Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][O:4][CH3:5].Cl.Cl[O-].[Na+]>CO>[CH3:18][O:17][C:16]1[C:7]2[N:6]=[C:2]([CH2:3][O:4][CH3:5])[NH:1][C:8]=2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COCC(=N)Nc1cc(C(=O)OC)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COCc1nc2c(OC)ccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of methyl 3-(1-imino-2-methoxy-ethylamino)-4-methoxybenzoate [15.7 g, Reference Example 4(a)] in methanol (150 ml) was treated with 1M hydrochloric acid (62.6 ml) then with sodium hypochlorite solution (32.3 ml, 13%). Further aliquots of sodium hypochlorite solution were added until all the starting material was consumed. The solution containing methyl 3-(1-chloroimino-2-methoxy-ethylamino)-4-methoxybenzoate was treated with a saturated solution of sodium carbonate (8.62 g) in water. The mixture was then refluxed for 1 hour, then cooled to room temperature, then diluted with water and then extracted with chloroform. The chloroform extract was washed with brine, dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) then with a mixture of ethyl acetate and hexane (6:1, v/v) to give the title compound (13.0 g) as a solid. M+250. NMR (CDCl3): δ 3.48(s,3H), 3.98(s,3H), 4.10(s,3 H), 4.78(s,2H), 6.70(d,J=8 Hz,1H), 7.87(d,J=8 Hz,1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[N:9]([Si](C)(C)C)=[N+:10]=[N-:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:9]([CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)=[N+:10]=[N-:11]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1nc(CCl)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CN=[N+]=[N-])cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Dissolve 4-(chloromethyl)-2-methyl-thiazole (350 mg, 2.37 mmol) and azidotrimethylsilane (315 μL, 2.37 mmol) in anhydrous THF (1 mL) under nitrogen. Add a 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56 mmol) in THF and stir at ambient temperature overnight. Pour the reaction mixture into water (10 mL), extract with ethyl ether (3×2 mL), wash the organic extracts with brine, thy over MgSO4, filter, and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (165 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11](Br)[C:12]#[CH:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH2:13]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
4-Nitrophenol (1.00 g, 7.19 mmol), propargyl bromide (80 wt % in toluene; 0.788 mL, 7.09 mmol), and K2CO3 (1.08 g, 7.84 mmol) were stirred in acetone (16.0 mL) at 60° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). 4-(prop-2-ynyloxy)nitrobenzene was isolated as a white solid by suction filtration (1.12 g). 1H NMR (CDCl3): δ 8.22 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 4.80 (d, J=2.4 Hz, 2H), 2.59 (t, J=2.4 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[SH:6].[OH-].[Li+].[I-].[Na+].[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29]Cl)[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:31]2[CH2:33][CH2:32]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([C:15]1[N:16]=[C:17]([CH:31]2[CH2:32][CH2:33]2)[CH:18]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][S:6][C:2]3[S:1][CH:5]=[N:4][N:3]=3)[CH2:23][CH2:22]2)[N:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Sc1nncs1
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCCl)CC2)n1
Agent: [I-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCSc3nncs3)CC2)n1
Temperature: 70 °C
Yield: 52.6 %

Procedure:
0.21 g of [1,3,4]thiadiazol-2-thiol (1.77 mmol) were dissolved in 20 ml of dimethylformamide. After addition of 0.04 g of lithium hydroxide (1.77 mmol) and 0.13 g of sodium iodide (0.88 mmol), the reaction mixture was stirred at 70° C. and 0.6 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclopropyl-pyrimidine (1.77 mmol), dissolved in 5 ml of dimethylformamide, were added dropwise within 2 h. The mixture was stirred at 80° C. for 2 h, cooled to room temperature and the solvent was evaporated. The residue was partitioned between 40 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution. The aqueous phase was reextracted twice with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness, to yield 0.69 g of the crude product, which was further purified by chromatography on silica gel using dichloromethane-methanol (1:1) and ethyl acetate. Fractions containing the product were combined and the solvents were evaporated. The oily residue crystallized upon standing to yield 0.39 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH2:20][CH3:21])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH2:20][CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 4.5 g. (0.0136 mole) of ethyl 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate in 28 ml. 0.5 N sodium hydroxide and 1 ml. of ethanol is heated under reflux for 30 minutes. The mixture is then poured into ice-dilute hydrochloric acid. The precipitated solid is filtered, air dried and recrystallized from 2-propanol to give 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid as a white solid, m.p. 129-131° C. Anal. Calcd. for C16H16ClNO3: C, 62.85; H, 5.29; N, 4.5%. Found: C, 62.58; H, 5.40; N, 4.83%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:23]C1C=C(N2C[C@H](CO)OC2=O)C=CC=1I>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([I:22])=[C:20]([F:23])[CH:21]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1

