Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:27]=[C:28]([C:31]3[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=3)[S:29][CH:30]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[N+:23]([C:13]1[CH:12]=[C:11]([C:26]2[N:27]=[C:28]([C:31]3[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=3)[S:29][CH:30]=2)[CH:10]=[C:9]([OH:8])[C:14]=1[OH:15])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3C(F)(F)F)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)thiazole (0.146 g, 0.26 mmol), in dichloromethane (10 mL) was cooled to −78° C. and treated under argon, with boron tribromide (0.26 g, 1.03 mmol). The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −78° C. The mixture was quenched by careful addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give 3-nitro-5-(2-(2-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)benzene-1,2-diol as a yellow solid, 0.087 g (87%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CO>[ClH:22].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:12]1[C:13]([S:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[N:11]1
Reactant: CN(Cc1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 166.8 %

Procedure:
tert-Butyl({1-(2-chlorophenyl)-5-[(6-chloropyridin-3-yl)thio]-1H-pyrazol-3-yl}methyl)methylcarbamate (350 mg) was dissolved in ethyl acetate (3 mL) and methanol (2 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate and hexane, and recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 252 mg, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1

Procedure:
A solution of 4-(5-trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.69 g, 2.00 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 246.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](=[O:17])[NH:9][CH:10]1[CH2:15][CH2:14][CH:13](C)[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+].CO.O1CCOC[CH2:23]1>>[CH3:23][C@@H:15]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:9][C:8]([C@@H:6]1[CH2:7][C@H:5]1[C:3]([OH:2])=[O:4])=[O:17]
Reactant: C1COCCO1
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)NC1CCC(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CCCC[C@H]1NC(=O)[C@@H]1C[C@H]1C(=O)O
Yield: 87 %

Procedure:
Stir a solution of trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropane-carboxylic acid monomethyl ester (Example 11a) (4.5 g, 19.8 mmol), 5N NaOH (40 mL) and MeOH/dioxane overnight. Concentrate the reaction mixture under vacuum, cool the resulting solution and acidify to pH 5. Collect the precipitate, wash (H2O) and dry under vacuum at 40° C. to obtain 3.7 g (87%) of solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=3[S:10](=O)(=O)[CH:11]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C=C2Oc1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol) in THF (90 mL) was added DIBAL-H (1.0 M in DCM, 33.6 mL, 33.6 mmol) in one portion. The mixture was heated to 75° C. for 2 h after which time the reaction was cooled to room temperature and quenched with EtOAc (32.9 mL, 336 mmol). The resulting solution was stirred for 10 min before carefully adding 75 mL of water and potassium sodium tartrate (33.100 g, 117 mmol). The mixture was vigorously stirred for 10 min and diluted with 75 mL EtOAc. The organic layer was collected, dried with anhydrous MgSO4 and concentrated in vacuo to afford 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (1.9 g, 5.67 mmol, 84% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.81 (s, 3H), 6.46 (s, 1H), 6.90 (d, J=9.09 Hz, 3H), 7.16-7.22 (m, 1H), 7.31-7.40 (m, 2H), 7.46 (d, J=9.09 Hz, 1H). LC/MS (m/z, MH+): 336.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (1.98 g, 0.0091 mol), 4chlorophenyl isothiocyanate (1.83 g, 0.011 mol) and toluene (10 ml) was refluxed for 3.5 hours, cooled and treated with diethyl ether to induce crystallisation of the product. Yield 1.98 g (56%), m.p. 141°-143
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OC1CCNCC1
Reactant: CCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN1CCC(O)CC1
Reaction time: 2 h

Procedure:
4-Hydroxypiperidine was dissolved in N,N-dimethylformamide (20 ml) and treated with potassium carbonate (1.5 g, 10.8 mmol) and 1-iodoheptane (1.8 ml, 11.3 mmol). After stirring for 2 h the mixture was diluted with ethyl acetate, washed with water, brine, dried and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 84.7 %

