Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC(Cl)=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24]>CN(C=O)C>[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[O:28][N:27]=1)([CH3:24])[CH3:25]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)ncnc2cc1O
Temperature: 60 °C
Yield: 12.7 %

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (200 mg, 0.71 mmol) (prepared as described in example 95A, steps 1 through 3) in anhydrous DMF (6 mL), was added 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (212 mg, 0.71 mmol) and the mixture was heated to 60° C. for 2.5 h. Concentration in vacuo followed by purification via preparative reverse phase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O), afforded 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea (41 mg, 13%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.64 (brs, 1H), 9.13 (brs, 1H), 8.48 (s, 1H), 7.55-7.56 (m, 2H), 7.41 (dd, J=8.1, 8.1 Hz, 1H), 7.32 (m, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 6.15 (s, 1H), 3.99 (s, 3H), 1.66 (d, J=22 Hz, 6H); LC-MS (ESI) m/z 454 (M+H)+.
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:19]([NH:21][NH:22][C:23]2[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][N:9]([CH2:12][C:13]1([C:19]([NH:21][NH:22][C:23]2[N:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][N:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11]
Reactant: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=CN(O)CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCC1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of N-benzyloxy-N-{1-[N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazinocarbonyl]-cyclohexylmethyl}-formamide (0.066 g, 0.15 mmol) in ethanol (5 mL) was added 10% Pd/C (0.03 g). The reaction mixture was subjected to hydrogenation for 3 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with ethanol (20 mL). Removal of the solvent provided the title compound as a white solid (0.045 g, 85%). MH+362.
Reaction SMILES: BrC1C=CC(C([N:8]2[CH2:11][CH2:10][C@:9]2([CH3:15])[C:12]([OH:14])=[O:13])=O)=CC=1.[ClH:18]>O1CCOCC1>[ClH:18].[CH3:15][C@:9]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:11][NH:8]1
Reactant: C[C@]1(C(=O)O)CCN1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]1(C(=O)O)CCN1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
After a chiral separation, Intermediate 33 (1 eq.) (100% ee) was solubilised in dioxane. A solution of HCl (4N) in dioxane was added and the reaction was stirred at 20° C. for 15 h. The solvent was removed under reduced pressure and the crude was crystallised in a mixture of DCM/iPr2O/pentane to afford (R)-2-methyl-azetidine-2-carboxylic acid hydrochloride.
Reaction SMILES: [C:1]1([N:7]=C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10](=O)(=[O:13])([OH:12])[OH:11]>>[S:10]([OH:13])(=[O:12])([C:4]1[CH:5]=[CH:6][C:1]([NH2:7])=[CH:2][CH:3]=1)=[O:11]
Reactant: O=C=Nc1ccccc1
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1

Procedure:
The reaction of phenyl isocyanate with sulfuric acid is reported by Bieber [J. Am. Chem. Soc. 75, 1405 (1953)] to give sulfanilic acid. ##STR1##
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]([N:14]1[CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A solution of 1-benzhydrylazetidine-3-carboxylic acid (4.20 g) in N,N-dimethylformamide (45 ml) were added potassium carbonate (6.53 g) and iodomethane (0.976 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=5:1, then 3:1). Fractions containing the target compound were concentrated to provide the titled compound as yellow crystals (3.57 g, 80.8%).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[NH:13][C:14]2[S:15][CH:16]=[C:17]([S:19]([CH3:21])=[O:20])[N:18]=2)=[CH:8][CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:13][C:14]2[S:15][CH:16]=[C:17]([S:19]([CH3:21])=[O:20])[N:18]=2)=[O:22])=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)c1csc(NC(=O)c2ccc(O)cc2)n1
Temperature: 25 °C

Procedure:
2 M hydrochloric acid (3.0 mL) is added to a suspension of 3 (0.12 g, 0.33 mmol) in tetrahydrofuran (3.0 mL), and the resulting suspension is warmed to reflux. The reaction becomes homogeneous upon heating. After refluxing for 1.5 h, the reaction is allowed to cool to room temperature, and is then partitioned between diethyl ether and water. The ether layer is washed with water, saturated aqueous sodium bicarbonate, and brine. The ether layer is dried with anhydrous sodium sulfate and concentrated in vacuo. The residue is triturated with ethyl acetate, the solvent is removed under a stream of nitrogen, and the resulting solid is dried in vacuo at 55° C. to give 4 as a light yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, and thereto were added 1.2 g of anhydrous potassium carbonate and 1.0 g of α-chloro-o-xylene. The resulting mixture was heated to 80° to 110° C. under stirring for 2 hours. After allowed to cool to room temperature, the mixture was incorporated with 100 ml of water and then stirred. The precipitated solid was filtered off, washed with water, dried and recrystallized from ethanol to give white needle-like crystals having the following physical properties (yield: 72.7%):
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:30])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].C[O-].[Li+].Cl[O:36][C:37](C)(C)C.[Cl-].[NH4+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CO.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:36][CH3:37])([NH:21][C:22](=[O:30])[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OCl
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: C[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO[C@@]1(NC(=O)Cc2ccccc2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Reaction time: 0.08 h

