Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (3.00 g, 13.6 mmol) in DMF (10 ml) was added under a nitrogen atmosphere imidazole (2.89 g, 42.0 mmol). After cooling to 0° C. tert-butyldimethylchlorsilan (3.37 g, 22.3 mmol) was added and the reaction mixture was stirred for 18 h in a thawing ice bath. It was diluted with water (20 ml) and extracted with EtOAc (20 ml). The aqueous layer was extracted with ethyl acetate (20 ml) and the organic layers were washed with water (20 ml) and brine (20 ml) and were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (4.35 g, 96%) as a colorless liquid. MS m/e: 279.0 [M−tBu]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[C:6]([NH2:8])[N:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.O1CCOCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:1][C:17]([CH3:18])=[O:19])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(N)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(N)n1

Procedure:
A stirring mixture of 5.0 grams (0.020 mole) of 3,5-diamino-6-(3,4-dichlorophenyl)-1,2,4-triazine (Compound 24; disclosed in J. Med. Chem., 1972, Vol. 15, No 8. 859-861), 2.0 grams (0.020 mole) of acetic anhydride and 0.01 gram (catalyst) of 4-dimethylaminopyridine in 40 mL of dioxane is heated at reflux for about two hours. The mixture is cooled and concentrated under reduced pressure to a residue. The residue is purified by column chromatography on silica gel, yielding 5-amino-3-methylcarbonylamino-6-(3,4-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: [NH2:1][NH2:2].[C:3]1(=O)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[O:4]1>O.CC(O)=O>[C:5]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3](=[O:4])[NH:2][NH:1]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of hydrazine (392 μL, 13.1 mmol) in water (6 mL) and HOAc (2 mL) is added 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (2 g, 13.1 mmol). The reaction mixture is refluxed for 3 h, then cooled down to room temperature and the precipitate is collected by filtration, washed with water and dried under vacuum oven to give 2,3,5,6,7,8-hexahydro-phthalazin-1,4-dione (compound 10d) (2.09 g, 95.7%). m/z=167.05 [M+1]
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC>C1COCC1.ClC(OCC)=O>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16]([CH:15]=2)=[CH:17][C:18]([CH2:22][OH:23])=[CH:19][CH:20]=3)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2cc3cc(CO)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: -7 °C
Reaction time: 2 h

Procedure:
To a solution of 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid and 50 μl NEt3 in 4 ml THF, 17 μl ethyl chloroformate were added at −7° C. After stirring for 2 h at −7° C. the reaction mixture was filtered, the filtrate was treated with 24 mg NaBH4 and warmed to room temperature. After 2 h additional 24 mg NaBH4 were added and the reaction mixture stirred for 16 h. Then, 110 μl MeOH in 4 ml THF were added within 2 h and the reaction mixture was stirred for additional 4 h at room temperature. After removal of the solvents under reduced pressure the residue was purified by chromatography on silica gel eluting with DCM/MeOH 8:2. The fractions containing the product were collected and evaporated under reduced pressure.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C[O-].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][C@@H:25]([CH3:26])[C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:8]2[CH:19]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 391 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:9][N:8]=1>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1cnc(CCl)cc1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cnc(CN=[N+]=[N-])cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium azide (2.82 g, 43.3 mmole) in 30 mL of N,N-dimethylformamide is added 2-chloromethyl-5-propoxy-pyridin-4-ol (8.74 g, 43.3 mmole). This is stirred for overnight at ambient temperature then quenched into ice water. The solid formed is filtered, washed with cold water and dried to give an off white solid, 5.74 g, (63%); MS (ES+): m/z 209.3 (M+H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH3:25])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (30.0 g), 2-methylimidazole (20.6 g), potassium carbonate (34.6 g), and N,N-dimethylformamide (50 ml) was stirred at 125° C. for 1 hour. The reaction mixture was poured into ice water (500 ml). The precipitated crystals were filtered, washed in sequence with water and isopropyl ether, and air-dried to give crude crystals of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole (34.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCC(=S)N2
Temperature: 105 °C
Reaction time: 1.17 h
Yield: 183.2 %