Procedure:
Prepared according to the procedure described for Example 60 using of 3-amino-4-methyl-N-phenyl-benzamide (0.5 g, 2.2 mmol) and 3,5-dichlorophenyl isothiocyanate (0.458 g, 2.2 mmol). Trituration in ethyl acetate afforded the product (0.802 g) in two crops; m.p. 182-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2.[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([F:17])=[CH:10]1)=[N:5]2
Reactant: CCN1CCC(N)CC1
Reactant: Fc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(F)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-fluoroacridine (J. Med. Chem. 1985, 28. 940-944) and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=358).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](O)([CH3:12])[CH3:11])[CH:5]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1
Reactant: COC(OC)c1cccc(C(C)(C)O)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cccc(C(OC)OC)c1
Yield: 95.7 %

Procedure:
0.4 g of the alcohol compound obtained above was dissolved in 8 ml of purified methylene chloride, and with stirring under ice cooling, 0.24 g of methanesulfonyl chloride and 0.38 g of triethylamine were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporatd under reduced pressure and then extracted by adding ethyl ether and water. The extract was worked up in a customary manner to give 0.35 g of crude 3-isopropenylbenzaldehyde dimethyl acetal as a pale yellow oil.
Reaction SMILES: C([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH2:9][CH2:10][OH:11])C1C=CC=CC=1>[Pd].CO>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][CH2:12][NH:8][CH2:9][CH2:10][OH:11]
Reactant: OCCN(CCc1cccc(F)c1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCCNCCc1cccc(F)c1

Procedure:
A suspension of V-2 (0.003 mol), such as 2-[benzyl(3-fluorophenethyl)amino]ethanol (0.82 g), and 10% Palladium on activated carbon (Pd/C, 450 mg) in MeOH (30 mL) was stirred at room temperature under hydrogen atmosphere overnight. The catalyst was then filtered out through celite. The celite pad was washed with MeOH (10 mL×3). The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH2Cl2:MeOH=8.5:1.5) to yield pale-yellow oil (V-3, 0.45 g, 82%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C:12]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCc2ccccc2C1(c1ccccc1)c1ccccc1

Procedure:
Chloroacetyl chloride (0.151 mL) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and p-toluenesulfonate monohydrate (11.3 mg) in toluene (5 mL). The mixture was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and EtOAc and an aqueous 1 M HCl solution were added to the residue. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH:4]1[CH2:3][N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: CN1CC(CO)Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CC(COS(C)(=O)=O)Oc2ccccc21
Reaction time: 10 h
Yield: 42.9 %

