Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[N+](C1C=CC=CC=1)([O-])=O>[C:5]([C:17]1[CH:18]=[CH:19][C:14]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:25][CH:26]=2)=[CH:15][CH:16]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cc2ccc(C(=O)c3ccccc3)cc2)cc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
In a 5-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 317.0 g of aluminum chloride and 1.5 liters of nitrobenzene were mixed and then 209.0 g of benzoyl chloride was introduced with ice cooling to be dissolved, and then a solution of 100.0 g of diphenylmethane in 100 milliliters of nitrobenzene was added dropwise for 30 minutes. 30 minutes after the end of the dropwise adding, the temperature was increased to 70° C. by removing an ice bath, and stirring was carried out with maintaining the temperature for 5 hours. After the end of the reaction was confirmed by a gas chromatography, the reaction solution was poured on 1.0 liter of ice, and then extracted with 2.5 liters of chloroform. Thereafter, the solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform and nitrobenzene by a rotary evaporator, and then 150.7 g of 1,1-bis(4-benzoylphenyl)methane was obtained as crystals after recrystallizing from ethyl acetate.
Reaction SMILES: CC(C)[O-:3].[Al+3:5].CC(C)[O-:8].CC(C)[O-:12].CC([OH:17])C.[OH2:18]>CC(O)(CC(O)C)C>[O-2:3].[O-2:8].[O-2:12].[Al+3:5].[Al+3:5].[OH-:17].[Al+3:5].[OH-:18].[OH-:3]
Reactant: CC(C)O
Reactant: CC(C)[O-]
Reactant: O
Agent: CC(O)CC(C)(C)O
Agent: [Al+3]
Product: [O-2]
Product: [OH-]
Reaction time: 4 h

Procedure:
γ-Alumina support was prepared by utilizing a complexing agent-assisted sol gel method. 500 grams of aluminum isopropoxide (AIP) (98%+, Aldrich Chemical Company, Inc.) was dissolved in 600 ml of 2-methyl-2,4-pentanediol (MPD) (99% Aldrich Chemical Company, Inc) in a beaker. The resulting mixture was stirred vigorously with a mechanical polyethylene stirrer. Once the mixture was mixed homogenously, the beaker was placed in a constant temperature bath at a temperature of about 120° C. and stirred continuously for about an hour. Once all the AIP was dissolved, a clear yellowish green solution was obtained. The AIP reacts with MPD to yield 2-propanol in the form of a vapor at the 120° C. reaction condition and the solution begins to gel. Once the gelation is completed after 4 hours, 400 ml of water was added to terminate the gelation and yield a white precipitate (aluminum hydroxide). The white solid product was redispersed in water and aged at 90° C. overnight under constant stirring.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13](O)[CH3:14]>>[O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCO
Product: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Glucose (500 g, 2.78 mol) and a strong acid cation exchange resin (100 g Amberlyst™ 15, BDH Chemicals) was suspended in ethanol (2000 ml, 34.3 mol) The mixture was stirred at 80° C. for 16 hours. The progress of the reaction was followed by HPLC. The ion exchange resin was removed by filtration and the solution was treated with activated carbon (10 g). After filtration the ethanol was removed in vacuo giving ethyl D-glucopyranoside (a 1:1 mixture of α and β anomers) as a syrup (578 g, quantitative yield).
Reaction SMILES: [C:1]1(C)[C:2]([C:7]([Cl:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.ClCl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:17])([Cl:15])[C:1]1[C:2]([C:7]([Cl:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Product: O=C(Cl)c1ccccc1C(Cl)(Cl)Cl
Yield: 80 %

Procedure:
Five g (0.032 mole) of o-toluic chloride was dissolved in 150 ml of carbon tetrachloride and reaction was carried by passing dry chlorine into the solution under irradiation with an ultraviolet lamp while refluxing carbon tetrachloride. From the reaction mass an amount thereof necessary for gas chromatographic analysis was occasionally withdrawn to examine the change of the peak of α,α-dichloro-o-toluic chloride by comparing with an authentic sample, the introduction of chlorine was stopped after the peak was disappeared. Part of the oily matter obtained by reduced pressure distillation for removal of carbon tetrachloride was withdrawn, and on analyzing it by gas chromatography it was possible to ascertain that 1,1,3,3-tetrachloro-1,3-dihydroisobenzofuran and α,α,α-trichloro-o-toluic chloride was formed in a mixed ratio by weight of about 6:4, yield 6.6 g (chlorination yield 80%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>ClCCl>[Br:21][CH2:22][C:23]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CBr)C1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.1 %

