Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH:18]1[CH:23]([CH3:24])[CH2:22][CH2:21][NH:20][CH2:19]1)[C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:23]([CH3:24])[CH:18]([N:8]([CH3:7])[C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC(C)C(N(C)c3ncnc4[nH]ccc34)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a stirred solution of 1 mL of pyridine and 9 ml of dichloromethane was added 40 mg (0.163 mmol) of the product from Method H and 20 L of 4-methoxy-benzenesulfonyl chloride and the resulting mixture stirred at room temperature for 18 hours. The reaction was then quenched upon addition of saturated NaHCO3 (aq), the organic layer was removed and the aqueous layer extracted with dichloromethane. The dichloromethane layer was dried over Na2SO4 and concentrated to dryness in vacuo. The residue was purified by PTLC (silica; 10:1 dichloromethane/methanol) affording 22 mg (32%) of the title compound as a light yellow solid. LRMS: 416.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](O)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1.Cl.[F:25][C:26]([F:37])([F:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].FC(F)(F)S(Cl)(=O)=O.N1(C(OC(C)(C)C)=O)CCNCC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:33]3[CH2:32][CH2:31][N:30]([S:27]([C:26]([F:36])([F:37])[F:25])(=[O:28])=[O:29])[CH2:35][CH2:34]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH2:16]1
Reactant: O=S(=O)(N1CCNCC1)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=S(=O)(Cl)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C(F)(F)F)CC4)[nH]c3cc2Br)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid; hydrochloride (example 1, intermediate a) and 1-trifluoromethanesulfonyl-piperazine (prepared in analogy to International Patent Application Publ. No. WO 2003/064413 by using trifluoromethanesulfonyl chloride and tert-butyl 1-piperazinecarboxylate) to afford the title compound as a yellow solid (48%).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])[O:25][C:24]1([CH3:57])[CH3:56])=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](=[O:54])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:50]([CH3:51])[CH3:52])[O:25][C:24]1([CH3:56])[CH3:57])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benztriazol-1-yl-N,N,N','-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124 c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4].[CH3:34]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:34])=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4]
Reactant: CB(O)O
Reactant: CNC(=O)c1sc(Br)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CNC(=O)c1sc(C)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Yield: 4.6 %

Procedure:
A solution of 5-bromo-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (50 mg, 0.09 mmol), methylboronic acid (16.4 mg, 0.27 mmol), 2 M aqueous potassium phosphate solution (2 mL) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.004 mmol) in 1,4-dioxane (2 mL) was heated at 100° C. for 24 hours. The mixture was cooled and extracted with methyl ene chloride. The organic layer was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography with preparative TLC (methylene chloride and methanol (40:1)) followed by semipreparative HPLC gave of 5-methyl-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (2 mg, 5%): 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.44 (d, 1H), 7.33 (d, 1H), 7.0 (d, 1H), 6.53 (q, 1H), 4.48 (t, 2H), 3.38 (s, 3H), 2.94 (d, 3H), 2.83 (t, 2H), 2.43 (s, 3H), 1.95 (s, 3H); MS (m/e): 487.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2F)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(F)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 61) according to the procedure of Example 63 as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.56–1.62 (m, 2H), 2.04 (m, 2H), 2.63–2.75 (m, 5H), 2.86–2.95 (m, 4H), 3.01–3.10 (m, 4H), 4.50–4.55 (m, 1H), 5.33 (brs, 1H), 6.57–6.65 (m, 2H), 6.84–7.09 (m, 3H), 8.22 (s, 1H), 7.22–7.29 (m, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 530.0 (MH+); HRMS Calcd. for C25H29FN5O5S (MH+): 530.1873. Found: 530.1876.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][N:2]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.[I-].[K+]>CC(C)=O>[CH3:11][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nnc2sccc12
