Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:15][N:14]=[C:6]([NH2:7])[C:5]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)cc(C(N)=NO)c1
Yield: 41.6 %

Procedure:
The title compound was prepared following the procedure described for of Intermediate-53 using of 3,5-dimethoxybenzonitrile (1.0 g, 6.12 mmol), ethanol (20 mL), hydroxylamine hydrochloride (0.634 g, 9.23 mmol) and potassium carbonate (2.53 g, 18.40 mmol) to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 3.75 (s, 6H), 5.79 (s, 2H), 6.49 (s, 1H), 6.84 (s, 2H), 9.62 (s, 1H); MS [M+H]+: 197.11.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:16][C:15]4[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:19]=[CH:20][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:16][C:15]4[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:34])[CH3:24])[CH:19]=[CH:20][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)cc3)[nH]c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)phenyl)-1H-benzimidazol-6-yl)oxy)propan-2-yl)carbamate (901 mg) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 20 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min, and concentrated. The residue was dissolved in methanol (10 mL) and THF (10 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (490 mg).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:10][C:9]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:8][C:7]=1[CH3:22]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[CH:2]([C:6]1[S:10][C:9]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:8][C:7]=1[CH3:22])=[O:1]
Reactant: CC(=O)Nc1nc(C=Cc2cc(C)c(C3OCCO3)s2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2cc(C)c(C=O)s2)cs1
Yield: 58.6 %

Procedure:
N-(4-{2-[5-(1,3-Dioxolan-2-yl)-4-methylthiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (4.42 g, 13.1 mmol) was dissolved in a mixture of ethyl acetate (400 ml) and acetic acid (100 ml), and 10% palladium carbon (2.21 g, containing 50% water) was added. The mixture was hydrogenated at room temperature under an atmospheric pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 200 g, ethyl acetate:dichloromethane=1:6) to give N-{4-[2-(5-formyl-4-methylthiophen-2-yl)ethyl]-1,3-thiazol-2-yl}acetamide (2.26 g, 7.68 mmol, yield 58.4%) as a yellow solid.
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].[O:23]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:23])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to -78° C. under argon, and a solution of diisobutyl alumninum hydride in toluene (30 ml of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1 H-imidazole; mp 98°-101° C.
Reaction SMILES: [NH:1]1[CH2:4][C:3](=[C:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:1]2[CH2:4][C:3](=[C:5]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]2)[CH3:18])=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)C(=C1CN(C(C)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.142 g (0.5 mmole) of methyl azetidin-3-ylidene(3,5-difluorophenyl)acetate, 0.142 g (1 mmol) of 4-chloroacetophenone and 0.15 mL (12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.422 g (2 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 h. The reaction was quenched by addition of saturated KHCO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated KHCO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1) to afford the title compound; Mass Spectrum: m/e=378 (M+1 35Cl) and 380 (M+1 35Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=CN(C)C)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.O1CCOCC1>O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccsc1C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 59.9 %

Procedure:
A stirred solution of 6.0 g of 4-chloro-β-(dimethylamino)-α-(3-methyl-2-thienoyl)-2-nitrosty rene, 50 ml of 1,4-dioxane and 10 ml of water was refluxed for 16 hr and allowed to cool. The cooled solution was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A stirred solution of the residue, dioxane and water was refluxed overnight and was worked-up as above. The residue was purified by preparative HPLC (Waters Associates Prep LC/Model 500, silica gel, sample applied in dichloromethane (20 ml), eluted with dichloromethane, 200 ml/min flow rate, Gow Mac Model 80-800 UV detector). The appropriate fractions were concentrated and the residue was recrystallized from 95% ethanol to give 3.03 g of product, mp 105°-107° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:9][NH:10][C:11](=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:14]1>N1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:15]2[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:23])([F:24])[F:22])[C:17](=[O:18])[N:13]([CH2:12][C:11]([NH:10][CH2:9][CH:8]([NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:42])[F:43])=[O:33])[N:14]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 13 μl of methanesulphonyl chloride were added to a solution of 90 mg (0.15 mmol) of the compound of Example 56A in 1.5 ml of pyridine. The mixture was stirred at RT for 1 h, and another 12 ml of methanesulphonyl chloride were added (0.32 mmol, 2.1 eq. in total). After 1 h, the volatile components were removed on a rotary evaporator. The residue was dissolved in a little DMSO and purified by preparative HPLC [Method 8]. This gave 59 mg (61% of theory) of the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O1CCOCC1>[C:1]1([NH:7][C:8](=[O:9])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Phenyl isocyanate and 4-aminophenol were added to dioxane solvent, and stirred for 2 hours to obtain 4-(N'-phenylureido)phenol (hereinafter, referred to simply as "Compound 8").