Procedure:
A cooled (-78°) solution of t-butyl (6R,7R)-3-acetoxymethyl-7-phenylacetamidoceph-3em-4-carboxylate (1.5 g.) in dry tetrahydrofuran (10 ml) was added over 3 minutes to a stirred and cooled (-78°) solution of lithium methoxide (358 mg) in dry methanol (8.8 ml) and tetrahydrofuran (50 ml) under nitrogen. t-Butyl hypochlorite (0.69 ml) was added after 3 minutes, and sitrring was continued for a further 5 minutes when the yellow solution was poured into a stirred mixture of ethyl acetate (150 ml) and water (150 ml) containing ammonium chloride (1 g) and sodium metabisulphite (1 g.). The aqueous phase was separated and extracted with ethyl acetate (50 ml) and the organic phases were combined and washed with brine (50 ml) and dried and evaporated to dryness in vacuo to give t-butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-phenylacetamidoceph-3-em-4-carboxylate (1.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:18]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10]([O:12][CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoic acid (550 mg, 2.399 mmol) in tetrahydrofuran (11 mL) at 0° C., was added TMS-diazomethane (4.80 mL, 4.80 mmol) dropwise over 5 min. The reaction mixture was then stirred at 0° C. for 15 min. After gradually warmed to room temperature, the mixture was stirred for 16 h. The reaction mixture was evaporated to dryness to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoate (580 mg, 2.386 mmol, 99% crude yield) as a dark yellow oil which was taken to the next step without purification. 1H NMR (400 MHz, CDCl3): δ ppm 4.91 (s, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 4.38 (q, J=16.00 Hz, 1H), 3.73 (s, 3H), 2.33-2.53 (m, 2H), 1.71 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([OH:20])[C@@H:12]2[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@@H:11]2[CH2:10]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[C@@H:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C@@H:11]2[CH2:10]1
Reactant: COC(=O)[C@@]1(O)C[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@]1(O)C[C@H]2OC(C)(C)O[C@H]2[C@H](OS(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
Triethylamine (5.0 mL, 35.9 mmol) was added dropwise to a 0° C. solution of Example 13B (4.4 g, 17.9 mmol) and methanesulfonyl chloride (1.38 mL, 17.9 mmol) in dichloromethane (60 mL). After stirring overnight, the reaction mixture was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated to afford the crude desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])([CH3:29])[CH3:28].IC1C=CC(NC(C2C(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=CC=NC=2)=O)=CC=1C>>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([NH:34][S:31]([C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:33])=[O:32])=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)cc1I
Reactant: CC(C)(C)S(N)(=O)=O
Agent: Cc1cc(NC(=O)c2cnccc2N2CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)cc1I

Procedure:
4-(2-Methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3-iodo-4-methyl-phenyl)-amide was prepared from 5′-(3-Iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid and t-butyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-Methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide. The product was isolated after a silica gel column purification with 2-5% MeOH in CH2Cl2. HRMS m/z calcd for C23H29N4O4SI [M+H]+: 585.1027. Found: 585.1027.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C.Cl.[N:16]([O-])=[O:17].[Na+]>O>[CH3:2][N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: CNCCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCc1ccccc1)N=O
Temperature: 70 °C
Yield: 81.6 %

Procedure:
A sample of N-methyl-2-phenylethylamine hydrochloride (6.4 g, 37.3 mmol) was dissolved in water (18 ml), ethanol (11 ml) and 2N hydrochloric acid (4 ml) were introduced and the solution was heated to 70° C. A solution of sodium nitrite (2.6 g, 37.7 mmol) in water (11 ml) was added dropwise to the reaction mixture over 30 min. During the addition the reaction mixture was acidified with 2N hydrochloric acid (4 ml). Cooling was followed by extraction with n-heptane (4×100 ml); the combined extracts were dried (MgSO4) and evaporated in vacuo to provide the N-methyl-N-nitroso-2-phenylethylamine as an oil (5.0 g, 81%) (a ca. 65:35 mixture of apparent geometric isomers), 1H NMR (DMSO-d6) γ 2.98 (3H, s,--CH3), 3.05 (2H, t, PhCH2 --), 4.37 (2H, t, --CH2 --N--), 7.13-7.36 (5 H, m, Ar-H) (major isomer); 2.78 (2H, t, PhCH2 --), 2.98 (3H, s,--CH3), 3.77 (2H, t,--CH2 --N--), 7.13-7.36 (5H, m, Ar-H) (minor isomer).
Reaction SMILES: OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH2:65][CH:66]3[CH2:68][CH2:67]3)[C:63](=[O:64])[C:39]=12)C1C=CC=CC=1>>[CH:66]1([CH2:65][N:62]2[CH2:61][CH2:60][N:40]3[C:41]([CH2:45][C:46]4([N:51]5[C:55]6=[N:56][CH:57]=[CH:58][CH:59]=[C:54]6[CH:53]=[CH:52]5)[CH2:47][CH2:48][CH2:49][CH2:50]4)=[N:42][C:43](=[O:44])[C:38]([OH:37])=[C:39]3[C:63]2=[O:64])[CH2:68][CH2:67]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1CC1CC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Product: O=C1c2c(O)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1CC1CC1