Procedure:
A solution of (S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (5.21 g) and triethylamine (4.68 ml) in dichloromethane (25 ml) was slowly added with bromoacetyl bromide (6.21 g, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was added with 0.5 N hydrochloric acid, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane, the combined organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (6.54 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH:12]=[C:13]1[NH:17][C:16](=[O:18])[NH:15][C:14]1=O.[H][H].CO.II>CN(C)C=O.[Pd].O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]=[C:14]3[NH:15][C:16](=[O:18])[NH:17][C:13]3=[CH:12][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: II
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc2nc3[nH]c(=O)[nH]c3cc2c1C
Yield: 329.5 %

Procedure:
5-[(2,3-Dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione (19.95 g, 76 mmol) in dimethylformamide (350 mL) was hydrogenated over 10% palladium on charcoal (3 g) at 60 p.s.i. in a Parr hydrogenation apparatus. After hydrogen uptake ceased, the mixture was filtered through kieselgehr and the solvent evaporated to leave a solid which was suspended in a refluxing methanol (1 L). Iodine (19.4 g, 76 mmol) was added portionwise over 5 minutes and the mixture refluxed for 15 minutes before being concentrated in vacuo to about 100 mL. A solution of sodium thiosulfate (21 g) and sodium carbonate (11 g) in water (300 mL) was added with vigorous stirring to afford a beige precipitate which was collected, washed with water and dried in air to give 15.7 g. This was combined with crude material from experiments performed on 40 g and 4.16 g of starting material, suspended in hot (80° C.) water, filtered, suspended in refluxing methanol and filtered. Crystallization from dimethylacetamide afforded 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (53.4 g, 65%), m.p. >300° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10]C(=O)C3C=CC=CC=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1.CO[NH3+].[Cl-:37].N1C=CC=CC=1>C(O)C>[ClH:37].[NH2:10][C:7]1[S:8][CH2:9][C@@H:4]2[CH2:3][C@@H:2]([OH:1])[CH2:19][C@:5]2([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[N:6]=1
Reactant: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Reactant: [Cl-]
Agent: CO[NH3+]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(N)=N4)c2)c1
Product: Cl
Temperature: 50 °C

Procedure:
A mixture of N-((4aR,6R,7aS)-6-hydroxy-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.061 g, 0.133 mmol), o-methylhydroxylamine hydrochloride (0.111 g, 1.3 mmol) and pyridine (0.105 g, 1.30 mmol) in ethanol (5 mL) is heated to 50° C. for 15 h. The mixture is concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 0.5% to 10% NH3 (7 N solution in methanol) in dichloromethane over 30 minutes to afford the title compound as a freebase (0.041 g, 87%). ES/MS m/e: 355 (M+1). A 1 N solution of HCl in Et2O (0.139 mL, 0.139 mmol) is added to a solution of (4aR,6R,7aS)-2-amino-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-6-ol (0.041 g, 0.116 mmol) in minimal dichloromethane and methanol. The solvent is removed under reduced pressure to give the title compound (0.045 g, 86%). ES/MS m/e: 355 (M+1).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[C:7](=[O:17])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8]>CCOCC>[CH2:10]([O:9][C:7]([NH:8][CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=CC(=O)O
Solvent: CCOCC
Solvent: O
Product: O=C(NC(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Glyoxylic acid monohydrate (20.3 g, 221 mmol) and benzyl carbamate (30.6 g, 202 mmol) are added to ether (200 mL). The solution is allowed to stir for 24 h at rt. The resulting thick precipitate is filtered, and the residue is washed with ether, affording ([(benzyloxy)carbonyl]amino)(hydroxy)acetic acid (C150) as a white solid (47% yield). MS (CI) for C10H11NO5+H m/z: 226 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[Br-:13].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-n2ccnc2)cc1
Reactant: CCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCn1cc[n+](-c2ccc(Cl)cc2)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
According to the general synthesis procedure 5.6 mmol (1.00 g) 1-(4-chlorophenyl)imidazole and 6.7 mmol (1.86 g, 1.82 ml) 1-bromotetradecane are dissolved in 5 ml THF and heated for 42 h to 90° C. At the end of the reaction the reaction mixture is cooled down to room temperature and the product is precipitated with diethylether.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9]O>C(O)(=O)C>[CH3:8][C:1]1[C:6](=[O:7])[CH:5]=[CH:4][C:3](=[O:9])[CH:2]=1
Reactant: OO
Reactant: Cc1ccccc1O
Solvent: CC(=O)O
Product: CC1=CC(=O)C=CC1=O
Temperature: 55 °C

