Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
A solution of 1,5-dichloro-2,4-dinitrobenzene (5.0 g), glycolonitrile (1.81 g) and anhydrous potassium carbonate (2.19 g) in dimethylformamide (20 g) was stirred at 25° to 30° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and washed with ether to give crude crystals (4.16 g), which were recrystallized from methanol to give 2,4-dinitro-5-chlorophenoxyacetonitrile (3.18 g; yield, 58.5%). M.P., 117°-118° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:14])[CH2:5]1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].[OH-].[K+]>OS(O)(=O)=O>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(N)=Cc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)N1CC(N)=Cc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-Acetyl-3-aminoquinoline, as described above in Step A, (9.76 g, 52.41 mmol) was dissolved in neat H2SO4 (100 mL) and cooled to 0° C. HNO3 (6.6 mL, 104.8 mmol) was slowly added over 20 minutes and the reaction was stirred at 0° C. for 45 min, then at ambient temperature 45 min. The reaction mixture was poured onto ice, solid KOH was added to neutralize the acid, and the mixture was stirred for 18 hours. The mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was treated with hot EtOAc and filtered. The filtrate was concentrated and crystallized from EtOAc/Hex (3×). The recovered solids were combined and dried in vacuo to yield the above-titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.ClCCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
A 2 L, three-neck flask fitted with a mechanical stirrer, addition funnel, and thermocouple probe was charged with 4-formyl-benzoic acid methyl ester (50.0 g, 0.31 mol, 1.0 eq) and 1,2-dichloroethane (700 mL). The resulting mixture was cooled to 10° C. Morpholine (53 mL, 0.61 mol, 2.0 eq) was then added dropwise over 10 min. After 5 min, sodium triacetoxyborohydride (90 g, 0.43 mol, 1.4 eq) was added in portions over 5 min. After stirring 30 min, the reaction mixture was warmed to room temperature. At this point, a slow and steady temperature increase was observed, and a water bath was used to keep the temperature of the reaction mixture below 25° C. The reaction mixture was stirred for 22 hrs at room temperature. Water/ice (100 mL) was added to the reaction and the reaction mixture was stirred for 15 min. NaOH solution (1.0 M in water, 400 mL) was added in several portions, followed by the addition of water (250 mL). The resulting mixture was stirred for 45 min. The layers were separated, and the aqueous layer was extracted with dichloromethane (150 mL). The combined organic layer was washed with brine (150 mL) and then dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a pale yellow, viscous oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[H][H].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1.C(O)C>[CH:8]([C:6]1[N:5]=[CH:4][N:3]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1)=[O:9]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c[nH]cn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of sodium hydride (60%, oil, 1.40 g) in tetrahydrofuran (80 mL) was slowly added 1H-imidazole-4-carbaldehyde (3.00 g) at room temperature. The reaction mixture was stirred at room temperature until hydrogen gas generation stopped, and ethyl bromoacetate (4.5 mL) was added over 30 min. The reaction mixture was stirred at room temperature overnight, and ethanol (5 mL) was added. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (3.94 g, yield 69%) was obtained as a yellow oil from a fraction eluted with tetrahydrofuran-hexane (5:1, volume ratio). MS: 183 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.[CH2:23](N(CC)CC)C.Cl[S:31]([C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])(=[O:33])=[O:32]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:31]([C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH2:39][CH3:23])=[O:37])(=[O:33])=[O:32])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccccc1S(=O)(=O)NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 400 mg of methyl 2-(chlorosulphonyl)benzoate in place of 4-methyl-benzenesulphonic acid chloride then the reaction medium is agitated at ambient temperature for approximately 30 minutes. Then 5 ml of water is added, followed by extracting with 2×10 ml of methylene chloride, washing with 5 ml of H2O, drying and evaporating. After chromatography on silica eluting with methylene chloride/ethyl acetate in a proportion of 70/30, 129 mg of expected product is thus obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.[H-].[Na+].Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1>CN(C=O)C>[N:19]1[N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[O:1][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=2)=[O:20])[N:16]=[CH:17][CH:18]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Oc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-[(1S,2S)-2-hydroxycyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 11; 200 mg, 0.73 mmol) in dry DMF (1.2 ml) was added sodium hydride (60% dispersion in mineral oil, 29.4 mg, 0.73 mmol). To this was then added 2-chloro-4-(trifluoromethyl)pyridine (CAS number 81565-18-6; 133 mg, 0.73 mmol) as a solution in dry DMF (1.2 ml). The reaction was stirred at room temperature for 17 hours and was then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crude oil was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20](C)[C:21](=O)C(F)(F)F)[CH:15]=2)=[O:12])=[CH:9][N:8]=[C:7]([NH:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CO.O>[CH3:21][NH:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)=[N:8][CH:9]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(N(C)C(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC)c1
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)-N-(3-(2,2,2 -trifluoro-N-methylacetamido)phenyl)pyrimidine-5-carboxamide (A7, 186 mg) in methanol (4 mL) and water (2 mL), potassium carbonate (92 mg) was added at room temperature, and the mixture was stirred at the same temperature for 13 hours and 30 minutes. To the reaction mixture, water and chloroform were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain N-(3-(methylamino)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A8, 141 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=1.Cl>C1COCC1>[OH:3][CH2:2][CH2:1][O:4][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=1
Reactant: OCCO
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCCO)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylene glycol (34 μl) was added to a suspension of sodium hydride (24 mg) in anhydrous THF (2 ml) at 0° C. After 30 min stirring at 0° C., 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (47 mg) dissolved in THF (1.2 ml) was added. The mixture was allowed to warm to RT and stirred overnight. A 1M HCl solution was added and the resulting mixture was extracted with EA. The org. phases were dried (Na2SO4) and evaporated off.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[CH3:15][NH2:16].O>C(#N)C>[Cl:13][C:4]1[C:3]([CH3:14])=[C:2]([NH:16][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1Cl
Reactant: CN
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(Cl)c(C)c1NC
Temperature: 50 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of ethyl 4,6-dichloro-5-methylnicotinate (2.6 g, 11.1 mmol) in acetonitrile (60 mL) was added dropwise 40% methylamine in water (689 mg, 22.2 mmol, 60 mL), and the mixture was stirred at 50° C. for 72 h. LCMS monitored the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (100 mL). The organic layer was separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate=2:1) to get the title compound (2.05 g, 81%) as a colorless oil. MS (ES+) C10H13ClN2O2 requires: 228, 230. found: 229, 231 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(F)cc1

