Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[S:12][C:8]=2[C:7]([C:23](O)=[O:24])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][NH2:33].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>O.CN(C)C=O>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][NH:33][C:23]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=1)=[O:24]
Reactant: NCc1nccs1
Reactant: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)O)cn3C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)NCc2nccs2)cn3C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.4 %

Procedure:
Anhydrous N,N-dimethylformamide (30 ml) was added to a mixture of 4-tert-butyl-2-(4-methyl-benzoylamino)-4H-pyrrolo[2,3-d]thiazole-6-carboxylic acid (1.1g, 2.9 mmol), C-thiazol-2-yl-methylamine hydrochloride (0.5 g, 3.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 0.4 g, 2.9 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC, 0.9 g, 4.4 mmol), and 4-methyl-morpholine (NMM, 0.8 ml, 7.2 mmol). The resulting solution was stirred at ambient temperature, under N2 blanket, for 15 hours, then slowly poured into 300 ml of rapidly stirred water. Precipitated solid was isolated by filtration, flash chromatographed (silica gel, 100% EtOAc), and then crystallized from ethyl acetate/hexanes to afford 0.9 g (68%) of the product as fine white crystalline powder, mp. 245-246° C. (decomp.). 1H NMR (d6-DMSO): δ 1.72 ppm, s, 9H, 2.40 ppm, s, 3H, 4.73 ppm, d, j=6.0 Hz, 2H, 7.35 ppm, d, j=7.8 Hz, 2H; 7.63 ppm, d, j=3.3 Hz, 1H, 7.74 ppm, d, j=3.3 Hz, 1H, 7.85 ppm, s, 1H, 8.03 ppm, d, j=8.1 Hz, 2H, 8.92 ppm, t, j=6.0 Hz, 1H, 12.49 ppm, s, 1H. MS: M+H=454.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:21]4[N:20]=[N:19][CH:24]=[CH:23][CH:22]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cc1cnc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6 (25 mg, 0.1 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (17 mg, 0.1 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 38 mg, 0.1 mmol) were added DMF (0.5 mL) and diispropylethyl amine (DIEA, 0.05 mL, 0.3 mmol) and the mixture was stirred at room temperature overnight. The crude DMF solution was directly purified by reverse phase HPLC to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 210 as white solid. MS m/z 405.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.18 (s, 1H), 9.23 (d, 1H), 9.14 (d, 1H), 8.61 (m, 1H), 8.56 (dd, 1H), 8.41 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 7.95 (dd, 1H), 7.91-7.86 (m, 1H), 7.81 (dd, 1H), 7.65 (s, 1H), 4.02 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[O:14]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=O)[CH2:20]2)=[N:15]1>O1CCCC1>[O:14]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=[CH:5][C:3]#[N:4])[CH2:20]2)=[N:15]1
Reactant: O=C1CC(c2ccon2)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CC(c2ccon2)C1
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 75 mg, 1.88 mmol) was added at once to a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.1 mmol) in tetrahydrofuran (8 mL). After stirring for 5 minutes, a solution of 3-isoxazol-3-ylcyclobutanone (258 mg, 1.88 mmol) in tetrahydrofuran (20 mL) was added. After 2 hours reaction time, the reaction mixture was partitioned between ethyl acetate and brine and the layers separated. The aqueous layer was extracted with two further portions of ethyl acetate and the combined extracts were dried over sodium sulfate, decanted and concentrated. The residue was then azeotroped with toluene and the product was used without further purification in Step 9.
Reaction SMILES: CO.[C:3]([O:7][C:8]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([N+:30]([O-])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>[C].[Pd].C(OCC)(=O)C>[NH2:30][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH:12]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a mixed solution of methanol 18 mL and ethyl acetate 18 mL of tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-nitrobenzoate 3.5 g was added 5% palladium-carbon 0.70 g, and it was stirred under hydrogen atmosphere at room temperature for 3 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated to give tert-butyl 2-amino-4-(3-(tert-butoxycarbonyl)oxyphenyl)benzoate 3.2 g of yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:24][CH:23]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:32]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)(=[O:33])=[O:34])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3cccnc23)CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and quinoline-8-sulphonic acid chloride analogously to Example 2.
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1)[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:11]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1)[CH2:12][CH3:13]
Reactant: CCCC1(CCC)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1(CCC)CCC(=O)CC1
Yield: 98 %

