Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31]O)[CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCCC1.CS(C)=O>[F:34][C:24]([F:23])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:26]=1
Reactant: OCc1cc(C(F)(F)F)ccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C1N(Cc2cc(C(F)(F)F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a solution of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.753 g, 2.55 mmol), [4-(trifluoromethyl)pyridin-2-yl]methanol (Ashimori et al., Chem. Pharm. Bull. (1990) 38:2446-2458) (0.655 g, 3.70 mmol) and tri-n-butylphosphine (0.93 mL, 3.7 mmol) in anhydrous tetrahydrofuran (20 mL) and anhydrous dimethylsulfoxide (0.2 mL) at ambient temperature was added over a period of 10 min a solution of diethyl azodicarboxylate (0.64 mL, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and was poured into 1 M hydrochloric acid (50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 80% to 100% gradient of dichloromethane in hexanes, followed by a 0% to 20% gradient of ethyl acetate in dichloromethane and recrystallization from methanol afforded 1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.164 g, 10%) as a colorless solid: mp 154-155° C. (methanol); 1H NMR (300 MHz, CDCl3) δ8.76 (d, J=5.1 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=5.1 Hz, 1H), 7.24-7.16 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.04 (d, J=16.1 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.23-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.8, 157.3, 155.3, 150.8, 144.8, 141.9, 139.8, 138.5, 132.3, 129.0, 124.1, 123.9, 121.1, 118.7, 117.6, 111.8, 109.3, 99.5, 80.1, 64.7, 64.0, 58.2, 45.8; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1F)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (805 mg, 3.36 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-fluorophenyl isocyanate (565 mg/ml, 5.04 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8c as oil. Yield: 1.02 g, 80.56%.
Reaction SMILES: B.[Na].[CH:3]([Si:6]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[C:7]1[O:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=1)([CH3:5])[CH3:4]>CO.N1C=CC=CC=1.O.C(OCC)(=O)C>[CH:17]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:14]([CH3:16])[CH3:15])[C:7]1[O:8][C:9]([CH2:12][OH:13])=[CH:10][N:11]=1)([CH3:19])[CH3:18]
Reactant: CC(C)[Si](c1ncc(C=O)o1)(C(C)C)C(C)C
Agent: B
Agent: [Na]
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[Si](c1ncc(CO)o1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodiumboron hydride (200 mg, 5.5 mmol) was added to a solution of 2-triisopropylsilyl-oxazole-5-carboxaldehyde (0.7 g, 2.7 mmol) in a mixture of methanol and tetrahydrofuran (1/1, 20 mL) and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give (2-triisopropylsilanyl-oxazol-5-yl)-methanol without further purifications. This material was treated with 4-chloro-2-nitro-phenol as described in Preparation 20, Step A, to give 0.7 g of 5-(4-chloro-2-nitro-phenoxymethyl)-2-triisopropylsilanyl-oxazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C(Cl)Cl.[Cu](I)I.O1CCOCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([N:23]2[C:24]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)cc(-n2c3ccccc3c3ccccc32)c1
Temperature: 95 °C

Procedure:
To a three neck round bottom flask, was charged bromo-3,5-dimethoxybenzene (1.54 g, 7.1 mmol), carbazole (1.186 g, 7.1 mmol), potassium phosphate (3 g, 14.2 mmol) and copper iodide (0.14 g, 0.7 mmol). Dioxane (40 ml) was added and the reaction flask. The flask was evacuated and flushed with argon. Dimethylethylene diamine (0.14 g, 1.6 mmol) was then added to the reaction flask under a strong purge of argon. The reaction mixture was then heated at 95° C. for 48 h under argon. The reaction was followed by TLC. After the reaction was complete, the solution was cooled down to room temperature, and 10 mL of H2O was added. The reaction mixture was extracted with methylene chloride and the organic and aqueous phases were separated. The organic phase was further washed twice with 100 mL of water (×2) and once with 100 mL of brine (×1) and dried over Na2SO4. After solvent removal under vacuo, afforded crude product. Crude product was dissolved in CH2Cl2 and hexanes were added until the colored residues precipitated out. The solution was filtered to remove the colored residues. The mother liquor was concentrated to afford 1.0 g (46.5%) of light yellow oil as the product. 1H NMR (CDCl3) δ 7.98 (d, 2H), 7.35 (d, 2H), 7.23 (d, 2H), 7.11 (t, 2H), 6.6 (s, 2H), 6.43 (s, 1H), 3.65 (s, 6H). EI-MS: 303(M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].COCCOC.