Procedure:
Using essentially the same procedure as that used for (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (above), but starting from (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (2.0 g, 1.0 mM) gave the title compound as a light yellow soild after chromatography using 50% ethyl acetate/hexanes (1.94 g).
Reaction SMILES: C([O:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:21]=[N:22][N:23]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=2)[CH:10]=1)(=O)C(C)(C)C.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[C:25]([N:23]1[N:22]=[N:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:10]=[C:9]([CH2:8][OH:7])[O:13][N:12]=2)=[N:24]1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)C(=O)OCc1cc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)no1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)no1
Temperature: -20 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
A 100 ml round-bottom flask, equipped with a magnetic stirring bar, septum, and nitrogen inlet, was charged with 348 mg (0.61 mmol, 1.0 equiv) of the starting pivaloate (from Step O) and 8 ml THF (over sieves). The system was cooled down to -20° C. 1.35 ml (1.0M solution in THF, 1.34 mmol, 2.2 equiv) L-Selectride solution was added dropwise into the solution. The reaction was moved to a -20° C. freezer, kept for 18 hours, and then quenched with a basic peroxide solution, containing 25% saturated aqueous sodium bicarbonate solution, 50% methanol, and 25% of the 30% H2O2 in H2O solution. The resultant mixture was warmed to 0° C. and stirred for half an hour. Ethyl acetate was added to create two phases. The organic layer was separated from the aqueous one, which was extracted with 5×10 ml ethyl acetate. The combined organic portion was washed with 2×20 ml saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (3 cm ×26 cm, 3:2=hexane:ethyl acetate, with 1% distilled triethylamine) to afford 250 mg of the desired product in 84% yield: Rf=0.15 (3:2=hexane:ethyl acetate, with 1% distilled triethylamine); 1H NMR δ5.87 (s, HC on the isoxazole ring), 4.41 (s, CH2OH); 13C NMR δ103.3 (HC on the isoxazole ring), 83.2 (C(C6H5)3), 56.3 (CH2OH).
Reaction SMILES: NC1C=CC=CC=1.C1(C)C=CC=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])C(O)=O)=[CH:18][C:17]=1[Br:27]>ClC1C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:26])=[CH:18][C:17]=1[Br:27]
Reactant: O=C(O)C(=O)c1ccc(F)c(Br)c1
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: O=Cc1ccc(F)c(Br)c1