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([OH:25])=O)[N:22]=[C:11]2[CH2:10][N:9]=1.S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([Cl:28])=[O:25])[N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: O=C(O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
An amount of 3.63 g (0.010 mole) of 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid is refluxed with 60 ml of thionyl chloride for two hours. The clear yellow solution is concentrated at 40° in vacuo and, to effect the total removal of thionyl chloride, the residue dissolved in 50 ml of abs. toluene and again concentrated by evaporation to obtain as residue crude 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carbonyl chloride. It can be optionally recrystallised from dioxane and has then a M.P. of 196°-198° (decomposition).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][CH2:23][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1
Reactant: Fc1cc(Cl)ccc1-c1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (1.451 g, 0.0109 mol) in dichloromethane (20 mL) under nitrogen at 5° C. was added dropwise a solution of 4-chloro-2-fluorobiphenyl (0.858 g, 0.00415 mol) in dichloromethane (13 mL) over 10 minutes followed by the dropwise addition of 3-carbomethoxypropionyl chloride (0.57 mL, 0.0046 mol) in dichloromethane (13 mL) over 25 minutes. The resulting mixture was stirred for 2.5 hours then allowed to warm slowly to room temperature. Stirred for 3 days, for convenience. Then the mixture was recooled and quenched with the dropwise addition of water (145 mL). The organic layer was washed with water, aqueous sodium bicarbonate, brine, and dried (MgSO4). The mixture was rotary evaporated to give 1.25 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid: mp 90.5-92.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N+:24](C1C=CC(C(ON)=O)=CC=1)([O-])=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[NH2:24])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Reactant: NOC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.3 g, 12.8 mmol) in NMP (64 mL) was added K-OtBu (1.6 g, 14.1 mmol). After 10 min a solution of O-4-nitrobenzoylhydroxylamine (3.0 g, 16.6 mmol) in NMP (16 mL) was added dropwise and the reaction was allowed to stir for 16 h. The reaction was quenched with LiCl solution (5% in water, 50 mL) and diluted with EtOAc (50 mL). The crude product was washed 3×50 mL with 5% LiCl solution, dried over Na2SO4, and purified by silica gel chromatography 0-30% EtOAc/hexanes to give 3-(N-tert-butoxycarbonyl-hydrazino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.6 g, 7.4 mmol).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6].C[O-].[Na+]>CCOC(C)=O.CN(C=O)C>[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27]([O:2][CH3:1])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6]
Reactant: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Reactant: CO
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CH3OH (10 mL) was added dropwise to a 100 mL RBF at 0° C. charged with sodium hydride (66.8 mg, 2.78 mmol). The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 10 minutes. To a 4 mL vial were added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL) and 1.2 mL of sodium methoxide solution (1.2 eq). The reaction was stirred at room temperature overnight. An extra 0.5 eq of sodium methoxide was added to the reaction and it was heated to 40° C. for 3 hours. The reaction mixture was then poured into EtOAc (10 mL). The organics were washed with H2O (2×) and then dried over Na2SO4 and concentrated to afford 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile. This material was taken up in CH3CN (1 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (10-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (34.8 mg) as a white fluffy powder. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.59-1.82 (m, 2H), 2.82 (d, J=3.8 Hz, 3H), 3.07-3.18 (m, 1H), 3.39-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.82-3.87 (m, 1H), 3.87-3.92 (m, 1H), 3.94 (s, 3H), 4.10-4.23 (m, 1H), 4.27-4.39 (m, 1H), 5.02 (s, 2H), 6.45-6.57 (m, 1H), 6.94 (bs, 1H), 7.52 (bs, 1H), 8.30-8.34 (bs, 1H), 11.53 (bs, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH2:7].C(N(CC)C(C)C)(C)C.Cl[C:20]([CH3:35])([CH3:34])[CH:21]([N:32]=[O:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]>C(#N)C>[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH:7][C:20]([CH3:35])([CH3:34])[C:21](=[N:32][OH:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]
