Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/B(O)O)=[CH:30][CH:29]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:25])[CH:3]=[C:2]3/[CH:35]=[CH:34]/[C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:39])[F:40])=[CH:33][CH:32]=2)=[CH:19][CH:20]=1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1cc(/C=C/c2ccc(C(F)(F)F)cc2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 2 h

Procedure:
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (80 mg, 0.185 mol, 1 equip), trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid (80 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 2 h. Additional trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid (80 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added and the resulting mixture was stirred overnight. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(4-(trifluoromethyl)styryl)quinolin-2(1H)-one.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>[Cl-].[Na+].O.CN(C)C=O>[N:20]1([C:14]([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5]4[NH:9][CH:8]=[CH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:19]=[CH:18][CH:17]=2)=[O:16])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Reactant: C1CSCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc(Nc2ncnc3cc[nH]c23)c1)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), thiomorpholine (0.091 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Thiomorpholine (0.030 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80). Diisopropyl ether was added and the precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate containing methanol, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue and the precipitate was collected by filtration to give the title compound (82 mg) as a pale-brown powder.
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:15])[CH2:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH2:12][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:15])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCOC(C)CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
7 g of 4-octyloxypentanol, 4.34 g of p-toluenesulfonyl chloride, 1.8 g of pyridine and 10 ml of benzene were stirred under N2 stream at room temperature for 22 hours. Thereafter, 6.5 ml of hot conc. NaOH aqueous solution was added to the reaction mixture and stirred for 5 min. Then, the mixture was poured into cold 10%-hydrochloric acid and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid, saturated NaHCO3 aqueous solution and water and dried with anhydrous MgSO4. After removing the solvent by distillation, the product was treated with alumina column (hexane) to obtain 6.6 g of 4-octyloxypentyl p-toluenesulfonate.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:8]([O:10]C)=[O:9])[NH:5][C:6]=1[Br:7].CC(C)([O-])C.[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[Br:7]
Reactant: COC(=O)c1[nH]c(Br)c(Br)c1OC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1c(C(=O)O)[nH]c(Br)c1Br

Procedure:
Methyl 4,5-dibromo-3-(1-methylethoxy)-1H-pyrrole-2-carboxylate (1.5 g, 0.004 moles) is stirred under nitrogen in DMSO (100 mL) at room temperature. Potassium tert-butoxide (2.5 g, 0.022 moles) is added. After 12 hours the mixture is stirred into water (600 mL) and extracted with ether twice. The ether extracts are discarded, and the aqueous phase is acidified with H3PO4, then extracted with CH2Cl2 (3x). The combined extracts are washed with brine and dried over MgSO4. Removal of the solvent under reduced pressure left the product as a clear oil (1.4 g), sufficiently pure for further use.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.C(=O)(O)[O-].[Na+]>CO.O1C=COC=C1>[NH2:25][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Agent: C1=COC=CO1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
A solution of N2-butyl-8-(methoxy)-9-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-9H-purine-2,6-diamine (54 mg) in methanol (1 ml) was treated with 4N HCl in dioxin (0.5 ml) and stood for 1.5 h. The solvents were stripped and the residue treated with water and made basic with saturated aqueous sodium bicarbonate. The precipitated material was filtered, washed with water and dried to give the title compound as a solid, yield 22.5 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Yield: 86.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.290 g; 0.76 mmol), LHMDS 1N in THF (0.84 mL; 0.84 mmol), 1-iodopropane (0.111 mL; 1.14 mmol) in DMF (3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.281 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[CH:16])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(C)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-((trimethylsilyl)ethynyl)phenyl)picolinate (50 mg, 0.13 mmol) in methanol (0.7 mL) was added potassium carbonate (24 mg, 0.17 mmol). The reaction was stirred at room temperature for 40 min, then diluted with water and extracted with dichloromethane (4×). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a brown oil (34 mg, 84%).
Reaction SMILES: [Cl:1][CH:2]([Cl:5])[C:3]#[N:4].C[O-].[Na+].Cl.[CH2:10]([O:12][C:13](=[O:18])[C@H:14]([CH2:16][SH:17])N)[CH3:11].O>CO.C(Cl)Cl>[Cl:1][CH:2]([Cl:5])[C:3]1[S:17][CH2:16][CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])[N:4]=1
Reactant: N#CC(Cl)Cl
Reactant: CCOC(=O)[C@@H](N)CS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CSC(C(Cl)Cl)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Dichloroacetonitrile (33.67 mL, 420 mmol) was added slowly, whilst maintaining the temperature below 0° C., over 30 min. to a solution of sodium methoxide ((25% w/w) 9.63 mL, 43 mmol) in methanol (84.5 mL) which was precooled to −10° C. This was allowd to stir for 30 min. before the addition of L-cysteine ethyl ester hydrochloride (78.32 g, 422 mmol) dissolved in methanol (67.4 mL) and then stirred overnight at RT. Water (136 mL) followed by DCM (136 mL) was added to the mixture and stirred vigorously. The organic layer was separated and the aqueous layer was reextracted with a further 136 mL of DCM. This was concentrated in vacuo to give the crude product (94.1 g, 93%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([O:52]C(C)(C)C)=[O:51])([CH3:49])[CH3:48])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C.[I-].[Na+].[NH2:59][C:60]1[N:64]([CH3:65])[N:63]=[CH:62][C:61]=1[NH:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][NH:73]C(OC(C)(C)C)=O)=[O:68].C(OCC)(=O)C>CN(C)C=O.O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([OH:52])=[O:51])([CH3:48])[CH3:49])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:63]4[N:64]([CH3:65])[C:60]([NH2:59])=[C:61]([NH:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][NH2:73])=[O:68])[CH:62]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: Cn1ncc(NC(=O)NCCCNC(=O)OC(C)(C)C)c1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)c(NC(=O)NCCCN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (1.0 g) in N,N-dimethylformamide (2.0 ml) was added sodium iodide (199 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 5-amino-4-(3-{3-[(tert-butoxycarbonyl)amino]propy}ureido)-1-methylpyrazole (415 mg) and the whole mixture was stirred at 32° C. for 24 hours. To the resulting reaction mixture were added ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated, and the organic layer was washed with 10% aqueous sodium trifluoroacetate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (100 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (3.6 ml) were added anisole (1.2 ml) and trifluoroacetic acid (2.4 ml). The resulting solution was stirred at room temperature for 4 hours and poured into diisopropyl ether (100 ml). The resulting precipitate was collected by filtration and dried in vacuo to give a crude product (939 mg), which was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(3-aminopropyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate (53 mg) as an amorphous solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Yield: 40.7 %