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2sccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a solution of 3H-thiopheno[2,3-d]1,2,3-triazin-4-one (80 mg, 0.522 mmol) in acetone (50 mL) was added sequentially potassium carbonate (144 mg, 1.04 mmol), iodomethane (0.04 mL, 0.627 mmol) and potassium iodide (catalytic) at rt and the mixture was stirred at rt for 3 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure, diluted with ice cold water and stirred for 10 min. The solution was extracted with chloroform (4×75 mL) and the combined CHCl3 layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as an off-white solid (50 mg, 57%), mp 104-108° C. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (1H, d, J=5.6 Hz), 7.64 (1H, d, J=5.6 Hz), 3.95 (3H, s); 13C NMR (100 MHz, CDCl3): δ 159.4, 153.9, 130.7, 125.6, 121.7, 37.3.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:36]1[C:37]([N:56]2[CH2:60][CH2:59][O:58][C:57]2=[O:61])=[CH:38][C:39]2[O:43][C:42]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=2[CH:55]=1.[F:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([Sn](C)(C)C)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:62][C:63]1[C:64]2[CH:65]=[C:66]3[C:75]4[N:76]=[C:77]([C:36]5[C:37]([N:56]6[CH2:60][CH2:59][O:58][C:57]6=[O:61])=[CH:38][C:39]6[O:43][C:42]([C:44]7[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=7)=[C:41]([C:51]([NH:53][CH3:54])=[O:52])[C:40]=6[CH:55]=5)[CH:78]=[CH:79][C:74]=4[O:73][CH2:72][N:67]3[C:68]=2[CH:69]=[CH:70][CH:71]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(Br)cc12
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 23.5 %

Procedure:
Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (11 mg, 0.02 mmol) was added to the mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (100 mg, 0.23 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (140 mg, 0.35 mmol) in dioxane/H2O (4 mL/0.2 mL) under N2. Then the reaction mixture was heated to 100° C. for 1 hour and filtered. The resulting residue was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:2) to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (32 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.94˜7.98 (m, 2H), 7.58 (s, 1H), 7.51 (m, 2H), 7.19˜7.23 (m, 4H), 7.11˜7.13 (d, J=8.0 Hz, 1H), 6.83˜6.88 (m, 1H), 6.12 (s, 1H), 6.00 (s, 2H), 4.37˜7.41 (m, 2H), 4.12˜4.14 (m, 2H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 593.
Reaction SMILES: [C:1]([O: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][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=1[CH3:25])(=[O:3])[CH3:2].O.C([O:31]O)(C)(C)C>C1CCCCC1.O.[Ru](Cl)(Cl)Cl>[C:1]([O: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][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19](=[O:31])[C:18]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)OCCCCCCCCCCCCC1=C(C)CCCC1(C)C
Agent: Cl[Ru](Cl)Cl
Solvent: C1CCCCC1
Solvent: O
Product: CC(=O)OCCCCCCCCCCCCC1=C(C)C(=O)CCC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
To a solution of 1-(12-acetoxydodecyl)-2,6,6-trimethyl-1-cyclohexene (321 mg, 0.92 mmol, 1 eq.) in cyclohexane (6 ml) was added water (0.8 ml), ruthenium trichloride hydrate (0.7% mol, 1.3 mg) and 70% t-BuOOH (1.26 ml, 10 eq.). The solution was stirred at room temperature for 6 hours, filtered through a pad of celite and poured into a solution of 10% Na2SO3. The solution was extracted with ether, washed with brine, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel, eluting with hexane-AcOEt (95-15 to 90-10) to give 3-(12-acetoxydodecyl)-2,4,4-trimethyl-2-cyclohexen-1-one as a colorless oil (227 mg, 53%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])[CH:29]=[C:28]([Cl:38])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][OH:27].[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[C:21]([Cl:20])=[CH:31][C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])=[CH:29][C:28]=2[Cl:38])=[CH:50][CH:51]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.69 g of azadicarboxylic acid diisopropyl ester are added dropwise at 0–5° C. to a solution of 1.97 g of triphenylphosphine in 60 ml of THF. After 30 minutes at 0–5° C., 2.5 g of 3-[2,6-dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propan-1-ol and 1.5 g of (4-hydroxy-phenyl)-carbamic acid tert-butyl ester dissolved in 30 ml of tetrahydrofuran are added dropwise. After being stirred for 24 hours at room temperature, the reaction mixture is concentrated and then purified over silica gel. (4-{3-[2,6-Dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propoxy}-phenyl)-carbamic acid tert-butyl ester (compound 1.6) is obtained.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(OCC)(=O)C.[CH3:57][N:58]([CH2:60][CH2:61]Cl)[CH3:59]>C1C=CC=CC=1>[CH3:57][N:58]([CH3:59])[CH:60]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:61]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To 28.2 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 360 ml ethyl acetate and 49.5 ml solution of dimethylaminoethylchloride in the amount of 11.7 g, which stoichiometrically corresponds to two times the molar volume, in benzene were added to be subjected to flux in oil bath at 90° C. for 16 hrs. After cooling, precipitated dicyclohexyl ammonium chloride was filtered off and ethyl acetate phase in the filtrate was washed with diluted hydrochloride to remove excessive dimethylaminoethylchloride contained therein. The filtrate was further washed with 10% aqueous solution of hydrogen sodium bicarbonate so as to remove the unreacted starting material and then with saturated brine to be neutral, which was then treated with sulfuric sodium anhydride for dehydration to be dried and subjected to reduced pressure distillation so as to distill off ethyl acetate and obtain the Intermediate I, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 21.5 g (yield; 96.8%).