Procedure:
To a suspension of 4-fluorobenzaldehyde (325.0 mg, 2.62 mmol), 1,1-dimethylnitroethane (542.3 mg, 5.26 mmol) and zinc (516.0 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (941.7 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 4.5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1-1/1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(C)=O.Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1>O>[CH3:1][N:2]([CH3:3])[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 130 °C
Yield: 30 %

Procedure:
To a 5 ml microwave vial 1 ml of dimethylamine 40% in water was added followed by 300μ of DMSO to dissolve 25 mg (0.067 mmol) 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoline. The reaction heated in a microwave for 2000 seconds at 130° C. The reaction mixture was filtered then purified via preparatory HPLC to return the title compound (7.7 mg, 30% yield). Analytical data is presented in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].N1CCCCC1>CCO>[CH:7]1[CH:6]=[C:3]2[CH:4]=[C:12]([C:10]#[N:11])[C:13]([NH:1][C:2]2=[CH:9][CH:8]=1)=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cc2ccccc2[nH]c1=O
Temperature: 75 °C

Procedure:
To a solution of o-aminobenzaldehyde (Sigma) (5.80 g, 48 mmol) in 250 mL of EtOH was added ethyl cyanoacetate (Aldrich) (6.20 mL, 58 mmol) followed by piperidine (Aldrich) (1.4 mL, 14 mmol) at RT. The reaction was heated at 75° C. for 15 h then cooled to RT. The solid was filtered, washed with EtOH and dried in vacuo to give a pale yellow crystalline solid. MS m/z: 171 (M+1); 169 (M−1).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][O:5][CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([OH:27])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)=[O:17]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)=CCC/C(C)=C/COCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 86.4 g (560 mmol) of (E)-3,7-dimethyl-octa-2,6-dien-1-ol and 64.5 g (1150 mmol) of potassium hydroxide in 150 ml of N-methylpyrrolidone a solution of 58.59 g (230 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-iso-propylphenyl)-ethanone in 100 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 45.3 g of compound 108, m.p. 70-71° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Mg]Cl)(C)C.CCOCC.[NH2:19][C:20]1[N:31]=[CH:30][C:29]([Br:32])=[CH:28][C:21]=1[C:22](N(OC)C)=[O:23]>O1CCCC1.CCOCC.CO>[NH2:19][C:20]1[C:21]([C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[O:23])=[CH:28][C:29]([Br:32])=[CH:30][N:31]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: Fc1cccc(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: Nc1ncc(Br)cc1C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-fluoropyridine (7.5 g, 42.6 mmol) in tetrahydrofuran (50 ml) at 0° C. was added a 2 M solution of isopropylmagnesium chloride in ether (21.3 ml, 42.6 mmol) over a period of 10 minutes. The ice-bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was added dropwise to a solution of 2-amino-5-bromo-N-methoxy-N-methylnicotinamide (3 g, 11.5 mmol) in tetrahydrofuran (40 ml) at room temperature over a period of 30 minutes. The resulting solution was stirred at room temperature for 18 hours. The solution was quenched by addition of an aqueous saturated solution of ammonium chloride at 0° C. and the mixture was stirred at room temperature for 20 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-100% EtOAc/Petrol) to give an orange sticky solid which was slurried in ether/MeOH, collected by filtration and dried. The desired compound was obtained as a yellow solid (196 mg, 6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)ccc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(Br)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 72 h
Yield: 104.5 %

