Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([C:20]3[C:25](F)=[CH:24][C:23](C#N)=[CH:22][C:21]=3F)C(OCC)=O)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].C[O:37][CH:38]([OH:40])C>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:20]3[CH:25]=[CH:24][C:23]([C:38]([OH:40])=[O:37])=[CH:22][CH:21]=3)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:31][CH:32]=1
Reactant: COC(C)O
Reactant: CCOC(=O)C(c1c(F)cc(C#N)cc1F)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cc2ccc(C(=O)O)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of ethyl 2-[5-(4-chlorobenzoyl)-1,4-dimethylpyrrol-2-yl]-2-(2,6-difluoro-4-cyanophenyl)acetate (0.05 g, 0.11 mmol) [prepared as described in Example 9, Step (a)] in methoxyethanol (4 ml) was added an aqueous solution of lithium hydroxide monohydrate (0.02 g in 0.5 ml H2O), and the reaction mixture was heated at reflux under an argon atmosphere. After 24 hr, the reaction mixture was cooled to room temperature and poured into a mixture of ice/water (40 ml) containing IN HCl (1 ml). The solid was filtered to give crude {4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.037 g) as a tan solid. Flash chromatography on a silica gel column (0.5% acetic acid-30% acetone:hexane), followed by recrystallization from methanol-acetone gave pure {4-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.032 g, 70.2% yield) as a white solid, mp 245-246.8° C. ##STR48##
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C.C(OCC)C>[NH2:5][CH2:6][CH:7]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 101.5 %

Procedure:
The solution of 4.25 g (10 mmol) of 2-phtalimidomethyl-1,4-di-phenylmethyl piperazine and 1.25 g (25 mmol) of hydrazine monohydrate in 50 ml ethanol was stirred 2 hours under reflux. Insoluble material was filtered off. The ethanol layer was evaporated to dryness to afford a residue taken up in 20 ml ethyl ether, filtered again and evaporated to give 3.0 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1[CH2:29][CH2:28][CH2:27][CH2:26]1.ICCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:26]([NH:1][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:27][CH2:28][CH3:29]
Reactant: CCOC(=O)c1c(N)nc(SC)n1C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1nc(SC)n(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To ethyl 4-amino-1-methyl-2-(methylthio)imidazole-5-carboxylate (3.014 g, 14.00 mmol), prepared by the method of Gompper et al., Tetrahedron Lett. 1885 (1966), in dimethylformamide (50 mL) at 0° C. was added a solution of 1.0M sodium bis(trimethylsilyl)amide in tetrahydrofuran (14.0 mL, 14.0 mmol). After 1 hour, 1-iodobutane (1.75 mL, 15.4 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue on silica gel eluting with 5% ethyl acetate in hexane afforded 2.706 g (71%) of the desired product as an oil. TLC (10% ethyl acetate/90% hexane) Rf =0.24. 1H NMR (CDCl3, 300 MHz) d 0.94 (t, 3H), 1.34 (t, 3H), 1.35-1.65 (m, 4H), 2.62 (s, 3H), 3.38-3.49 (m, 2H), 3.66 (s, 3H), 4.28 (q, 2H), 5.58 (br s, 1H). MS (DCl/NH3) m/e 272 (M+H)+.
Reaction SMILES: NC1C(NCCSCC2C=C(CN(C)C)SC=2)=NS(=O)N=1.[NH2:22][C:23]1[C:27]([NH:28][CH2:29][CH2:30][S:31][CH2:32][C:33]2[O:34][C:35]([CH2:38][N:39]([CH3:41])[CH3:40])=[CH:36][CH:37]=2)=[N:26][S:25](=O)[N:24]=1>>[NH2:22][C:23]1[C:27]([NH:28][CH2:29][CH2:30][S:31][CH2:32][C:33]2[O:34][C:35]([CH2:38][N:39]([CH3:41])[CH3:40])=[CH:36][CH:37]=2)=[N:26][S:25][N:24]=1
Reactant: CN(C)Cc1ccc(CSCCNC2=NS(=O)N=C2N)o1
Agent: CN(C)Cc1cc(CSCCNC2=NS(=O)N=C2N)cs1
Product: CN(C)Cc1ccc(CSCCNc2nsnc2N)o1