Reaction SMILES: FC1C(O)=C(F)C(F)=C(F)C=1F.[NH:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])[CH2:15][C:16](=[O:18])[NH2:17].[NH2:36][C@H:37]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:64]([NH:66][C@H:67]([C:77]([NH:79][C@H:80]([C:83]([NH:85][C@H:86]([C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[CH3:87])=[O:84])[CH2:81][OH:82])=[O:78])[CH2:68][CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:65])[CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH3:38].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:64]([NH:66][C@H:67]([C:77]([NH:79][C@H:80]([C:83]([NH:85][C@H:86]([C:88]([O:90][C:91]([CH3:92])([CH3:93])[CH3:94])=[O:89])[CH3:87])=[O:84])[CH2:81][OH:82])=[O:78])[CH2:68][CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:65])[CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH3:38])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
2.45 g. (13.3 mmoles) of pentafluorophenol, 1.31 g. (4.02 mmoles) of Z-Asn-Gly-OH (see Example 1) and 5.4 g. (4.02 mmoles) of H-27-32-OtBu are dissolved in 24 ml. of dry DMF, thereafter the solution is cooled to 0°C, and 0.915 g. (4.43 mmoles) of DCC are added to it. The reaction mixture is stirred at 0°C for 0.5 hours and at room temperature for 2.5 hours. The separated DCU is filtered off, and the filtrate is evaporated to dryness. The solid residue is triturated with ethyl acetate, filtered, and washed with hot ethyl acetate. 4.12 g. (89 %) of Z-25-32-OtBu are obtained. M.p.: 200°-201°C; Rf3 = 0.6; [α]D = -13.9° (c = 1, in DMF).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].O.[Cl-].[Na+]>N1C=CC=CC=1>[C:13]([O:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]#[N:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: N#Cc1cccc2c1CCC2O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c(C#N)cccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
3.89 g of (RS) 1-hydroxy-4-indanecarbonitrile in 39 ml of pyridine is cooled to 0° C., 3.45 ml of acetic anhydride is added drop by drop, and the whole is agitated for 16 hours at 20° C. The reaction mixture is poured into 300 ml of water containing sodium chloride and extracted with isopropyl ether; the ethereal phase is washed with 2N hydrochloric acid and then with water until pH 7 is obtained. The ethereal phase is dried and brought to dryness, and the residue is taken up in 1,2-dichloroethane, and again concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of hexane, agitated for one hour, filtered, and 4.46 g of expected product is recovered. M.p.=65° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Formic acid (7 mL, 186 mmol) and acetic anhydride (140.1 mL, 150 mmol) were heated together at 55° C. for 2 hours. The mixture was cooled to room temperature, THF (11 mL) was added followed by 4-bromoaniline (10 g, 58 mmol) in THF (20 mL). The mixture was stirred at room temperature for 3 hours before evaporating to dryness. Trituration of the solid gave the subtitled compound as a light brown solid (8.22 g). MH− 198/200. 1H NMR δ (CDCl3) 6.93-7.04 (2H, d), 7.24 (2H, s), 8.59-8.70 (1H, d).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][CH3:2]
Reactant: CNCCCC(=O)O
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNCCCC(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(methylamino) butyric acid HCl was dissolved in methanol and thionyl chloride in catalytic amount was added drop by drop. The reaction mixture was stirred at 0° C. for 30 min. Thereafter, the solvent was reduced in vacu, yielding a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=c1[nH]c(=O)n(-c2ccc(F)c(F)c2)o1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(F)c(F)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4-Difluorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4-difluorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.