Procedure:
102.3 g (1.1 moles) of freshly distilled aniline were added dropwise to a mixture of 1,300 ml of toluene or chlorobenzene and 247 g of 4-fluoro-3-bromophenylglyoxylic acid at 70° to 80° C. The reaction mixture was then heated to the reflux temperature, and was stirred under reflux for a further 4 hours in order to bring the decarboxylation to completion. Thereafter, the solvent was stripped off in vacuo. 270 g (97% of theory) of the anil remained in the form of a colorless powder with a melting point of 45° to 47° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[S:43][CH3:44])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.CC(O)=[O:49]>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[S:43]([CH3:44])=[O:49])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cc(F)ccc1Cc1cnc(-c2nc3n(CC(=O)N4CC(C)OC(C)C4)ccn3c(=O)c2OCc2ccccc2)s1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CC1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5S(C)=O)s4)nc23)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
The mixture of the product of example 168 (160 mg, 0.25 mmol), H2O2 (30%, 1 ml) and HOAc (5 ml) was stirred at room temperature for 3 h. H2O (6 ml) was added and then extracted with ethyl acetate. The organic layer was washed with H2O, dried and concentrated. The residue was purified by column chromatography (ethyl acetate) to give the titled compound (170 mg, 100% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:37][CH:36]=1
Reactant: OCc1ccc(F)cc1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccc(F)cc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-fluorobenzyl alcohol. A colorless powder (145 mg). HPLC analysis (Agilent 1100 system): purity 98% (retention time: 4.33 min). MS (ESI+): 571 (M+H), 573.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:19]1([CH:27]=O)[C:20]([CH:25]=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(O)(=O)C>ClCCl>[O:26]=[C:25]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][N:1]1[CH:2]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(N)CC(=O)O)cc(OC)c1OC
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
3-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3.66 mmol, 1 eq), benzene-1,2-dicarbaldehyde (1 eq) and acetic acid (16 eq) are suspended in dichloromethane and refluxed for 2 h. The filtrate is concentrated in vacuo, dissolved in DCM and extracted with water. The organic phase is reduced under vacuum. The resulting oil is suspended in 1 M NaOH and stirred for 30 min at room temperature. The solution is washed with EtOAc and the aqueous phase is acidified with 1 M HCl (pH 2) and extracted with EtOAc. The organic phase is reduced under vacuum, dissolved in DCM and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin is added. The suspension is shaken at rt for 16 h. The filtrate is concentrated in vacuo, dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propionic acid is obtained as a clear colourless film (20% yield); ES-MS (MH+)=372.0; mp. 162-164° C.; 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 12.37 (br s, 1H), 7.69 (d, 1H, 7.6 Hz), 7.62-7.45 (m, 3H), 6.70 (s, 2H), 5.68 (t, 1H, 7.9 Hz); 4.53 (d, 1H, 17.9 Hz), 4.20 (d, 1H, 17.9 Hz), 3.76 (s, 6H), 3.63 (s, 3H), 3.14 (d, 2H, 7.9 Hz).
Reaction SMILES: [CH:1]1([C:10]([NH:12][C@H:13]([C:32]([O:34][CH3:35])=[O:33])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=3[Cl:30])=[CH:17][CH:16]=2)=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[C:36]1([CH3:46])[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1.CCN(C(C)C)C(C)C.CCCCCC>C(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:46][C:36]1[CH:37]=[C:38]([S:42]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[C:10]([NH:12][C@H:13]([C:32]([O:34][CH3:35])=[O:33])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=3[Cl:30])=[CH:17][CH:16]=2)=[O:11])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)C1NCC2CCCCC21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)C1C2CCCCC2CN1S(=O)(=O)c1cccc(C)c1
Yield: 101.9 %

Procedure:
N-(Octahydroisoindole-1-carbonyl)-4-(N-(3,5-dichloroisonicotinoyl)amino)-(L)-phenylalanine, methyl ester (30 mg) was dissolved in 0.15 each of CH2Cl2 and THF. To this was added m-toluenesulfonyl chloride (0.051 mmol, 9.7 mg), followed by DIPEA (0.153 mmol, 20 mg) and 4-DMAP (0.01 mmol, 1.24 mg). This mixture was stirred at rt overnight when TLC (1:2 hexane:ethyl acetate) indicated the disappearance of all starting material. The volatiles were removed in vacuo and the residue was purified by flash column chromatography on silica gel eluted with a gradient of hexane and EtOAc to yield N-(N-(3-methylbenzenesulfonyl)-octahydroisoindole-1-carbonyl)-4-(N-(3,5-dichloroisonicotinoyl)amino)-(L)-phenylalanine, methyl ester (35 mg) as a sticky foam (homogeneous by TLC (1:2 hexane:ethyl acetate)).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]3([CH2:31][O:30]3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]2[CH2:33][CH2:32][C:29]([CH2:31][O:9][C:8]3[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=3)([OH:30])[CH2:28][CH2:27]2)=[CH:22][CH:23]=1)#[N:17]
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
60% sodium hydride (46 mg) was added to an anhydrous dimethylformamide solution (4 mL) of hydroquinone (0.18 g) under cooling with ice-water and the mixture was stirred at room temperature for fourty minutes under nitrogen atmosphere. The compound (0.40 g) obtained in Step 3 was added to the mixture, and the reaction mixture was stirred at 80° C. for four hours under nitrogen atmosphere. Water (40 mL) was added to the mixture under cooling with ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate and then, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=49:1 to 19:1) and the obtained fractions were concentrated and washed with ether-ethyl acetate to obtain the titled compound (52 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].O>[N:11]1([CH2:14][CH2:15][O:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: NC(=O)COCCN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: NC(=O)COCCN1CCNCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
II.2.1. 13.9 g (0.05 mol) of 2-(4-benzyl-1-piperazinyl)ethoxyacetamide prepared in Example I.2.1. and 139 ml of ethanol are introduced into a 250 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 1.4 g o palladium on-charcoal (10% by weight) and 15.8 g of ammonium formate are then added. The mixture is heated at 30° C. for 30 minutes, and then at 40° C. for 1 hour, and again at 60° C. for 30 minutes. The mixture is allowed to cool to 40° C. and is filtered through diatomaceous earth (dicalite). The palladium is washed with ethanol. The filtrate is concentrated on a rotary evaporator under reduced pressure. 9.5 g (100%) of 2-(1-piperazinyl)ethoxyacetamide are obtained in the form of a colorless oil which crystallizes.
Reaction SMILES: [C-:1]1([CH:6](CC)[C:7](O)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].[H-].[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C-:12]1([CH:7]([OH:8])[CH2:6][CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:17]
Reactant: CCC(C(=O)O)[c-]1cccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCC(O)[c-]1cccc1