Procedure:
A mixture of o-cresol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2-methyl-1,4-benzoquinone formed (96%) was separated by chromatographic purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:52]1[CH2:56][CH2:55][CH:54]([CH2:57][OH:58])[CH2:53]1>CN(C)C=O>[OH:58][CH2:57][CH:54]1[CH2:55][CH2:56][N:52]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:53]1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: OCC1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(CO)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.01 mol 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (CAS: 845616-82-2) in 40 ml N,N-dimethylformamide were added successively 3.57 g TBTU, 8.5 ml N-ethyldiisopropylamine and 1 g rac-pyrrolidin-3-yl-methanol (CAS: 5082-74-6). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The mixture was taken in ethyl acetate and washed twice with water and twice with saturated NaHCO3. The organic phase was dried over Na2SO4 and filtered. The solvent was evaporated. The crude oil was purified on silica gel (eluent: ethyl acetate) to yield the title compound as an off white foam. MS (m/e): 396.1 (M+H+, 100%).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[O:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1OC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.42 g, 8.38 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.75 ml, 12.57 mmol) was added and the resulted solution was cooled to 0° C. p-Fluorobenzenesulfonyl chloride (1.63 gr, 8.37 mmol) was added and the reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 30 min of stirring, dichloromethane (90 ml) was added and the resulting solution was washed with water (2×10 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give AF715 (1.23 g, 98.7% chemical purity) as an off-white powder. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.87 (m, 2H, CHCSO2), 7.27-7.22 (m, 2H, CHCF), 5.05 (q, J=5.23, 1H, CHCH3), 3.33 (d, J=10.26 Hz, 1H, CHHNS), 3.19 (d, J=10.26 Hz, 1H, CHHNS), 2.52-2.42 (m, 1H), 2.34-2.25 (m, 2H), 2.23 (s, 3H, NCH3), 2.18-2.09 (m, 1H), 1.77-1.72 (m, 2H), 1.52 (d, J=5.23 Hz, 3H, CH3CH), 1.25-1.18 (m, 1H), 1.10-1.03 (m, 1H) ppm; 13C NMR (CDCl3, 500 MHz) δ 166.45 and 164.42 (C), 134.0 (C), 130.37 (CH), 130.29 (CH), 116.68 (CH), 116.50 (CH), 86.95 (CH), 66.30 (C), 55.48 (CH2), 52.57 (CH2), 52.11 (CH2), 46.04 (CH3), 35.64 (CH2), 32.84 (CH2), 22.95 (CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1(N)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[N:26]1C=CC=CC=1>C(Cl)Cl>[C:20]1([C:4]2[C:3]([N+:12]([O-:14])=[O:13])=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH2:26])(=[O:10])=[O:9])[C:19]2[C:24](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccncc1
Reactant: Nc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.3 %