Procedure:
5-Bromo-2-fluorotoluene (7.65 g) was added to concentrated sulfuric acid (40 ml), and potassium nitrate (4.2 g) was added portionwise to the mixture at -20° C. The temperature of the reaction mixture was given back to room temperature to conduct stirring for 3 days, and then poured into ice water to conduct extraction with ethyl acetate. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (9.9 g) as a pale yellow oil.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4([CH3:41])[CH2:34][CH2:33][N:32](OCC)[CH:31](C)[C:30]4=C=O)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1.Cl.[CH2:60]1[CH2:64][O:63]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:50])[F:51])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4([CH3:41])[CH2:30][CH2:31][N:32]([CH2:60][C:64]([OH:2])=[O:63])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1
Reactant: [OH-]
Reactant: CCON1CCC(C)(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)C(=C=O)C1C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Solvent: O
Product: CC1(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10.0 mg (0.42 mmol) LiOH in 5 mL water was added to 100 mg (0.12 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-ethoxy-carbonyl-methyl-4-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL THF and the reaction mixture was stirred for 3 h at RT. 0.42 mL (0.42 mmol) 1 M HCl were added and the mixture was evaporated down i. vac. The residue was taken up in a little DCM/MeOH (1:1), filtered through a little silica gel and eluted with DCM/MeOH (1:1). The filtrate was evaporated down i. vac. and dried under a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7]>C(Cl)(Cl)Cl.C(Cl)Cl.CO.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[CH3:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=NO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(F)cncc1-c1cc2cnc(Cl)cc2c[n+]1[O-]
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A slurry of 2-chloro-5-((5-fluoro-4-methylpyridin-3-yl)ethynyl)isonicotinaldehyde oxime (400 mg, 1.38 mmol) in chloroform (10 mL) was treated with silver nitrate on silica gel (10% w/w, 357 mg, 0.210 mmol). The reaction mixture was heated at 60° C. for 2 hours and then diluted with DCM (20 mL) and methanol (5 mL), loaded on silica gel, and purified by flash chromatography (12 g, Silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (270 mg, 66% over two steps). 1H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.40 (s, 2H), 8.01 (s, 1H), 2.12 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[C:6]([S:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.O>C1COCC1>[CH2:1]([NH:3][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([S:19][C:6]2[C:5]([CH3:4])=[CH:14][C:13]3[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)=[CH:28][CH:27]=1)[CH3:2]
Reactant: Cc1cc2c(cc1Sc1ccc(C(=O)Cl)cc1)C(C)(C)CCC2(C)C
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
640 μl (8 mmol) of a 70% solution of ethylamine and 20 ml of THF were introduced into a round-bottomed flask. A solution of 735 mg (2 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoyl chloride dissolved in 30 ml of THF was added dropwise and the mixture was stirred at room temperature for three hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]2[CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH:30]([OH:31])[CH2:32][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=3)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1ccc2[nH]c3ccc(Cl)cc3c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Product: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccc(Cl)cc3c3cc(Cl)ccc32)CC1
Yield: 74 %

Procedure:
The same method as employed in the preparation of Example 1 but starting from 3,6-dichloro-9H-carbazole and (±)-4-oxiranylmethyl-piperazine-1-carboxylic acid tert-butyl ester gives after flash chromatography the title compound as a white foam in a 74% yield.