Procedure:
To a suspension of 10% palladium on carbon (0.1 equivalents) in ethyl acetate was added 4,4 dipropylcyclohex-2-enone, prepared as described in Example 3. The reaction mixture was hydrogenated at 300N/m2 hydrogen in a Parr hydrogenation apparatus at room temperature until hydrogen uptake has ceased (0.5-5 hours). The catalyst was removed by filtration through celite and the filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification. Yield 98%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]#[N:26])[C:22]3[N:27]=[CH:28][NH:29][C:21]=3[CH:20]=2)=[CH:15][C:14]=1[C:30]([F:33])([F:32])[F:31])([CH3:7])[CH3:6].[CH:34](N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]#[N:26])[C:22]3[N:27]=[CH:28][N:29]([CH3:34])[C:21]=3[CH:20]=2)=[CH:15][C:14]=1[C:30]([F:31])([F:32])[F:33])[CH:5]([CH3:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)NCCCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.008 ml) was added dropwise to a solution of 6-(4-(3-(isopropylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (15 mg) and diisopropylethylamine (0.031 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to give 6-{4-[3-(N-acetyl-N-isopropylamino)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (DMSO) δ: 8.72 (s, 1H), 8.64 (s, 1H), 8.46-8.42 (m, 2H), 7.43 (t, 1H), 3.99 (s, 3H), 3.40+3.28 (2xt, 1H), 2.04-1.96 (m, 3H), 1.16-1.10 (dd, 6H). MS m/z 460 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23]C(S)=[CH:21][CH:20]=1)=[O:17].C(#N)C.C(N(CC)CC)C>O>[Cl:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:12]([S:9][C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[N:5]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccc(S)cc1)c1ccccc1Cl
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A 250 mL round bottom flask was charged with 4,6-dichloro-2-methanesulfonylpyrimidine (7.00 g, 26.6 mmol), 2-chloro-N-(4-mercapto-phenyl)-benzamide (6.33 g, 27.9 mmol) and acetonitrile (100 mL) under nitrogen. Once the solid had dissolved, the reaction mixture was cooled to 0° C. and triethylamine (3.7 mL, 26.6 mmol) was added dropwise. The solution was stirred at 0° C. for 10 min and then allowed to warm to room temperature and stirred for 1 h. After this time, water (50 mL) was added and a white solid precipitated and the reaction mixture stirred for an additional 4 h. After this time, the reaction mixture was filtered and the solid washed with acetonitrile (2×10 mL) to give the title compound as a white solid (8.03 g, 74%). 1H NMR (DMSO) 7.4-7.6 (5H, m), 7.7 (1H, s), 7.80-7.85 (2H, d), 10.9 (1H, s). MS (ES+): 412
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:36]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:36])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Br)c(N)c(Br)c1)CC2
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(4-amino-3,5-dibromophenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-])=O.Cl.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:15][C:16](=[O:20])[CH2:17][N:18]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[NH2:1])[CH3:19])[CH3:14]
Reactant: CCOC(=O)CNC
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN(C)Cc1ccccc1N

Procedure:
A mixture of 8.6 g o-nitrobenzyl chloride, 7.6 g sarcosine ethyl ester hydrochloride and 13.8 g K2CO3 was refluxed in 300 ml acetone for 16 hours, whereafter the mixture was filtered and evaporated. The oily residue was partitioned between ether/1N HCl. The aqueous phase was separated and pH was adjusted to 10 with dil. NaOH, whereafter it was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated. This left an oil which was hydrogenated using a standard procedure by means of 5% PD/C to give N-(o-aminobenzyl)sarcosine ethyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=O)#[N:2].[CH3:21][NH2:22]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:22][CH3:21])=[O:18])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 2.5 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added 20 ml of 40% aqueous monomethylamine. The reaction mixture was stirred at room temperature for approximately two and one-half hours whereupon the solution was poured into ice water. The precipitate was collected by filtration and recrystallized from methanol/water to afford 1.3 g of 5-cyano-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. mp=182°-183° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:5]1([CH2:4][O:3][C:1](=[O:2])[NH:11][C@H:12]([CH3:13])[C:14](=[O:16])[NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
To a stirred solution consisting of carbobenzyloxy-D-alanine (10.0 g) and N-aminopyrrole (3.68 g) in dry DCM (224 ml) was added DCC (9.71 g) at 0° C. under nitrogen. The cooling bath was removed after ten minutes and the reaction mixture was allowed to stir at room temperature for 24 hours. The suspension was filtered and the DCU filter cake was washed with hot ethyl acetate. Concentration of the filtrate gave the crude product. Recrystallization from EtOAc/hexane afforded 11.69 g of the desired product as a solid, m.p. 172°-174° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:9])([F:8])[S:4](Cl)(=[O:6])=[O:5].C(=O)([O-])O.[Na+].[OH:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].O>C(#N)C>[F:8][C:3]([F:9])([S:4]([O:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])(=[O:6])=[O:5])[CH2:2][OH:1]
Reactant: O=S(=O)(Cl)C(F)(F)CO
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(=O)N1OS(=O)(=O)C(F)(F)CO
Temperature: 0 °C
Yield: 57.9 %

