Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][O:16]1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:15](=[O:14])[C:23]2[CH:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]=2[CH2:17][OH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc2c(c1)C(=O)OC2
Reactant: Cc1c(N)cccc1Br
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1cc(C#N)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Step 1 A solution of 3-bromo-2-methylaniline (0.67 g, 3.60 mmol) in DCM (18 mL) was treated dropwise with trimethylaluminum (2 M in toluene, 1.801 mL, 3.60 mmol) and the resulting solution was stirred at rt for 30 min. A solution of 3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (0.573 g, 3.60 mmol) in DCM (18.00 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was diluted with DCM, washed with an aqueous solution of sodium potassium tartrate (Fehling's Reagent II) and water, then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to provide N-(3-bromo-2-methylphenyl)-5-cyano-2-(hydroxymethyl)benzamide as a white solid (170 mg, 14%) which was used without further purification. Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]([CH2:26][C:27]([NH:29][NH2:30])=[O:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:27]2[O:28][C:34]([OH:36])=[N:30][N:29]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)NN)Cc2ccc(Cl)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(Cc2ccc(Cl)cc2)Cc2nnc(O)o2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of the Intermediate obtained in step b above (1 eq.) in dioxane was added triphosgene (1.5 eq.) under nitrogen. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with Hept/EtOAc/DCM/MeOH: 50/50/0/0 to 50/50/95/5) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(5-hydroxy-[1,3,4]oxadiazol-2-ylmethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:29]1C=C2C(C3N=C(N[C@H]4CCNC4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH3:29])(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 49 %

Procedure:
According to the procedure for compound 398 using 50 mg (0.10 mmol) of 7c and ethanesulfonyl chloride (54 μL, 0.57 mmol) afforded 21.7 mg (49% yield) of 399, as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(OC(Cl)C)=O.[OH-].[Na+]>ClCCCl.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH:11]3[NH:16][CH:14]([CH2:13][CH2:12]3)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2C=C(c3ccc(Cl)c(Cl)c3)CC1CC2
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CO
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1Cl
Yield: 50 %

Procedure:
To 1.08 g (4.03 mmol) 3-(3,4-dichloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene in 20 mL Cl(CH2)2Cl is added 1.31 mL (1.73 g, 12.08 mmol) of 1-chloroethyl chloroformate, and the resulting mixture is heated to reflux for 24 h. Evaporation of all volatiles gives an orange oil which is dissolved in methanol (20 mL) and heated to reflux for 1 h. Evaporation of all volatiles yielded an orange solid which is dissolved in 100 H2O and treated with 50 mL of 2.5 N NaOH. Extraction with 3×25 mL CH2Cl2, combining the organics and washing with 1×50 mL H2O, 1×50 mL brine, drying over MgSO4, filtering and evaporation a dark orange oil. Flash chromatography on SiO2 gel, eluting with EtOAc, then 10/1 EtOAc/2.0M NH3 in MeOH), gives 511 mg (2.01 mmol, a 50% yield) of the title compound as an orange solid. The oxalate salt of the title compound may be prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates. mp: 185-186° C. MS (ES) m/z 255 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)F)nn1CC(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c(C(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 2-(4-chloro-3-difluoromethyl-5-methyl-pyrazol-1-yl)acetic acid (0.023 g, 0.10 mmol) and NEt3 (0.065 mL, 0.46 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.032 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.44 (m, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 6.67 (d, J=54 Hz, 1H), 5.11 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.30 (s, 3H), 2.10 (m, 2H); MS: (ES) m/z calculated for C19H17ClF3N5O [M+H]+ 424.1, found 424.1.
Reaction SMILES: [Br-:1].[C:2]([O:5][C:6]1[C:15]2[N+:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:16])(=O)C.COC1C=CC(N)=CC=1.C(O)(C)C>C(OCC)(=O)C>[CH3:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH3+:10])=[CH:14][CH:15]=1.[Br-:16].[Br:16][C:7]1[CH:8]=[CH:9][N+:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[OH:5].[Br-:1]
Reactant: CC(=O)Oc1c(Br)cc[n+]2ccccc12
Agent: [Br-]
Solvent: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc([NH3+])cc1
Product: Oc1c(Br)cc[n+]2ccccc12

