Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:18].O>C(Cl)(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][Br:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(C#Cc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
The resulting acetylene compound (116 mg) was dissolved in 1 ml of chloroform, and 0.1 ml of phosphorus tribromide was added. The mixture was stirred at room temperature for 1 hour. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give 150 mg (yield 99%) of the captioned compound as a colorless oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7].[CH3:23]O>>[ClH:1].[CH3:23][O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH2:3]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
L-Phenylalanine (7.4 g, 0.045 mole) was stirred in 90 ml of water. The pH of this solution was adjusted to 10.2 (0°-2° C.) with 50% NaOH. Then a solution of pure NCA (8.3 g, 0.048 mole) in 8 ml of THF was added in 15 min. with vigorous stirring. The pH was maintained at 10.0-10.2 by the addition of 7N NaOH solution. The reaction mixture was then stirred at 0°-2° C. for 2 hr (pH 10.0-10.2). Sufficient 37% hydrochloric acid (9.7 g) was added at the end of the hold period to neutralize the NaOH. The solution was then warmed to 25° C. Liquid chromatography indicated an 80-82% yield of aspartyl ester based on L-phenylalanine. This clear solution was extracted twice with 50 ml portions of ethyl acetate. To the aqueous solution, 4.2 g of 37% HCl (0.043 mole) was added. The solution was concentrated under vacuum to a total weight of 31.1 g. Another 8.4 g (0.085 mole) of 37% HCl was added and the reaction slurry was held at 40° C. for 6 h to convert the aspartyl ester to α-L-aspartyl-L-phenylalanine hydrochloride. Solid (NaCl) was collected at 40° C. and washed with 2.6 g (0.026 mole) of 37% HCl and 7.5 g of methanol. Seed crystals were added to the combined filtrate and washings. The resulting solution was stirred at ambient temperature for 68 hours. The thick slurry was cooled to 0°-2° C. and the solid was collected by filtration and washed with 7 ml of cold water. The dry weight of α-APM.HCl was 9 g (55% yield based on L-phenylalanine). Product identity was confirmed by LC analysis.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:15](=[S:18])([OH:17])=[O:16])[C:12]([F:14])=[CH:13][C:8]=3[C:7](=[O:19])[NH:6][C:5]2=[O:20])[CH2:3][CH2:2]1.[H-].[Na+].[N+:23](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:23][N:6]1[C:7](=[O:19])[C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15](=[S:18])([OH:17])=[O:16])=[N:10][C:9]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(S(=O)(O)=S)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 0.47 g (1.57 mmol) of 1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Example 35) in 20 mL of dimethylformamide/dioxane (1:1) is treated portionwise with 0.08 g (2.0 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred at room temperature for 1 hour and 0.32 g (1.6 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 100 mL with ice and water and stirred at 5° C. for 1 hour. The aqueous solution is extracted with ethyl acetate (3×50 mL) with the combined organic layers being washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.4 g of the title compound, mp 167–169° C.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[I:1][C:2]1[C:3]2([CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1)[O:13][CH2:12][CH2:11][O:10]2
Reactant: OCCO
Reactant: CC1(C)CC=C(I)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CC=C(I)C2(C1)OCCO2
Yield: 46.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67a by using 2-iodo-5,5-dimethylcyclohex-2-en-1-one (J. Org. Chem., 1994, 59, 5393-5396; 6.10 g, 24.4 mmol), ethylene glycol (3.00 g, 48.3 mmol), p-toluenesulfonic acid hydrate (230 mg, 1.22 mmol) and benzene (70 mL), to yield the title compound (3.33 g, 46%) as a brown oil.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([OH:32])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CO>[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([O:32][CH3:3])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C1=NC(C)(C(C)C)C(=O)N1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A solution of diazomethane in ether is added to a suspension of 1-benzyl-4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-2-methyl-5-benzimidazolecarboxylic acid (1.15 g, 2.84 mmol) in methanol until the yellow color persists The reaction is stirred for 5 minutes, quenched with 2 drops of acetic acid and concentrated in vacuo. The resultant residue is purified by HPLC (silica gel, ethyl acetate eluent) to give the title product as a white powder (0.480 g, 40.3%), mp 194°-196° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CN(C)C=O.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ncc(/C=C\c2ccc([N+](=O)[O-])cc2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Yield: 26.7 %