Procedure:
2-Cyclopropylmethyl-9-hydroxy-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (416) was prepared following the same method as described for 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) from 9-benzyloxy-2-cyclopropylmethyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl methyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (415) (50 mg, 0.09 mmol) and was obtained as an off-white solid (36 mg, 85%).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[OH:54][CH2:55][CH2:56][NH:57][CH2:58][CH2:59][NH-:60].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:54][CH2:55][CH2:56][NH:57][CH2:58][CH2:59][NH-:60]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCNCCO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 88 mg of Z-Phe-His-OH, 60 mg of H-Leu-Val-Ala-2-(2-hydroxyethylamino)-ethyl amide, 31 mg of HOBt and 48 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B11). Rf (B11)=0.24.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]=[C:44]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:58][C:56]([CH3:59])([O:55][C:54]([NH:53][C:44]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[N:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[O:60])[CH3:57]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CC(=O)NCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1.05 g (8.10-3 mol) of monoethyl malonate are dissolved in 15 ml of anhydrous chloroform, the solution is then cooled to 0° C. and 1.65 g (8.10-3 mol) of 1,3-dicyclohexylcarbodiimide and 0.108 g (0.8.10-3 mol) of 1-hydroxybenzotriazole hydrate are added. After stirring for 0.5 hour at 0° C., a solution of 1.5 g (4.19.10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 5 ml of anhydrous chloroform is added. The mixture is then stirred for 48 hours at room temperature, after which the reaction medium is concentrated under reduced pressure. The crude product obtained is purified by medium pressure chromatography on silica using a hexane/ethyl acetate mixture (1/1 v/v) as the eluent to give 1.95 g (yield=99%) of the expected product in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([OH:7])=[O:6].C(OCC)(OCC)O[CH2:19][CH3:20]>C(O)(C)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:4]=1[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(OC)c1OC
Yield: 80 %

Procedure:
Condensation of 2,3-dimethoxy-6-nitrobenzoic acid (1 eg) with (1.5 eg) of triethyl orthoformate gave after isopropanol crystallization an 80% yield of the title compound, mp 120°-122° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:14]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:13][CH:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:58][C:59](=[O:62])[CH2:60]Cl)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:14]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:13][CH:11]1[O:12][CH2:60][C:59]([OH:62])=[O:58])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1OC(O)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: O=C(CCl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(O)COC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 59.66 g (100 mmol) of 2,3,4,6-tetra-O-benzoyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.2 g (110 mmol) of anhydrous potassium carbonate in 500 ml of dimethylformamide is cooled to 0° C. At 0° C., 36.92 g (200 mmol) of chloroacetic acid benzyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 10° C. 250 ml of methyl-tert-butyl ether is added, the organic phase is separated, it is filtered and evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol and mixed with 5 g of palladium (10%) on activated carbon. It is hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol, and the combined solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[CH:8]=[CH2:9].[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([S:31][CH3:32])=[C:18]([S:20]([C:23]2[CH:28]=[C:27]([OH:29])[CH:26]=[C:25]([Br:30])[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[O:14].O>CN(C=O)C.CCOC(C)=O>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([S:31][CH3:32])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([Br:30])[CH:26]=[C:27]([O:29][CH2:9][CH:8]=[CH2:7])[CH:28]=2)(=[O:21])=[O:22])[CH:19]=1)=[O:14]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(O)cc(Br)c2)c(SC)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(Br)cc(S(=O)(=O)c2cc(C(=O)OC)sc2SC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (33 mg, 0.1 mmol) and allylbromide (30 μL, 0.35 mmol) were added to a solution of 4-(3-bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step d) 30 mg, 0.71 mmol) dissolved in dry DMF (3 mL). After stirring for 16 h at rt, the solution was poured into a mixture of water (20 mL) and EtOAc (30 mL). The layers were separated and the organic layer was extracted with water (5×5 mL), brine (20 mL), and was dried over sodium sulfate. The solvent was removed in vacuo to yield the title compound, which was used without further purification.