Procedure:
The general procedure of Example 5 is repeated except that the 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide utilized therein is replaced by an equimolar amount of 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide [prepared according to U.S. Pat. No. 4,374,248], and the title compound is thereby produced. Treatment of a portion of the product with an equivalent amount of 2 N HCl in methanol produces the hydrochloride salt of the title compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[O:37])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(=CC)C.[O-:48]Cl=O.[Na+].Cl>C1COCC1.CC(O)(C)C.O.CCOC(C)=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:48])=[O:37])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: [O-][Cl+][O-]
Reactant: CCN(CCCCC=O)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCCCC(=O)O)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]pentanal (6.8 mg, 0.011 mmol) in THF (20 μL) and t-BuOH (60 μL) was added 2-methyl-2-butene (20 μL), followed by a solution of NaClO2 (3.0 mg, 0.024 mmol) and NaH2PO4 (3.5 mg, 0.024 mmol) in water (25 μL). The reaction was stirred at room temperature for 30 minutes and then diluted with EtOAc (8 mL) and water (2 mL), acidified with 1 N HCl (2 mL), and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (EtOAc) afforded 5-[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]pentanoic acid. Rf=0.20 (EtOAc). LCMS=631.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.18-7.15 (m, 3H), 5.73 (d, J=8.0 Hz, 1H), 4.75 (d, J=16.5 Hz, 1H), 4.58 (m, 1H), 4.03 (s, 1H), 2.97 (m, 4H), 2.31 (t, J=7.3 Hz, 2H), 1.40-1.23 (m, 5H), 1.00 (t, J=6.7 Hz, 3H), 0.69 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 78.2 %

Procedure:
10.6 g of 4'-hydroxybiphenyl-4-carboxylic acid and 18.7 g of (+)-2-methylbutanol were heat-refluxed for 20 hours in benzene together with 1 ml of sulfuric acid. The mixture was subjected to filtration, condensation acid recrystallization to obtain 11.0 g of the objective product (yield: 83%).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:44])([CH3:43])[NH:37][S:38]([CH2:41][CH3:42])(=O)=[O:39]>C(Cl)(Cl)Cl>[CH3:35][Si:36]([CH3:44])([CH3:43])[N:37]=[S:38]([Cl:1])([CH2:41][CH3:42])=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)N[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(Cl)=N[Si](C)(C)C

Procedure:
Hexachloroethane (0.1110 mol, 26.81 g), triphenylphosphine (0.1121 mol, 29.70 g), triethylamine (0.1110 mol, 15.7 mL), monosilylsulfonamide (3f) (0.1110 mol, 20.1 g). 1H NMR signals (90 MHz, CHCl3): 0.00 (s, 9H), 1.27 (t, 3H), 3.23 (q, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[CH:6][NH:7]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[CH:6][NH:7]2
Reactant: COc1ccc(-c2c[nH]c3c(OC)ccc(F)c3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccc(O)cc2)c[nH]c2c(O)ccc(F)c12
Temperature: -10 °C
Reaction time: 15 h
Yield: 39.7 %

Procedure:
5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (1.0 g, 3.34 mmol) was suspended in dichloromethane (40 ml), and the suspension was cooled to −10° C. in a methanol-ice bath. A 1N boron tribromide (17 ml) was added thereto, and the resulting mixture was stirred at room temperature for 15 hours. Ice water and dichloromethane were added to the reaction mixture, and the resultant insoluble matter was collected by filtration. The substance remaining on the filter was washed with water, dried and purified by silica gel column chromatography (dichloromethane:methanol=20:1→8:1→ethyl acetate:methanol=4:1). The purified product was concentrated under reduced pressure and ethyl acetate was then added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and dried to thereby obtain 360 mg of powdery pale gray 5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4-one (yield: 40%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18]C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:11]>ClCCl>[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Trifluoroacetic acid (13.47 mL, 19.94 mmol, 15.0 eq) is added at 0° C. to a stirred solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester (3.53 g, 11.66 mmol, 1.0 eq) in dichloromethane (100 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and water (50 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-amino-cyclohexanecarboxylic acid methyl ester as a yellow oil (1.53 g, 79% yield).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[S:28]1[CH2:32][CH:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH:30][CH2:29]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:30]2[CH:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:32][S:28][CH2:29]2)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)C1CSCN1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1