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(N)=O)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 93 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol), [4-(aminocarbonyl)phenyl]boronic acid (52.9 mg, 0.31 mmol), bis(triphenylphosphine)palladium(II) chloride (8.7 mg, 0.01 mmol), DME/water (4 mL, 3:1) and sodium bicarbonate (54 mg, 0.62 mmol). The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica gel. The product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH (gradient 0 to 90:10:1). The collected solid was suspended in EtOH, sonicated, and filtered. After further washing with EtOH/DCM, the filtered solid was then air-dried for 15 min, and then in vacuum oven overnight. The final product was collected as 70 mg (69%). LCMS E-S (M+H)=459.3 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1 H) 9.00 (t, J=4.93 Hz, 1 H) 8.41 (s, 1 H) 8.36 (s, 1 H) 8.34 (s, 1 H) 8.24 (s, 1 H) 8.13 (s, 1 H) 8.06 (s, 1 H) 8.04 (s, 1 H) 7.51 (s, 1 H) 5.91 (s, 1 H) 5.37 (quin, J=6.69 Hz, 1 H) 4.42 (d, J=4.80 Hz, 2 H) 2.23 (s, 3 H) 2.13 (s, 3 H) 1.56 (s, 3 H) 1.55 (s, 3 H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1c(N)cccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
Add isopropyl chloroformate (20.7 mL, 20.7 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-fluor-benzoic acid methyl ester (3.5 g, 20.7 mmol) and pyridine (4.2 mL, 51.75 mmol) in dichloromethane (41 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.00 g, 63%). MS (ES+): 256 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:42]([OH:45])[C:43]#[CH:44].CCN(CC)CC>CN(C=O)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:44]#[C:43][CH2:42][OH:45])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Temperature: 90 °C
Yield: 51.9 %

Procedure:
A mixture of compound 34C (0.38 g, 0.564 mmol), prop-2-yn-1-ol (0.047 g, 0.846 mmol), CuI (0.011 g, 0.056 mmol), Et3N (1.57 mL, 11 mmol) and Pd(PPh3)2Cl2 (0.02 g, 0.028 mmol) in DMF (2 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with CH2Cl2. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with 3:2/hexanes:EtOAc to provide 0.19 g of the desired product 36B as a mixture of two inseparable isomers: MS (ESI(+)): m/z 649 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[C:5]([N+:25]([O-:27])=[O:26])[CH:4]=1.Cl.[NH2:29]O>N1C=CC=CC=1>[CH2:20]([C:19]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:25]([O-:27])=[O:26])=[C:15]([CH2:16][CH3:17])[O:18][N:29]=1)[CH3:21]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1[N+](=O)[O-])C(=O)CC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1CCCCCCOc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
3,5-Diethyl-4-[6-(4-methoxy-2-nitrophenoxy)hexyl]isoxazole [I; Ar is 2-O2N-4-CH3OC6H3, Y is O(CH2)6, R is C2H5 ] was prepared from 10.0 g. of 4-[6-(4-methoxy-2-nitrophenoxy)hexyl]-3,5-heptanedione and 2.0 g. of hydroxylamine hydrochloride in 40 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a yellow oil, b.p. 200°-205° C. (0.02 mm.); yield 7.5 g.; MIC=3 μg/ml (herpes 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:14]([F:15])([F:17])[F:16])[CH:4]=3)[CH2:9][CH2:10]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [NH2:1][C@@:2]([C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[F:24])([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([O:6][CH2:7][C:8](OCC)=[O:9])[CH3:5].C[Al](C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C@:2]2([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([CH3:5])[O:6][CH2:7][C:8](=[O:9])[NH:1]2)[CH:22]=1
Reactant: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(N)c1cc(Br)ccc1F
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Temperature: 23 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of (R)-ethyl 2-(4-amino-4-(5-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (intermediate A22A) (6.85 g, 16.6 mmol) in toluene (205 ml) at 23° C. was dropwise added trimethylaluminum (2 M in toluene, 10.8 ml, 21.6 mmol) and the light yellow solution was stirred at 23° C. for 2 h. Poured into sat. NaHCO3-sol., extracted with ethyl acetate, washed organic layer with brine, dried over Na2SO4, filtered off and evaporated totally, dried in high vacuum to give the (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (5.95 g, 16.2 mmol, 97.8% yield) as a light yellow solid, which was used without further purification. MS (ISP): m/z=366.2 [(M+H)+] and 368.1 [(M+2+H)+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]#[N:22])=[CH:16][C:15]=1[O:30][CH3:31].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[C:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:21]#[N:22])[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([O:30][CH3:31])[CH:16]=1)[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1ccc(F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a −78° C. cooled solution of diisopropylamine (5.11 ml, 35.8 mmol) in THF was added n-butyllithium (22.40 ml, 35.8 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up <−40° C. 2-(4-Fluoro-3-methoxyphenyl)-3-phenylpropanenitrile (6.1 g, 23.89 mmol) dissolved in THF was added followed by ethyl chloroformate (3.42 ml, 35.8 mmol). The reaction mixture was stirred over night and was allowed to heat up to room temperature. Evaporated solvents and redissolved in EtOAc, washed with 10% citric acid, water and brine and the combined organic layers were dried over MgSO4, filtered and evaporated to obtain 7.2 g of a yellow oil, that was purified by flash chromatography on 330 g SiO2 using 20% EtOAc in cyclohexene to obtain 18.26 g of the desired product as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)C3)ccc1-2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(N)CC4)C3)ccc1-2