Procedure:
A solution of 20.0 g of 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepin-2(1H)-one (G. M. Clarke, J. B. Lee, F. J. Swinbourne & B. Williamson, J. Chem. Res. Synop. 1980, 400) in 100 ml of hexamethylphosphoric acid triamide was treated with 14 g of Lawesson reagent and the mixture was stirred at 105° C. for 70 min. The reaction mixture was poured into 800 ml of saturated aqueous sodium hydrogen carbonate solution and 800 ml of water. After stirring at room temperature for 15 min. the precipitate was filtered off, washed with water and dried. There were obtained 20 g of crude 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione, which was used in this form for the next step.
Reaction SMILES: Br[C:2]1[C:3](=[O:27])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:5]=2.[Cu][C:29]#[N:30].[Cl-].[NH4+]>CN(C)C=O>[O:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[C:29]#[N:30]
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
2-Bromo-3-phenyl-6-(3-phenylpropoxy)indene-1-one (1.0 g, 2.3 mmol) was dissolved in N,N-dimethylformamide (10 ml). Copper (I) cyanide (617 mg, 6.9 mmol) was added thereto and the mixture was stirred for 3 hours at 150° C. The mixture was cooled, and saturated ammonium chloride was added thereto. The organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:3) to obtain the title compound (700 mg, yield 80%) as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>O1CCCC1.C(OCC)(=O)C>[C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])(=[O:18])[NH2:29]
Reactant: N
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 91.2 %

Procedure:
A solution of 1.05 g (2.5 mmol) of crude (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride in 29 ml (9.3 mmol) of 0.32M ammonia in tetrahydrofuran was stirred at room temperature for 5 hours. Subsequently, the reaction solution was diluted with 40 ml of ethyl acetate and extracted with 20 ml of 1N hydrochloric acid. The ethyl acetate extract was then washed with 20 ml of saturated sodium hydrogen carbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There was obtained 0.92 g of benzyl rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamate as a colourless solid, MS: 312 (M-benzyl)+.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)(=O)C>[F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:27]=1
Reactant: COc1ccc(NN)cc1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(SC)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of 4,4-difluoro-1-[4-(methylthio)phenyl]-butane-1,3-dione (2.4 g) and 4-methoxyphenylhydrazine hydrochloride (1.9 g) in acetic acid (10 ml) was stirred at 100° C. for 1 hour. The solvent was evaporated and the residue was purified by column chromatography on silica gel (30 g) eluting with toluene. The purified oily product was crystallized from ethanol to give crystals of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (2.5 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Yield: 78.7 %

Procedure:
Cyclohexylamine (2.95 mL, 25.78 mmol) was added to a solution of Compound 39 (4.4 g, 12.89 mmol) in toluene (50 mL) and refluxed for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 4.0 g (78%) of white solids. M.P. 130–134° C. 1H NMR (DMSO-d6): δ 1.37 (m, 5H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 3.87 (m, 1H), 5.29 (s, 2H), 7.17 (m, 2H), 7.23 (m, 1H), 7.33 (m, 1H), 7.46 (dd, J=3.9, 9.1 Hz, 1H), 7.57 (td, J=2.9, 8.3 Hz, 1H), 7.81 (dd, J=2.9, 8.8 Hz, 1H). EIMS m/z 394 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCNc1ccccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCCNc1ccccn1)c1ccccc1

Procedure:
A mixture of 2-(3-aminopropylamino)pyridine (6 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for 1 hour and concentrated to give N-benzoyl-N'-[3-(2-pyridylamino)propyl]thiourea. The benzoyl thiourea is added to a solution of potassium carbonate (1.4 g.) in water (80 ml.) at 60°. The solution is maintained at this temperature for 1 hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid is removed by filtration and the filtrate is basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the title product is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16].[C:17]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])([CH3:20])([CH3:19])[CH3:18]>C(#N)C.O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][C:23]([CH3:25])([CH3:24])[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:27])=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: COc1cc(F)ccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(F)ccc1OC(C)(C)C(=O)OC(C)(C)C