Procedure:
Into a 500 ml., 3-neck flask was placed a mixture of 1-acetoxy-2-bromoquinolizinium bromide (12.0 g., 0.035 mole), p-anisidine (9.6 g., 0.078 mole) and isopropanol (240 ml.). The stirred solution was boiled under reflux for 4.5 hours. After cooling in an ice bath the reaction mixture was treated with ethyl acetate to induce crystallization. The yellow solid (11.0 g., 74%) was removed by filtration, washed with ether and ethyl acetate and dried at 63°. Recrystallization from isopropanol/ethyl actate provided a pale yellow powder which melted at 129°-133°.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][C:7]=1Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.C(=O)([O-])[O-].[Rb+].[Rb+]>>[N:28]1([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][N:3]3[N:2]([CH3:14])[CH3:1])=[CH:7][CH:8]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: CN(C)N=CCc1ccc(Cl)cc1Cl
Reactant: c1cc[nH]c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Rb+]
Product: CN(C)n1ccc2ccc(-n3cccc3)cc21

Procedure:
6-(1-pyrrolyl)-1-(dimethylamino)indole was prepared in the same manner as in Example 12 except that 2,4-dichlorophenylacetaldehyde N,N-dimethylhydrazone was used in place of 2,6-dichlorophenylacetaldehyde N,N-dimethylhydrazone, tri(t-butyl)phosphine was used in place of 1-(N,N-dimethylaminomethyl)-2-(di-t-butylphosphino)ferrocene, pyrrole was used in place of piperazine, and rubidium carbonate was used in place of t-butoxysodium. (Yield: 2′%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([CH3:63])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:44]=[CH:45][C:40]([CH3:63])=[CH:41][CH:42]=2)(=[O:48])=[O:47])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of 150 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[(5-hydroxypyridin-2-yl)methyl]-L-glutamate (0.32 mmol) in N,N-dimethylformamide (8 mL) was added 126 mg of cesium carbonate (0.39 mmol), followed by 143 mg of 1,2-ethanediol di-p-toluenesulfonate (0.39 mmol). The mixture was stirred for 5 h at room temperature. Water was added, the mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The crude product was purified by preparative HPLC (method A) to give 86 mg (40% yield) of the title compound.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:9]([O:11][CH3:12])=[O:10].[C:17](O)(=[O:19])[CH3:18]>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N:16]([CH2:2][CH2:1][OH:3])[CH2:18][CH2:17][OH:19])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: C1CO1
Product: COC(=O)c1ccc(N(CCO)CCO)c(OC)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
Ethylene oxide (16.5 ml; 333 mmol) was added dropwise under ice cooling to a solution of 3.9 g (22 mmol) of methyl 3-methoxy-4-aminobenzoate in 33 ml of a 30% acetic acid suspension. The thus-obtained was stirred for 1 hour and then stirred at room temperature for 2 nights. The mixture was then stirred for 2 hours while bubbling nitrogen gas therethrough. Sodium hydrogencarbonate was added to the mixture to neutralized the same. Sodium chloride was then added until saturation, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (methylene chloride/ethyl acetate=1:1→0:1), whereby 3.1 g of a pale yellow oil were obtained (yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Cl[C:13]1[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]([C:5]1([CH3:11])[CH2:6][CH2:7][N:8]([C:13]2[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Product: COC(=O)C1(C)CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
Prepared from 4-methylpiperidine-4-carboxylic acid methyl ester and (2-chloropyrimidin-5-yl)boronic acid according to the method of Intermediate 45.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]\[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: COC(=O)/C=C\C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reaction time: 5.5 h
Yield: 52 %