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a suspension of (1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4N HCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for 18 hours. The resulting solid was filtered off and washed with diethyl ether before being partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM). The resulting solid was suspended in ether and collected by filtration to give 425 as a white solid (108 mg, 59%). LCMS: RT=7.96 min, [M+H]+=451. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d, J=8.20 Hz), 8.02 (1H, s), 7.20 (1H, dd, J=8.22, 1.81 Hz), 7.05 (1H, s), 5.86-5.78 (1H, m), 4.59 (2H, t, J=9.01 Hz), 4.40 (2H, t, J=5.07 Hz), 4.20 (2H, d, J=7.67 Hz), 3.85 (1H, t, J=7.50 Hz), 3.44 (2H, t, J=5.08 Hz), 2.18 (2H, s), 1.58 (6H, d, J=6.59 Hz), 1.09-1.06 (2H, m), 0.70 (2H, q, J=3.28 Hz)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[Cl:38]>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:23][C:40](=[O:41])[NH:39][C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CN(CC(C)C(OC(=O)Nc2ccc(Cl)c(Cl)c2)c2ccc(C(C)(C)C)cc2)CC(C)O1
Yield: 76.9 %

Procedure:
6.8 g (0.021 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) and 0.6 mole of triethylamine were dissolved in 60 ml of acetonitrile, and a solution of 4.0 g of 3,4-dichlorophenyl isocyanate in 10 ml of acetonitrile was added dropwise at room temperature. The mixture was subsequently stirred under reflux for one hour, cooled and concentrated. The residue was taken up in ethyl acetate and the ethyl acetate was washed with water, dried over sodium sulphate and concentrated. 8.2 g (70% of theory) of 1-(p-tert.-butyl-phenyl)-1-(3,4-dichlorophenyl-carbamoyloxy)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].N([O-])=[O:25].[Na+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: O=N[O-]
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide are dissolved in 15 ml of 90 % sulfuric acid and while stirring at 20° to 30° a solution of 0.7 g sodium nitrite in a little water is passed dropwise under the surface. Gentle heating is carried out until the evolution of gas is terminated and the mixture is then poured on to an ice and water mixture. 5-Chloro-3-p-chlorophenyl-1-phenylpyrazole-4-acetic acid is produced; F 179.5°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.ClCCl.C(Cl)(=O)C(Cl)=O.C[N:22](C=O)C>>[CH3:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:22])=[O:7]
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A magnetically stirred mixture of acid 4-chloro-2-methylbenzoic acid (50 g, 0.29 mol), dichloromethane (200 mL), and 0.5 mL DMF was cooled in an ice-bath. The cooler was connected to a gas absorption trap. Oxalyl chloride (44.5 g, 0.35 mmol) was added dropwise in 1 h. The mixture was stirred at r.t. overnight during which time all solid dissolved. The solution was concentrated in vacuo and stripped with dichloromethane to remove excess oxalyl chloride. The residue was taken in THF (200 mL) and mechanically stirred in an ice-water bath. Aqueous 25% ammonia (100 mL) was added in 15 min, which resulted in the formation of a precipitate. The THF was removed with the rotavap and extra water (100 mL) was added. The suspension was stirred at r.t. overnight. The solid was collected by filtration and dried in vacuo to give 2-methyl-4-chlorobenzamide (43.7 g, yield 89%) that was used without purification in the next step.
Reaction SMILES: O.O.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([OH:9])=O.[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].CO>CCCCCO>[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([CH:18]([NH2:19])[CH2:17][CH2:16][CH2:15][C@@H:14]([C:20]([OH:22])=[O:21])[NH2:13])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Solvent: CCCCCO
Solvent: O
Solvent: CO
Product: NC(CCC[C@H](N)C(=O)O)C(=O)CC[C@H](N)C(=O)O

Procedure:
The 350 g of the L-lysine L-glutamate dihydrate, α-phase, previously prepared, still containing approximately 15% by weight of methanol, are suspended in 0.85 liter of n-amyl alcohol in a nitrogen atmosphere. The n-amyl alcohol is then heated, followed by the distillation at around 70° first of a ternary mixture containing n-amyl alcohol, methanol and water (approximately 0.1 liter) and then of a binary mixture of n-amyl alcohol and water (approximately 0.1 liter). Heating is terminated at the reflux temperature of the n-amyl alcohol i.e. at 138° C. After a total heating time of 20 hours, the precipitate formed is separated by filtration. This gives 400 g of crude product containing ε-(γ-L-glutamyl)-L-lysine and approximately 1 liter of amylic mother liquors from which 20 g of L-pyroglutamic acid are recovered from recycling after conversion into L-glutamic acid. The n-amyl alcohol is purified for recycling.