Procedure:
A mixture of N-{5-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1 g) and 10% palladium carbon (1.04 g) in ethyl acetate (100 ml) and N,N-dimethylformamide (20 ml) was stirred under 4 atm hydrogen at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl ether to give N-{5-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (240.9 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1.[OH-:23].[Na+]>>[Cl:1][C:2]1[NH:7][C:6](=[O:23])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1
Reactant: [OH-]
Reactant: OC1(c2ccc(F)cc2)CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: [Na+]
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Yield: 58.5 %

Procedure:
1-(4,6-Dichloro-1,3,5-triazin-2-yl)-4-(4-fluorophenyl)piperidin-4-ol (304 mg, 0.89 mmol) synthesized in Reference Synthesis Example 12 and 1 M sodium hydroxide aqueous solution (1.80 mL, 1.80 mmol) were used to obtain the title compound (169 mg, yield 59%) by synthesis in a similar manner to Reference Synthesis Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A mixture of 4-nitroindazole (2.0 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) was stirred for 30 minutes, after which 2-(dimethylamino)ethylchloride hydrochloride (2.7 g 18 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by Flash Chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.6g, 50% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.74(t, J=6.44, 2H), 3.31 (s, 6H), 4.63 (t, J=6.44, 2H), 7.64 (m, 1H), 8.16 (m, 1H), 8.30 (m, 1H), 8.51(m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[CH:20]12[O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]2>C1COCC1.O>[CH3:1][N:2]1[C:6]([C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[OH:26])=[CH:5][CH:4]=[N:3]1
Reactant: C1CCC2OC2C1
Reactant: Cn1cccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCCC[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of 1-methylpyrazole (9.34 g, 114 mmol) and N,N,N′,N′-tetramethylethylenediamine (17.1 mL, 114 mmol) in THF (300 mL), butyl lithium (1.63 M solution in hexane; 81.7 mL, 133 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 30 minutes. Then, cyclohexene oxide (13.9 mL, 137 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution, water (1 L) was added, followed by extraction with ethyl acetate (500 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (11.2 g, 55%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([N+:25]([O-])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2]>O1CCCC1.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([NH2:25])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(N3CCCCC3)c12
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)c(N3CCCCC3)c12
Reaction time: 0.1 h
Yield: 79.3 %