Procedure:
3.58 g of hydrazine monohydrate was dropwise added to a mixed liquid comprising 25 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxoisocrotonate and 250 ml of ethanol, followed by reflux with heating. After stirring for 5.5 hours, the reaction liquid was stood to cool. The precipitated crystals were subjected to suction filtration. The crystals collected after the filtration were washed with ethyl acetate and then with hexane and air dried to obtain 13 g of the desired product.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[CH3:7][C:8]([O:11][C:12](ON=C(C1C=CC=CC=1)C#N)=[O:13])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(Cl)(Cl)Cl>[NH2:6][C:2]([CH3:5])([CH3:1])[CH2:3][NH:4][C:12](=[O:13])[O:11][C:8]([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(N)CN
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(N)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
2-Methylpropane-1,2-diamine (5.0 g) was dissolved in dichloromethane (200 ml) and stirred for 15 minutes at 0° C. A solution of BOC-ON (15 g) in dichloromethane (60 ml) was added dropwise thereto and then stirred for 2 hours at room temperature. The reaction mixture was diluted with chloroform with ice cooling and then acidified by 10% citric acid solution, and the organic phase was separated. The aqueous phase was alkalinized by 5 N sodium hydroxide solution, then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give t-butyl (2-amino-2-methyl-1-propyl)carbamate (7.9 g, Y.:74%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C@@H:4]1[C@H:7]([CH3:8])[N:6]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]1=[O:16].[OH-].[Na+].S(=O)(=O)(O)[O-:21].[Na+]>COCCOC>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][NH:6][C@@H:7]([CH3:8])[C@@H:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:5]([OH:21])=[O:16]
Reactant: CC(C)C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)C[C@@H](C(=O)O)[C@H](C)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(3R,4S)-3-(2-Methyl-1-propyl)-4-methyl-1-(2-tetrahydropyranyloxy)azetidin-2-one (3.5 g, 14.5 mmol) in 30 mL of ethylene glycol dimethyl ether is treated with 20 mL of 2.5 M aqueous sodium hydroxide solution. The mixture is stirred at 25° C. for 16 h and is then brought to pH 3 by addition of saturated aqueous sodium bisulfate solution. The mixture is extracted with ether and the organics are dried over magnesium sulfate and concentrated under reduced pressure to give 3.2 g (84%) of (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)butanoic acid as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:20]2[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (1 g, 5.8 mmol) in 10 mL of DMSO was added, 1-(methylsulfonyl)piperazine (1.15 g, 7.02 mmol), and K2CO3 (2.42 g, 17.5 mmol). The mixture was heated to 80° C. overnight. In the morning, the mixture was poured into 100 mL of H2O, Solid precipitated and was filtered off, washed with H2O and let air dried for a few hours. After drying under high vacuum overnight, the title compound of step A was isolated as a yellow solid. (1.09 g, 3.46 mmol, 60%). MS (ESI): 316 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][NH:5][C:6](=[O:44])[C@H:7]([CH2:39][O:40][CH2:41][CH:42]=[CH2:43])[NH:8][C:9](=[O:38])[C@H:10]([CH:35]([CH3:37])[CH3:36])[NH:11][C:12](=[O:34])[C@H:13]([CH:31]([CH3:33])[CH3:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[NH:17]C(OC(C)(C)C)=O.CCOCC.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[CH3:1][O:2][C:3](=[O:45])[CH2:4][NH:5][C:6](=[O:44])[C@H:7]([CH2:39][O:40][CH2:41][CH:42]=[CH2:43])[NH:8][C:9](=[O:38])[C@H:10]([CH:35]([CH3:36])[CH3:37])[NH:11][C:12](=[O:34])[C@H:13]([CH:31]([CH3:33])[CH3:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[NH2:17]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](COCC=C)C(=O)NCC(=O)OC)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOC[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)COCC=C)C(C)C)C(C)C)C(=O)NCC(=O)OC
Yield: 96 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valyl O-allyl L-seryl glycine methyl ester 22 (SEQ ID NO: 1) (0.734 g, 1.14 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (16 mL). The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated affording an oil. Addition of Et2O (25 mL) resulted in the precipitation of a white solid. The mixture was centrifuged and the Et2O decanted off. The residue was washed with an additional 2×25 mL Et2O and dried under reduced pressure overnight affording a fine white powder (0.719 g, 96%); δH (300 MHz; d6-DMSO) 8.48 (1H, d, J 9, NH(Valx)), 8.41 (1H, t, J 6, NH(Gly)), 8.24 (3H, br s, NH3+), 8.01-7.98 (2H, m, NH(Valy)/NH(Ser(All)2)), 5.90-5.77 (2H, m, CH═CH2), 5.30-5.10 (4H, m, CH═CH2), 4.56-4.50 (1H, m, CαH(Ser(All)2)), 4.32 (1H, dd, J 7 and 9, CαH(Valx)), 4.24 (1H, dd, J 7 and 8, CαH(Valy)), 4.10 (1H, br s, CαH(Ser(All)1)), 3.98-3.93 (4H, m, CH2CH═CH2), 3.86-3.84 (2H, m, CαH2(Gly)), 3.72-3.52 (4H, m, CH2(Ser(All)1)/CH2(Ser(All)2)), 3.61 (3H, s, OCH3), 2.08-1.89 (2H, m, CH(CH3)2), 0.88-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 170.6, 170.4, 169.9, 169.8, 166.2, 158.3 (q, JCF 37) 134.8, 134.4, 117.1, 116.9 (q, JCF 293), 116.5, 71.4, 71.0, 69.5, 68.3, 57.9, 57.6, 52.4, 52.2, 51.6, 40.6, 30.6, 30.4, 19.1, 18.1, 17.9; m/z (ESI) 542.3181 (M+; C25H44N5O8 requires 542.3189)
Reaction SMILES: CS(O)(=O)=O.[NH2:6][N:7]=[CH:8][NH:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[CH:23]([OH:24])[CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11].[CH3:25]S(O)(=O)=O>CO>[NH2:6][N:7]=[CH:8][NH:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[CH:23]([O:24][CH3:25])[CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11]
Reactant: CS(=O)(=O)O
Reactant: NN=CNC(=O)c1[nH]c2cccc3c2c1CCC3O
Solvent: CO
Product: COC1CCc2c(C(=O)NC=NN)[nH]c3cccc1c23
Yield: 109.2 %