Procedure:
To a solution of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-methanol (6.0 g, 33.51 mmol) in dichloromethane (20 mL) was added triethylamine (10.15 g, 100.5 mmol) under nitrogen atmosphere at 25° C. Methanesulfonyl chloride (5.75 g, 50.25 mmol) was added to the above reaction mixture at 0° C. and stirring was continued for further 10 h at 25° C. Water (50 mL) was added and extracted with chloroform (2×25 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and hexane (2:8) to yield (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl methanesulfonate (3.7 g, 43%) as a syrup.
Reaction SMILES: Br[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.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl.O1CCO[CH2:40][CH2:39]1>O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([CH:39]=[CH2:40])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 g, 2.39 mmol), boronic ester (0.442 g, 2.87 mmol) and Pd(PPh3)4 (0.276 g, 0.238 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, solution of Na2CO3 (0.91 g, 8.58 mmol) in water (4.3 mL) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.8 g, 91.6%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[Cl:31]>ClCCl>[Cl:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[NH:20][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 5.43 g of 4-nitrophenyl chloroformate in 100 mL of dichloromethane was added 2.4 mL of pyridine under ice-cooling, and 5 g of methyl 4-amino-3-chlorobenzoate was added to the obtained mixture, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, followed by washing with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The obtained solid was dissolved in 200 mL of toluene under heating, and left to be cooled to room temperature, and further cooled in an ice bath. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5.59 g of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate as a white solid.
Reaction SMILES: [CH:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([CH:19]3[C:32]4[CH:31]=[C:30]([CH:33]=[O:34])[CH:29]=[CH:28][C:27]=4[O:26][C:25]4[C:20]3=[CH:21][C:22]([C:35]([O:37][CH3:38])=[O:36])=[CH:23][CH:24]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH:1]1([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([CH:19]3[C:32]4[CH:31]=[C:30]([CH2:33][OH:34])[CH:29]=[CH:28][C:27]=4[O:26][C:25]4[C:20]3=[CH:21][C:22]([C:35]([O:37][CH3:38])=[O:36])=[CH:23][CH:24]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)C(C(=O)NC1CCN(CC3CCCCCCC3)CC1)c1cc(C=O)ccc1O2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)C(C(=O)NC1CCN(CC3CCCCCCC3)CC1)c1cc(CO)ccc1O2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
12 mg of N-[1-(cyclooctylmethyl)piperidin-4-yl]-2-formyl-7-methoxycarbonylxanthene-9-carboxamide was dissolved in 1.0 ml of ethanol, 10 mg of sodium borohydride was added thereto, followed by stirring for 40 minutes at room temperature. Sodium sulfate decahydrate was added to the reaction solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=95/5), and 10 mg of the title compound as a colorless solid was obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([C@@:20]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40](O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH:40]([O:22][C:21](=[O:23])[C@:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, diisopropyl azodicarboxylate (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylhydroxyphenylacetic acid (1.1 g, 5 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5.5 mmol), and triphenyl-phosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: [N:1]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:36]([NH:38]N)=[O:37])CC1C=CC=CC=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].NCC(N[C@H:55]([C:60]([NH:62][C@H:63]([C:68]([NH2:70])=[O:69])[CH2:64][CH2:65][CH2:66][CH3:67])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=O>>[N:1]1([C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:36]([NH:38][C@H:55]([C:60]([NH:62][C@H:63]([C:68]([NH2:70])=[O:69])[CH2:64][CH2:65][CH2:66][CH3:67])=[O:61])[CH2:56][CH:57]([CH3:58])[CH3:59])=[O:37])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 69 %

Procedure:
Condensation of BocPro-Phe-Phe-PheNHNH2 (Example 1, 1.09 g.) and HGly-Leu-NleNH2 (0.70 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-NleNH2 in 69% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-NleNH2 (1.0 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-NleNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 65% yield.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]([N+:24]([O-])=O)=[CH:15][C:14]=2[NH:13][C:12](=[O:27])[C:11]1=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[H][H]>CN(C=O)C.[Pt]=O.O>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]([NH2:24])=[CH:15][C:14]=2[NH:13][C:12](=[O:27])[C:11]1=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3ccccc3c21)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc(N)c3ccccc3c21)OCC

Procedure:
0.3 mmol of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester in 10 ml of DMF z.A. is dissolved, and 10 mg of platinum oxide catalyst, which was previously saturated with hydrogen, is added. It is hydrogenated with hydrogen for three hours at normal pressure and room temperature. The catalyst is suctioned off on Celite, the mother liquor is diluted with water and the precipitate that is produced is suctioned off. 44% of theory of (6-amino-2,3-dioxo-1,2,3,4-tetrahydro-benzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained. The latter is described as in Example 1e) or saponified according to standard conditions with HCl to (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid (or to its hydrochloride, respectively).
Reaction SMILES: CO[C:3](=[NH:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:33])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[NH3:35]>>[C:3]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[O:33])=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)(=[NH:34])[NH2:35]
Reactant: N
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(N)c1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1

Procedure:
3-{3-[4-(4-Sulfamoylbenzylcarbamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (370 mg) was dissolved in methanolic ammonia solution (5 ml, 7 M) and refluxed for 4 h. The mixture was filtered, the filtrate concentrated in vacuo and diethylether was added. The resulting precipitate (300 mg) was filtered off. 100 mg were suspended in ethyl acetate/methanol/ammonia, filtered off, washed with ethyl acetate and ether and dried in vacuo to yield 60 mg of 4-[3-(3-carbamimidoylphenyl)-ureido]-N-(4-sulfamoylbenzyl)-benzamide.