Procedure:
Potassium carbonate (0.97 g) was added to a solution of 2-methoxy-4-fluorophenol (1.0 g) and tert-butyl-2-bromoisobutyrate (1.31 ml) in acetonitrile (20 ml) and heated under reflux for 26 h. The mixture was diluted with water and extracted with ethyl acetate, the organics were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with using isohexane:diethylether 3:1, yield 0.83 g.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:11])[CH3:10]>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:11])[CH3:10]
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 25 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of 4-dimethyl-aminopyridine (476 mg, 3.9 mmol) in ethyl acetate (15 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in ethyl acetate (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (118 mg, 25%) as a colorless clear syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([CH3:20])=[C:6]([CH3:19])[C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl.[Cl:29][CH2:30][C:31](=N)OCC>C(Cl)(Cl)Cl>[Cl:29][CH2:30][C:31]1[N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]2[C:6]([CH3:19])=[C:5]([CH3:20])[N:4]=[C:3]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:2]=2[N:1]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(Oc2ccccc2)c2nc(CCl)n(CCNC(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
tert-Butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate (17.9 g, 48.1 mmol), prepared as described in U.S. Pat. No. 6,545,016 Example 23, Parts A through C, was dissolved in chloroform (250 mL). Ethyl 2-chloroacetimidate hydrochloride (15.2 g, 96 mmol) was added to the solution and the reaction mixture was stirred at 60° C. for 5 hours. Additional ethyl 2-chloroacetimidate hydrochloride (1.9 g) was added to the reaction mixture and stirred for 0.5 hours. The reaction mixture was cooled and filtered. The filtrate was diluted with chloroform (250 mL), washed with brine (2×300 mL), and the layers were separated. The combined organics were dried over magnesium sulfate, filtered with CELITE filter aid, and concentrated under reduced pressure. The material was recrystallized and filtered from acetonitrile to yield 13.28 g of tert-butyl 2-[2-(chloromethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethylcarbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[N:11]1.[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[C:12]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[N:11]1
Reactant: c1c[nH]cn1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1n1ccnc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
66 g (0.1 mol) of 1-(2,4,6-trichlorophenyl)-3-[α-(2,4-di-tert-amylphenoxy)butyramido]-4-bromo-5-oxo-2-pyrazoline and 27.2 g (0.4 mol) of imidazole were well mixed with each other in a mortar, then stirred for 2 hours under heating to 100° C. To the reaction mixture was added 200 ml of methanol to prepare a solution. Then 1 liter of ethyl acetate was added thereto, followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate, and concentrated. Upon crystallization of the residue from acetonitrile-ethyl acetate (volume ratio:20.1), 48 g of pure Coupler (1) was obtained. The melting point of the coupler was 185°-187° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([OH:59])=O)[NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:60]([O:67][C:68](=[O:91])[NH:69][CH2:70][CH2:71][CH2:72][C@H:73]([NH2:90])[C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[O:81])=[O:75])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([NH:90][C@H:73]([C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)=[O:81])=[O:75])[CH2:72][CH2:71][CH2:70][NH:69][C:68]([O:67][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:91])=[O:59])[NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
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: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
350 mg (0.92 mmol) of HATU and 330 mg (2.56 mmol) of N,N-diisopropylethylamine are added to a solution of 320 mg (0.88 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine and 350 mg (0.73 mmol) of benzyl{(4S)-4-amino-5-[(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-5-oxopentyl}carbamate (Example 122A) in 5 ml of anhydrous DMF at 0° C. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is stirred with water, collected by filtration and dried under high vacuum.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][CH2:20][NH2:21].Cl.Cl>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH2:20][NH2:21])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC(=O)[C@@H](N)CCCN
Agent: Cl
Product: NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
It is also possible according to the present invention to employ a non-proteinogenic amino acid as a nucleophile. Mal-Tyr-OEt, an electrophile, and Orn-OEt.2HCl, a nucleophile, were reacted using α-CT as a catalyst. After a reaction time of 20 minutes, the solution was concentrated, the enzyme was separated off by ultrafiltration with a membrane with MWCO 10,000, and the dissolved fraction was lyophilized. Both Mal-Tyr-Orn and the Orn delta-lactam cyclization product were isolated by preparative HPLC and identified by 1H-NMR. The combined yield of the two products (about 1:1) was about 45-50%.