Procedure:
In 100 mL of acetonitrile, 25.5 g of a liquid of 2-hydroxy-1,1-difluoroethanesulfonyl chloride (purity: 98%, equivalent to 0.138 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 14.0 g (0.166 mol) of sodium hydrogencarbonate and 17.5 g (0.152 mol) of N-hydroxysuccinimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water. The organic layer was further subjected to concentration and purified by distillation. With this, 20.7 g of the target compound was obtained as a colorless oily substance (yield: 52%, purity: 90%, pure content: 18.7 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:37][NH2:38]>>[C:26]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=2)=[O:12])=[O:7])=[CH:30][CH:31]=1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: C=C1C[C@@H](C(=O)NCc2ccc(OC)c(OC)c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=457.2.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])(=[O:11])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[CH:27]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)[nH]n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n[nH]1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(5-methyl-1H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=404.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([NH2:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:14]([NH:32][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Product: CCCCCCCCCCCCCCCCCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
The synthesis is carried out analogously to Example 1 using 2-chloro-3,5-dinitropyridine (Fluka) and octadecylamine as the starting materials. Octadecylamine is recrystallized several times from ethanol before the synthesis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C=O)C>[NH2:20][C:18]1[N:19]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 90 °C

Procedure:
150.6 mg (0.864 mmol) of tert-butyl (3-aminopropyl)carbamate, 300 mg (1.73 mmol) of 6-chloro-3-nitropyridine-2-amine and 173 mg (1.73 mmol) of potassium bicarbonate are suspended in 10 ml of DMF and heated at 90° C. for 16 h. Water is added to the mixture, which is then extracted three times with ethyl acetate. Purification of the crude product by preparative HPLC and drying under high vacuum result in 195 mg (65% of theory) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[C:22]=1[Br:23].Cl.[OH:25][CH:26]1[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]1[NH2:28].[C:37](=O)([O-])[O-:38].[K+].[K+]>CC(C)=O.O>[Br:23][C:22]1[C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:8][C@@H:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:1][C:37](=[O:38])[NH:28][C@H:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])[CH:26]=[O:25]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(NC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO)c2Br)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-[6-bromo-5-(o-chlorophenyl-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate [obtained in accordance with details in Example 1(f) from 10 g (0.0254 mol) of (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one] in acetone is treated with a solution of 16 g of D-glucosamine hydrochloride and 7.3 g of potassium carbonate in 100 ml of water, the mixture is stirred at room temperature for 10 minutes and extracted several times with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated, whereupon the residue is recrystallized from tetrahydrofuran/methylene chloride. There is obtained 2-[3-[(S)-6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]-2-deoxy-D-glucose as a diastereomeric mixture with a melting point of 185° (decomposition); [α]25D =+45° (0.8 percent solution in methanol).
Reaction SMILES: COC1C=CC2N[C:8]([S:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=3)=[O:11])=NC=2C=1.ClC1C=CC=C(C(OO)=O)C=1>C(OCC)(=O)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:10]([CH3:8])=[O:11])[CH:23]=1
Reactant: COc1ccnc(-c2ccccc2S(=O)c2nc3cc(OC)ccc3[nH]2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2ccccc2S(C)=O)c1

Procedure:
The product of step (a) above (750 mg) in ethyl acetate (7 ml) was cooled to -10° and treated with a solution of m-Chloroperbenzoic acid (660 mg) in ethyl acetate (4 ml). After 1 hour the solution was washed with sodium bicarbonate solution, sodium bisulphate solution and brine then dried and evaporated. The residue was flash chromatographed (ethyl acetate) to produce the subtitle compound as a clear oil MS (FAB) M+1 at 248 bp 232.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20].[C-:22]#[N:23].[Na+].O.CC(OC)(C)C>CN(C=O)C>[CH3:20][O:19][C:9]1[C:10]([CH3:18])=[C:11]([CH3:17])[C:12]([O:15][CH3:16])=[C:13]([CH3:14])[C:8]=1[CH2:7]/[CH:6]=[C:5](\[CH3:21])/[CH2:4][CH2:3][CH2:2][C:22]#[N:23]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCI)c1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (412 mg, 1.024 mmol) was combined with NaCN (247.7 mg) and dissolved in DMF (2 mL). The reaction was stirred for 25 h at 45° C. then cooled to room temperature. To the mixture was added H2O (10 mL) followed by MTBE (6 mL) and the layers separated. The aqueous phase was extracted into MTBE (4×6 mL) and the combined organics washed with H2O (2×5 mL) followed by saturated NaCl solution (2×5 mL) and dried over Na2SO4. The organics were concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile as a pale yellow oil, 306.4 mg (99.0%). 1H NMR (400 MHz, CDCl3) d 5.14 (t, J=6.4 Hz, 1H), 3.65 (s, 6H), 3.37 (d, J=6.8 Hz, 2H), 2.26 (t, J=7.2 Hz, 2H), 2.18 (s, 9H), 2.12 (t, J=7.2 Hz, 2H), 1.76 (m, 4H). 13C NMR (100 MHz, CDCl3) d 153.1, 152.6, 132.5, 131.0, 128.5, 128.0, 125.4, 119.7, 60.8, 60.1, 38.2, 38.2, 26.1, 23.5, 16.4, 15.9, 12.8, 12.7, 12.2.