Procedure:
A mixture of the N-(aminoiminomethyl)-1,3,4,5-tetrahydro-5-hydroxy-benz[cd]indole-2-carboxamide methanesulfonate (0.13 g, 0.37 mmol) obtained in Example 7, methanesulfonic acid (0.036 g, 0.37 mmol) and methanol (20 ml) was heated under reflux for 2 hours. Subsequently, the reaction mixture was concentrated to a volume of about 5 ml under reduced pressure and a 5% aqueous sodium chloride solution was added to the residue. The resulting mixture was made basic with 28% aqueous ammonia and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=96/4) to obtain N-(aminoiminomethyl)-1,3,4,5-tetrahydro-5-methoxy-benz[cd]indole -2-carboxamide (0.11 g). This compound (0.11 g) was treated with a solution of methanesulfonic acid (0.05 g) in tetrahydrofuran (2.5 ml) to obtain N-(aminoimino-methyl)-1,3,4,5-tetrahydro-5-methoxy-benz[cd]indole-2-carboxamide methanesulfonate (0.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: COc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CSc2cccc(OC)c2)cccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 806.2 %

Procedure:
To a solution of 3-methoxythiophenol (0.54 g, 0.48 mmol) and triethylamine (0.43 ml, 0.59 mmol) in dichloromethane (30 ml) was slowly added methyl 2-bromomethyl-6-nitrobenzoate (1.45 g, 5.3 mmol) under ice-cooling, followed by stirring for 3 hours. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give methyl 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoate (1.29 g, 99%).
Reaction SMILES: CS[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:33][NH:34][CH3:35].ClCCl>CO>[CH3:33][N:34]([CH3:35])[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: CNC
Solvent: ClCCl
Solvent: CO
Product: CN(C)C(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
Part B: To a stirred mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) was added dimethylamine (10 ml) and dichloromethane (75 ml) and the resulting solution was stirred at room temperature for 6 hours. Evaporation in vacuo and subsequent flash chromatographic purification (diethyl ether/petroleum ether=1/1 (v/v), followed by diethyl ether) gave a solid which was further purified by recrystallisation from diisopropyl ether to yield N1,N1-dimethyl-N2-((4-chloro-phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2.63 gram, 63% yield). Melting point: 182° C.