Procedure:
One-tenth mole of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([C:18]1[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:23]([C:21]2[O:20][N:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:22]=2)=[O:24])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Nc2nc(Br)ccc2[N+](=O)[O-])on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-bromo-3-nitro-pyridin-2-ylamine (500 mg, 2.29 mmol) in THF (10 mL) was treated with NaH (275 mg, 6.88 mmol) at room temperature for 1 h. Simultaneously a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (524 mg, 3.10 mmol, prepared as described in Example I) in DCM (10 mL) was treated with oxalyl chloride (270 μL, 3.10 mmol) and DMF (2 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a solid. 1H-NMR (400 MHz, CDCl3) δ: 10.85 (br. s., 1H), 8.37 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.03 (s, 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C13H13BrN4O4: 369.0 (M+H). Measured: 369.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:18])[C:8]3([CH2:17][CH2:16]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1.[CH3:19]I.[H-].[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3([CH2:16][CH2:17]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1
Reactant: CI
Reactant: CC(C)N1CC2(CC2)C(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)N1CC2(CC2)C(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 2′-chloro-9′-isopropyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 209; 5.055 g, 19 mmol) in DMA (300 mL) was added methyl iodide (1.305 mL, 20.9 mmol), followed by sodium hydride (60% mineral oil dispersion; 814 mg, 20.33 mmol). The mixture was stirred at room temperature for 30 minutes. The DMA was removed in vacuo, then water (50 mL) was added. The product precipitated as a sticky gum, which turned into a solid on sonication. The solid was collected by filtration to give a brown powder. This material was dissolved in DCM and dried over sodium sulfate, then purified by column chromatography, eluting with 25% ethyl acetate in hexane, to yield the title compound as a white solid (3.73 g, 70%)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:9]([CH2:10][CH3:11])[CH2:8]1.C[O-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[C:1]([O:6][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=C(C)C(=O)OCCCCO
Temperature: 25 °C
Reaction time: 98 h
Yield: 51.9 %

Procedure:
Methacrylic acid (86 g.), 1,2-epoxybutane (36 g.), and a 40% solution of benzyltrimethylammoniummethoxide in methanol (21 g.) were charged to a round bottom flask and stirred at room temperature for 98 hours. 300 ml. of a 7% sodium hydroxide solution and 200 ml. of ethyl acetate were added to the mixture, the organic layer separated, and the basic aqueous layer given a second wash with 200 ml. of ethyl acetate. The organic fractions were then combined, and washed successively with 300 ml. of 7% sodium hydroxide and three 200 ml. portions of water, the spent wash solutions being decanted between washings. Excess moisture was removed from the washed organic phase with sodium sulfate and the ethyl acetate was stripped off to yield hydroxybutyl methacrylate (41 g.). This product was taken up in 60 ml. of benzene and pyridine (22 g.). Cinnamoyl chloride (50.4 g.) in 75 ml. of benzene was added dropwise with stirring to the hydroxybutyl methacrylate solution and the resulting mixture allowed to react for a period of 24 hours. After the reaction was complete pyridine hydrochloride formed by the reaction was filtered off, the filtrate washed and the product cinnamoylated hydroxybutyl methacrylate recovered in the manner described in Example 8.
Reaction SMILES: ClC1C=C(C2C=C(C([N:16]3[CH2:20][CH2:19][S:18][CH2:17]3)=O)OC=2C2C=C(C#N)C=CC=2)C=C(F)C=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([OH:44])=O)=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:16]3[CH2:20][CH2:19][S:18][CH2:17]3)=[O:44])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: N#Cc1cccc(-c2oc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)c1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1)N1CCSC1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with the compound from Example 21A. 144 mg (48% of theory) of the title compound are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.[CH2:31]1[C:34]2([C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]2)[CH2:33][NH:32]1.C(OC1C=CC(C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)=C(C(F)(F)F)C=1)(C)C.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:22]1([C:16]2[O:15][N:14]=[C:13]([C:12]3[O:11][N:10]=[C:9]4[C:28]5[C:5]([CH2:6][CH2:7][C:8]=34)=[CH:4][C:3]([CH2:2][N:32]3[CH2:31][C:34]4([C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]4)[CH2:33]3)=[CH:30][CH:29]=5)[C:17]=2[C:18]([F:21])([F:19])[F:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=O)C2(CNC2)N1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CN(Cc3ccc4c(c3)CCc3c-4noc3-c3noc(-c4ccccc4)c3C(F)(F)F)C2)N1
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 65.4 %

