F)F)cc2)CCC2(CC1)OCCO2

Procedure:
A solution of 1.0 g (0.00465 mole) of the ketal from Example 1, part A and 0.47 g (0.65 ml) of triethylamine in 15 ml of THF was cooled in an ice bath. To this cooled solution there was added a solution of 0.97 g (0.00465 mole) of p-trifluoromethylbenzoyl chloride in 10 ml of THF over 10 minutes while stirring. The mixture was placed in a refrigerator overnight. Upon removal from the refrigerator, the bulk of the solvent was removed on a rotary evaporator. The residue was taken up in diethyl ether and aqueous sodium bicarbonate solution. The separated aqueous layer was extracted with diethyl ether. The diethyl ether liquid fractions were pooled and dried to yield the crude, named product, 2.07 g, m.p. 128°-130° C. Recrystallization from a mixture of methylene chloride and Skellysolve® B gave product weighing 1.56 g, m.p. 129°-130.5° C. The elemental analysis was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.Cl.[CH3:21]NOC.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl.N1C=CC=CC=1>[Cl:9][C:4]1[C:5]([CH3:21])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH:13]=[O:15]
Reactant: Cc1cc(Cl)c(Nc2ccccc2C(=O)O)c(Cl)c1
Reactant: CNOC
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Yield: 120.7 %

Procedure:
A mixture in dry dichloromethane (135 mL) of 2-[(2,6-dichloro-4-methylphenyl)amino]benzoic acid (meclofenamic acid) (7.0 g, 23.6 mmol), N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.9 mmol), carbon tetrabromide (17.2 g, 51.9 mmol), triphenylphosphine (13.6 g, 51.9 mmol), and pyridine (10 mL) was stirred at ambient temperature for 48 hours. The reaction mixture was poured into 10% HCl (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. Purification by chromatography on silica gel (9:1 hexane/ethyl acetate) provided 7.98 g (99%) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde as a colorless solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NCCC(c1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3,3-diphenylpropylamine (0.74 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.68 g, 2.0 mmol, yield: 63%) as colorless powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]([O-])(=[O:24])C.[Na+]>CN(C)C=O.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:22]=[O:24])=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(C=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 150 ml of dimethylformamide 46 ml of phosphorus oxychloride were added dropwise care being taken that the temperature of the reaction mixture did not rise above 20° C. Subsequently to the obtained mixture 103.5 g of 1-methyl-2-phenyl-indole dissolved in 200 ml of dimethylformamide were added dropwise. During the addition the temperature of the reaction mixture was kept in the range of 20° to 40° C and thereupon for 1 hour between 40° and 45° C. Then the reaction mixture was poured into a solution of 490 g of sodium acetate dissolved in 500 ml of water to which 500 g of ice were added. The precipitated aldehyde was separated by suction, washed with water and methanol.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OS(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc(CCN)cc1
Yield: 99.8 %

Procedure:
4-{2-[(tert-Butoxycarbonyl)amino]ethyl}phenyl methanesulfonate (3.98 g, 12.62 mmol) was dissolved in DCM (12 mL) and TFA (10 mL) and stirred at rt for 4 h. The reaction mixture was concentrated and redissolved in EtOAc, washed with saturated aqueous K2CO3, and the organic phase was dried with Na2SO4, filtered and evaporated affording the title compound (2.71 g, 99.8%). 1H NMR (500 MHz, CD3OD): δ 2.79 (t, 2H), 2.89 (t, 2H), 3.21 (s, 3H), 7.26 (d, 2H), 7.32 (d, 2H); 13C NMR (125 MHz, CD3OD): δ 36.24, 38.34, 42.95, 122.11, 130.19, 139.44, 148.28; Mass Spectrum: M+H+ 216.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:5](N(OC)C)=[O:6].NC1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.[F:30][C:31]1[C:36]([OH:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41].C1CCC(N=C=NC2CCCCC2)CC1>>[F:30][C:31]1[C:32]([F:41])=[C:33]([F:40])[C:34]([F:39])=[C:35]([F:38])[C:36]=1[O:37][C:5](=[O:6])[C:4]1[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:2]([NH2:1])[CH:3]=1
Reactant: CON(C)C(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Product: Nc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Starting material (1(b)) was prepared as follows. A mixture of 3-amino-5-nitrobenzoic acid (10 g), pentafluoro-phenol (10 g) and DCCI (11.3 g) was stirred at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate poured onto a chromatography column which was then eluted with ethyl acetate/hexane (10:90) to give 3-amino-5-nitrobenzoic acid 2,3,4,5,6-pentafluorophenyl ester (1(a)) as a yellow solid (5.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=[C:10]1[S:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>C(Cl)Cl.O>[C:16]([CH:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:26][CH2:27][CH2:28][CH3:29])=[N:11][CH:12]=1)[C:21]([OH:23])=[O:22])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCSc1ncc(CC(C(=O)O)C(=O)OCC)n1Cc1ccccc1Cl