Reactant: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Reactant: NCC(F)(F)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Reaction time: 0.5 h

Procedure:
To a mixture of 1,3-diamino-2,2-difluoropropane dihydrochloride (title A diamine) (1.10 g, 6.01 mmol) and N,N-diisopropylethylamine (2.72 g, 21.04 mmol) in acetonitrile (10 mL) at 40° C. was added 4-chloro-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-nitrosopentane (Example 3, step (B)) (0.50 g, 1.90 mmol) in small portions with stirring under nitrogen atmosphere. After the addition, the stirring was continued for an additional 30 minutes and the solvent was removed on a rotary evaporator. The paste obtained was treated with silica gel and the silica gel powder impregnated with the compound was loaded onto a silica gel column and eluted with CH3OH—CH2Cl2 (5:95). The fractions containing compound were collected and evaporated to give the title product as a light yellow colored solid. Yield: 0.42 g (66%), mp. 112-114° C.; 1H NMR (CDCL3) d 1.19[s, 6H, C(CH3)2], 2.88[m, 4H, C(=N)CH2 & NHCH2], 3.71(t, 3H, JHF=13.19 Hz, CH2NH2), 4.72(t, 2H, J=7.26, CH2CH2N), 7.11 & 7.26(2s, 2H, nitroimid-H) and 10.79(s, 1H, NOH). MS m/e 335 (M+H)+.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CC#N>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:6]([N:8]([CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCc1ccncc1
Solvent: CC#N
Product: O=C(c1ccc(NCc2ccncc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
4-Fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (120 mg, 0.345 mmol) and 4-(aminomethyl)pyridine (0.070 mL, 0.380 mmoL) were stirred in 3 mL of CH3CN. The solvent was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3, brine and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using EtOAc as eluent affording the title compound as yellow oil. Yield: 145 mg (79%); 1H NMR (CDCl3) 4.19 (q, J=8.59 Hz, 4H), 4.71 (d, J=6.25 Hz, 2H), 6.69 (d, J=8.79 Hz, 1H), 7.45 (m, 3H), 8.32 (s, 1H), 8.65 (d, J=6.25 Hz, 2H), 8.73 (m, 1H); MS (ESI) 437.24 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1)\[CH3:22])[CH3:17]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1
Temperature: 23 °C
Yield: 46.6 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 3-methoxy-phenol (6.24 g, 0.050 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (5.50 g, 46%) as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2([C:28]([NH:15][C:13]3[N:14]=[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:3]5[CH:4]=[CH:5][O:1][CH:2]=5)[N:11]4[N:12]=3)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCCC1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)C1(c2ccc(Cl)cc2)CCCC1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 1-(4-chlorophenyl)-1-cyclopentanecarbonyl chloride (Lancaster, 91 mg; 0.37 mmol; 1.5 eq.) as a white foam (61.1 mg, 60%). HPLC, Rt: 4.64 min. (purity 73.4%). LC/MS, M+(ESI): 407.4, M−(ESI): 405.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:44])[C:26]([CH3:43])([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:44])[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:30][CH:29]=1)([CH3:43])[CH3:27])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[C:13]1C=C(Br)N=C([N+]([O-])=O)C=1O.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1nc(Br)cc(Br)c1O
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a heterogeneous 60:40 mixture of 6-bromo-3-hydroxy-2-nitropyridine (30): 4,6-dibromo-3-hydroxy-2-nitropyridine (31) (2.18 g, 10 mmol), K2CO3 (2.08 g, 15 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added dimethyl sulfate (DMS) (1.13 mL, 12 mmol) and the resulting mixture was stirred at 60° C. for 24 hours. The reaction mixture was poured over ice-water (100 mL), extracted with ethyl acetate (3×50 mL), and the organic phase was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to afford 6-bromo-3-methoxy-2-nitropyridine (32). LCMS: purity: 92%; MS (m/z): 233 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23](=[O:25])[CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 56.9 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.