Procedure:
To a stirred mixture of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6C, 25 mg, 0.053 mmol), 2,5,7-triazaspiro[3.4]octane-6,8-dione, hydrochloric acid (Preparation 17B, 11 mg, 0.079 mmol), and anhydrous dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.046 mL, 0.263 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 80 min. The reaction mixture was concentrated and subjected to prep HPLC conditions (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were concentrated to yield an aqueous suspension of the product, to which saturated aqueous sodium bicarbonate solution (1 mL) was added to make the mixture basic. The solid was filtered and washed with water (3×1 mL) and then lyophilized to give 2-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)-2,5,7-triazaspiro[3.4]octane-6,8-dione (19 mg, 0.034 mmol, 65.4% yield) as a white solid. The compound had an HPLC retention time=3.19 min (condition C); LC/MS M+1=536.3; 1H NMR (400 MHz, MeOD) δ ppm 7.92 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.58-7.71 (3H, m), 7.40 (1H, s), 7.37 (1H, d, J=7.7 Hz), 3.78 (2H, s), 3.75 (2H, d, J=8.6 Hz), 3.48 (2H, d, J=8.8 Hz), 3.08 (4H, s).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:32]([NH:34][C@@H:35]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:80]([NH:82][C@H:83]([C:87]([O:89][CH3:90])=[O:88])[C@@H:84]([CH3:86])[OH:85])=[O:81])[CH2:73][S:74][CH2:75][NH:76][C:77]([CH3:79])=[O:78])=[O:70])[C@@H:66]([CH3:68])[OH:67])=[O:63])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54]C(OC(C)(C)C)=O)=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])[CH2:14][S:15][CH2:16][NH:17][C:18]([CH3:20])=[O:19])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.SC(O)C.[C:102]([OH:108])([C:104]([F:107])([F:106])[F:105])=[O:103]>C(Cl)Cl>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:32]([NH:34][C@@H:35]([C:46]([NH:48][C@H:49]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:80]([NH:82][C@H:83]([C:87]([O:89][CH3:90])=[O:88])[C@@H:84]([CH3:86])[OH:85])=[O:81])[CH2:73][S:74][CH2:75][NH:76][C:77]([CH3:79])=[O:78])=[O:70])[C@@H:66]([CH3:68])[OH:67])=[O:63])[CH2:50][CH2:51][CH2:52][CH2:53][NH2:54])=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])[CH2:14][S:15][CH2:16][NH:17][C:18]([CH3:20])=[O:19])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:105][C:104]([C:102]([OH:108])=[O:103])([F:107])[F:106]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O)[C@@H](C)O
Agent: CC(O)S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](N)Cc1ccccc1)[C@@H](C)O)[C@@H](C)O
Temperature: 0 °C

Procedure:
The octapeptide ester XVIII (11 g, 7.9 mm anisole, 2 ml) and mercaptoethanol (2 ml) are suspended in DCM (20 ml) under N2. The suspension is cooled to 0° C. and TFA (80 ml) is added. Stirring is continued for one and half hour at same temperature. The TFA and DCM are evaporated under vacuum at 30° C., ether (200 ml) is added to the residue under stirring. The precipitates are filtered, washed with diethyl ether (300 ml) and dried in vacuum to give compound XIX: Yield 10.0 g (91%). ESMS=1191 (M+H). H-(D)-Phe-Cys(Acm)-Phe-(D)-Trp-Lys-Thr-Cys(Acm)-Throninol·2TFA  (XVI)
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)CCCCN.N[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18]>>[NH2:1][CH2:2][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18]
Reactant: NCCCCC(=O)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Product: NCCCCCC(=O)C(=O)O

Procedure:
In an alternative embodiment, lysine is first converted to 6-amino-2-oxohexanoic acid by an aminotransferase enzyme (EC 2.6.1.x) or a dehydrogenase (EC 1.4.1.x or EC 1.4.3.x). Preferred enzymes are listed in Table 7 and may be engineered to catalyze the desired substrate to product reaction. In a subsequent step, 6-amino-2-oxohexanoic acid is subjected to a carbon elongation enzymatic step to produce 7-amino-2-oxoheptanoic acid.