Procedure:
A solution of diethyl [1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]methylmalonate (0.62 g, 1.41 mmol), sodium carbonate (1.5 g, 14.2 mol), ethanol (10 mL) and water (10 mL) was stirred at 25° C. for 18 hours, then heated for 15 minutes on a steam bath. The mixture was cooled, neutralized with aqueous hydrochloric acid solution, and the product was extracted-into methylene chloride, washed with water, dried and concentrated to 0.425 g of product. Crystallization from ethyl acetate/hexane provided 0.23 g 55%) of 2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]propanoic acid; mp 118°-120° C.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.O>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[C:20](=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CN(CCCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred solution of N,N-dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (1 g, 3.80 mmol) in dichloromethane (20 ml) was added phenyl carbonochloridate (0.715 ml, 5.70 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 50-100% ethyl acetate in hexanes, giving the desired phenyl methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol, 72.7% yield). 1H NMR (DMSO-d6) δ 7.88 (t, J=7 Hz, 1H), 7.78 (s, 1H), 7.37 (t, J=7 Hz, 2H), 7.20 (t, J=7 Hz, 1H), 7.12-7.06 (m, 2H), 6.70 (d, J=9 Hz, 1H), 3.50-3.33 (m, 6H), 3.06, 2.93 (2s, 3H), 2.76-2.71 (m, 2H), 1.92-1.81 (m, 4H). ESI-MS (m/z, %) 370 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].CO.[CH3:30][Si](C=[N+]=[N-])(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[N:24]([CH3:30])[C:23](=[O:27])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5]
Reactant: O=C(NCCc1ccccc1Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzamide (70 mg, 0.173 mmol) in dioxane (1.5 ml) was added methanol (0.36 ml) followed by a 2.0 M solution of (trimethylsilyl)diazomethane (0.35 ml). After stirring for 16 hours at ambient temperature the mixture was concentrated under reduced pressure to give 75 mg of a white amorphous solid. Purification by silica gel chromatography eluting with 2:1 hexaned/ethyl acetate provided 39 mg of the title compound as a white amorphous solid. Melting Point 157–161° C.;
Reaction SMILES: O.[OH-].[Na+].[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+](C1C=CC=CC=1)([O-])=O.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].Cl>C(#N)C>[C:18]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: C=C(C)C(=O)NCC(=O)O
Temperature: -20 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To 400 ml of water containing 80 g (2.0 mol) of sodium hydroxide dissolved, were added 150 g (2.0 mol) of glycine and 4 ml of nitrobenzene. To the mixture, there were simultaneously added 200 ml of an aqueous solution containing 96 g (2.4 mol) of sodium hydroxide and 230 g (2.2 mol) of methacrylic chloride under cooling (at -20° C.) with stirring over a period of about 2 hours. After adding 800 ml of acetonitrile and 160 ml of concentrated hydrochloric acid, the organic layer was separated. The solvent was distilled off under a reduced pressure and the crystals thus deposited were collected by filtration and recrystallized from ethyl acetate to obtain 184 g (64.3% yield) of α-methacryloylaminoacetic acid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to the procedure of Example 4, as an off-white solid: mp 193–194° C.; 1H-NMR (CDCl3) δ 9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calc. For C18H18N2O4.0.3H2O: C, 65.17, H, 5.65, N, 8.44. Found: C, 65.31, H, 5.60, N, 8.10.