Procedure:
Acid (2) (12 g) was dissolved in ether (distilled from sodium/potassium) and treated with lithium hydride (1.27 g) in a nitrogen atmosphere. When reaction was complete the excess lithium aluminium hydride was destroyed using ethyl acetate and then water. The organic phases were separated and the aqueous phase washed with ether (2×20 ml). The organic phases were combined and dried (MgSO4) and after filtration the solvent was removed on the rotary evaporator 4. The red oil resulting had two components. Column chromatography (30 cm×2 cm) on silica eluted with 1:1 ether:hexane gave the alcohol and an ester.
Reaction SMILES: [Na][Na].[P:3]([CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11])([OH:6])([OH:5])=[O:4].Cl[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15].[OH-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>O>[CH2:17]([O:16][C:14]([N:8]([CH2:7][P:3]([OH:6])([OH:5])=[O:4])[CH2:9][C:10]([OH:12])=[O:11])=[O:15])[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: CCCCOC(=O)Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: CCCCOC(=O)N(CC(=O)O)CP(=O)(O)O
Reaction time: 2 h
Yield: 157.1 %

Procedure:
To a stirred solution containing 16.9 g (0.10 mol) of disodium-N-phosphonomethylglycine in water at 20°-25° C. was added 15 g (0.11 mol) of n-butyl chloroformate. After stirring the reaction mixture for 2 hours, a 50% sodium hydroxide solution was slowly added until the pH of the mixture stabilized at a phenolphthalein endpoint. The reaction mixture was concentrated and the residue dried over potassium hydroxide pellets to yield 42.3 g of N-n-butoxycarbonyl-N-phosphonomethylglycine, disodium salt, as a white solid having the following analysis: Calculated: C, 33.00; H, 5.19; P, 10.64. Found: C, 32.77; H, 5.16; P, 10.69.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)Cn1cc([N+](=O)[O-])cn1

Procedure:
A suspension of 4-nitro-1H-pyrazole (0.4 g, 3.54 mmol), 2-chloro-N,N-dimethylacetamide (0.546 ml, 5.31 mmol) and potassium carbonate (0.733 g, 5.31 mmol) in 18 ml acetone was refluxed for 6 hours. The cooled suspension was filtered with acetone washes and the concentrated residue was flash chromatographed (50 mm, 3% methanol in CH2Cl2) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH3:18])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].[F:19][C:20]1[C:21]([F:33])=[C:22]([F:32])[C:23]([F:31])=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]=12>C(O)(=O)C>[CH2:17]([C:2]1([N:1]2[C:29](=[O:28])[C:24]3=[C:23]([F:31])[C:22]([F:32])=[C:21]([F:33])[C:20]([F:19])=[C:25]3[C:26]2=[O:27])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[NH:4][C:3]1=[O:16])[CH3:18]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CCC1(N)C(=O)NC(=O)N(c2ccccc2)C1=O
Solvent: CC(=O)O
Product: CCC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(c2ccccc2)C1=O
Yield: 60.1 %

Procedure:
A mixture of about 250 mg (about 1 mmol) of 5-amino-5-ethyl-1-phenylbarbituric acid, about 260 mg (about 1.2 mmol) of tetrafluorophthalic anhydride, and about 7 mL of acetic acid was refluxed for about 3 hours. The solvent was evaporated to dryness under reduced pressure of from about 200 to about 15 mbar. The residue was recrystallized from ethyl alcohol to yield about 270 mg 5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid (a 60% yield) having a melting point of about 218° to about 220° C.