Procedure:
140 mg of 5-piperidino-6-nitro-beta-carboline-3-carboxylic-acid-ethylester in 10 ml of tetrahydrofuran is mixed with the four-fold molar amount of titanium trichloride in water. After 6 minutes, the substance is neutralized, filtered and evaporated. The residue is extracted with methylene chloride, and the extracts are concentrated and recrystallized from glacial acetic acid. 102 mg of 5-piperidino-6-amino-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 188°-190° C. is obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Pd]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2nccs2)cc1
Temperature: 120 °C
Yield: 3.3 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.2 mmol) in 5 ml of anhydrous DMF was added 2-tributylstannyl thiazole (0.071 g, 0.2 mmol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine palladium (0) (0.026 g, 0.2 mmol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.003 g, 3%). 1H NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J=8.4 Hz (o-coupling), 7.13 (dt, 1H), 7.39-7.47 (m, 1H), 7.51 (d, 2H, J=8.4 Hz (o-coupling), 7.52-7.58 (m, 1H), 7.59-7.86 (m, 2H), 7.68 (d, 1H, J=3.2 Hz), 7.84 (d, 1H, J=3.2 Hz), 7.89 (broad s, 1H), 8.18 (broad s, 1H), 9.12 (s, 1H); MS ES+ (460.01), HPLC (method 5) Rt=15.64 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2O.P(Cl)(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[Cl:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)-3-methylbutan-1-one (300 mg, 0.970 mmol) was added to phosphoryl chloride (9.7 mL) and the reaction was stirred at 85° C. for 1 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a 2:1 solution of satd. aq. sodium bicarbonate/ethyl acetate that was cooled to 0° C. The organic layer was separated and was washed with satd. aq. sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product (309 mg, 98%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.91 (dd, J=8.9, 2.0 Hz, 1H), 2.96 (d, J=6.9 Hz, 2H), 2.39-2.23 (m, 1H), 1.03 (d, J=6.7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:4]=[CH:5][N:6]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:20](=[O:23])[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2]1[N:3]([C:7]2[N:11]([CH2:21][C:20]([C:19]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:17]([CH3:16])[CH:18]=3)=[O:23])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:4]=[CH:5][N:6]=1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Reactant: Nc1ncnn1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)Cn2c(-n3ncnc3N)nc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 3-amino-2-(1H-benzimidazol-2-yl)-1,2,4-triazole (0.15 g, 0.75 mol), 3,4-dimethyl phenacyl bromide (0.204 g, 0.9 mmol) and dry potassium carbonate (0.258 g, 1.87 mmol) is stirred at room temperature for 16 hours. The mixture is diluted with water and the product extracted with ethyl acetate. The product is purified by chromatography on silicagel. M.p. 190-193° C., 1H-NMR (400 MHz, d6-DMSO): 7.84 (m, 1H); 7.77 (m, 3H); 7.65 (m, 2H); 7.50 (s, 1H); 7.33 (d, 1H); 6.22 (s, 2H); 2.30 (s, 6H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:3]1=[O:32].[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1.C(N(CC)CC)C>C1COCC1>[CH3:33][O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:20]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:32])=[O:22])[CH:38]=1
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Reactant: COC(=O)Cc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (1.92 g, 4.47 mmol) was dissolved in THF (25 ml) and treated with a solution of (3-aminophenyl)acetic acid methyl ester (670 mg, 4.06 mmol) in THF (5 ml) followed by triethylamine (615 mg, 6.09 mmol). The mixture was stirred at ambient temperature for 4 days. The solvent was removed in vacuo and the residue was treated with water (20 ml) and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1M NaOH, then with 10% citric acid, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:1 hexane:ethyl acetate. The product fractions were combined and evaporated to dryness in vacuo and the residue crystallized from ethyl acetate to give (R)-3-((((2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)amino)carbonyl)amino)phenyl acetic acid methyl ester. This ester (885mg, 1.94mmol) was dissolved in THF (5 ml) and treated with a solution of lithium hydroxide (815 mg, 19.4 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 3 hours, diluted with water (100 ml), acidified with 1N HCl, and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, filterate, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with chloroform followed by 9:1 chloroform:methanol. The product fractions were combined and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate to provide the title compound: (mp 167°-170° C.).
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([F:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH:45][CH3:46])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[F:1][C:2]1[C:15]([NH:16][C:17]2[N:45]([CH3:46])[C:22]3=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]4)[CH:39]=[C:21]3[N:20]=2)=[C:14]([F:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(F)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc21

Procedure:
The title compound is prepared from N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (150 mg, 0.38 mmol) and 5-amino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-nicotinamide (150 mg, 0.38 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C(Cl)Cl>[C:28]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Yield: 78.8 %

Procedure:
A solution of 397 (100 mg, 0.38 mmol), Et3N (160 μL, 1.14 mmol) and nicotinoyl chloride HCl salt (68 mg, 0.38 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour and quenched by adding saturated NH4Cl sat solution (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to produce a residue which was purified by flash chromatography using 5% MeOH in DCM as an eluent to afford the title compound (110 mg, 79% yield). LRMS: (calc) 367.2; (found). 368.1 (M+H1).