Procedure:
To acetic anhydride (32 g.) was added formic acid (14.4 g.) under ice-cooling and stirred at 40° to 45° C. for an hour. 2-(2-Aminothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 20 g.) and tetrahydrofuran (100 ml.) were added to the solution under ice-cooling and stirred at 35° C. for 3 hours. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether, and dried over phosphorus pentoxide to give 2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 9.04 g.), mp. 158° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.[ClH:40].CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:26].[ClH:40].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: Cc1cc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)nc(N)n1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of compound C3 (200 mg, 0.49 mmol) in EtOH (20 mL) and H2O (10 mL) was added 4-chloro-6-nitroquinoline (113 mg, 0.54 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 3 h., diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc/Charcoal/Celite to give Cpd. GG4 (247 mg 87%) as a yellow solid.; M.P (MeOH/EtOAc) 295-300° C.; 1H NMR [(CD3)2SO] δ13.50 (br, 2 H, 2×N+H), 11.32 (br, 1 H, NH), 11.00 (brs, 1 H, NH), 10.51 (s, 1 H, NH), 9.81 (d, J=2.2 Hz, 1 H, ArH), 8.69 (dd, J=9.3, 2.2 Hz, 1 H, ArH), 8.59 (d, J=6.9 Hz, 1 H, ArH), 8.24 (d, J=9.3 Hz, 1 H, ArH), 8.06-7.98 (m, 7H, ArH & NH2), 7.48 (d, J=8.9 Hz, 2 H, ArH), 6.90 (d, J=6.9 Hz, 1 H, ArH), 6.32 (s, 1 H, ArH), 2.32 (d, J=0.4 Hz, 3 H, CH3); HRMS (FAB+) calc. for C27H23N8O3 (M+) m/z 507.1893, found 507.1896.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]>ClCCl.O>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH:29][C:36]([O:38][CH2:39][CH:40]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=2[C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCC2c3ccccc3-c3ccccc32)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.5 g, 0.011 mole) dissolved in dichloromethane (30 ml), was added sodium bicarbonate (1.0 g, 0.011 mole) dissolved in water (16 ml). The reaction mixture was cooled to 0° C. and 9-fluorenylmethyl chloroformate (3.0 g, 0.012 mole) was added. After stirring for 5 minutes the reaction mixture was warmed to room temperature and stirred vigorously for 16 h. The organic layer was separated and washed with brine (10 ml). The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo to give an orange solid which was purified by flash chromatography using dichloromethane as eluent. Pure fractions were collected and evaporated in vacuo affording 5.6 g (81%) of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 25.72 mL (336 mmol) of diketene in 100 mL of toluene was added dropwise at 90° C. to a solution of 51.0 g (288 mmol) of 4-bromoaniline in 200 mL of toluene and the reaction mixture was kept at this temperature for 5 hours. The reaction solution was cooled in the ice bath, and the precipitate formed was filtered and washed with toluene until the product was virtually colorless. Subsequently it was dried at 50° C. in the circulating air dryer until a constant weight was obtained. Yield: 50.0 g (68% of theoretical); C10H10BrNO2 (M=256.096); calc.: molpeak (M+H)+: 256/258 (Br); found: molpeak (M+H)+: 256/258 (Br); HPLC-MS: 4.7 minutes (method B).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:70])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:26]([O:64][CH3:65])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:62][CH3:63])[C@@H:36]([CH3:61])[C:37]([NH:39][C@@H:40]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2].O[N:72]1[C:76](=[O:77])[CH2:75][CH2:74][C:73]1=[O:78].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C1C=CN=CC=1)C>[O:78]=[C:73]1[CH2:74][CH2:75][C:76](=[O:77])[N:72]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:70])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:26]([O:64][CH3:65])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:62][CH3:63])[C@@H:36]([CH3:61])[C:37]([NH:39][C@@H:40]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 mg (18 μmol) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 98) were dissolved in 2.8 ml of dichloromethane and admixed with 20 mg (174 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 10 mg (52 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.21 mg (0.17 μmol) of DMAP. After stirring at RT for 4 h, the reaction mixture was concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 8.2 mg (43% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]3[C:20]=2[CH3:21])=[CH:4][C:3]=1[OH:22].[CH3:23][N:24]=[C:25]=[O:26].C(OCC)(=O)C>O1CCCC1.CO>[OH:22][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]3[C:20]=2[CH3:21])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][CH3:23])=[O:26]
Reactant: COc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: CN=C=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(CCc2nc3cc(OC)ccn3c2C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (2.5 g) and methyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) and methanol (2.5 ml) was stirred for 1 hour at ambient temperature. To the reaction mixture was added ethyl acetate (30 ml) and the resulting precipitate was collected by filtration. The precipitate was washed with ethyl acetate and dried to give 2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (2.11 g).