Procedure:
4-Chloro-3-nitrobenzenesulphonyl chloride (0.992 g, 3.87 mmol) was added to a solution of naphthalen-1-ylamine (0.665 g, 4.64 mmol) and pyridine (3.1 mL, 38.7 mmol) dissolved in DCM (5 mL). The solution was stirred at room temperature for 2 days and the volatiles were evaporated. The crude mixture was dissolved in EtOAc and the organic phase was washed with 1 N HCl, dried with MgSO4, filtered and concentrated to give 1.1 g of naphthalen-1-yl-3-nitro-4-chloro-benzenesulphonamide. Naphthalen-1-yl-3-nitro-4-chloro-benzenesulphonamide was dissolved in CH3CN (10 mL) and piperazine (0.683 g, 7.93 mmol) was added. The mixture was stirred at 65° C. for 16 hours. The mixture was concentrated and the crude product was purified by flash chromatography on silica using DCM→DCM/MeOH (10%)+aqueous NH3 (0.4 as eluent to give 0.531 g of the free base which was converted to its HCl-salt.
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22](OB(C=C)OCCCC)[CH2:23]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:17][NH:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([CH:22]=[CH2:23])[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]=2[CH3:18])=[CH:9][CH:10]=1)=[O:15]
Reactant: CNC(=O)c1ccc(-c2cc(Cl)c([N+](=O)[O-])cc2C)cc1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(-c2ccc(C(=O)NC)cc2)c(C)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
To a mixture of 5′-chloro-N,2′-dimethyl-4′-nitrobiphenyl-4-carboxamide (Step 2, 100 mg, 0.33 mmol), vinylboronic acid dibutyl ester (90 mg, 0.5 mmol) and sodium carbonate (245 mg, 2.31 mmol) in THF/H2O (8/2 mL) is added dichlorobis(triphenylphospine) palladium (II) (12 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is extracted with ethyl acetate (3×15 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (30% ethyl acetate in DCM) to afford N,2′-dimethyl-4′-nitro-5′-vinylbiphenyl-4-carboxamide as a yellow solid. The obtained solid is dissolved in methanol (20 mL). To this solution is added Pd/C (10%). The reaction mixture is degassed and purged with H2 for several times and stirred under atmospheric hydrogen overnight. The mixture is filtered and concentrated to afford 4′-amino-5′-ethyl-N,2′-dimethylbiphenyl-4-carboxamide as a yellow solid. ESMS m/z 269.2 (M+H+).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.[ClH:22].[OH-].[NH4+]>>[ClH:22].[ClH:22].[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:20]([C:17]4[CH:18]=[CH:19][S:15][CH:16]=4)=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: c1cn(Cc2ccc3[nH]c(-c4ccsc4)nc3c2)cn1
Reaction time: 36 h
Yield: 8.5 %

Procedure:
A mixture of 5 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 3 parts of 3-thiophenecarboxaldehyde and 50 parts of a hydrochloric acid solution 3N was stirred for 36 hours at reflux temperature. After cooling, the mixture was poured into 100 parts of crushed ice and ammonium hydroxide. The product was extracted three times with 75 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:0.1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 8 parts of 2-propanone and ethanol at 0° C. The salt was filtered off and crystallized from a mixture of methanol and 2-propanone. The product was filtered off and dried, yielding 0.8 parts (8.5%) of 5-(1H-imidazol-1-ylmethyl)-2-(3-thienyl)-1H-benzimidazole dihydrochloride; mp.>300° C. (dec.) (compound 205).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[F:5][C:6]1[C:11]([N:12]=[N:13][N:14]2CCCC2)=[C:10]([F:19])[CH:9]=[CH:8][C:7]=1[CH:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1>Cl>[N:12]([C:11]1[C:6]([F:5])=[C:7]([CH:20]2[CH2:24][NH:23][C:22](=[O:25])[CH2:21]2)[CH:8]=[CH:9][C:10]=1[F:19])=[N+:13]=[N-:14]
Reactant: O=C1CC(c2ccc(F)c(N=NN3CCCC3)c2F)CN1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1c(F)ccc(C2CNC(=O)C2)c1F
Reaction time: 1.5 h

Procedure:
In a 25 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, NaN3 (0.133 g, 2 mmol) is added to a solution of 4-[2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-pyrrolidin-2-one a13 (0.2 g, 0.68 mmol) and HCl (1N, 10 ml) at room temperature. After 1.5 h, the reaction mixture is quenched by NaOH (1N, 10 ml), extracted with CH2Cl2 (3 times), and the organic layer is dried on MgSO4, filtered and concentrated in vacuo to afford the crude 4-(3-azido-2,4-difluoro-phenyl)-pyrrolidin-2-one a14 which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][C:16]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]=1[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1cc2cccnc2n1CCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3ncccc23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (112 mg, 0.55 mmol) and 4-(2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)morpholine (143 mg, 0.59 mmol) in 2.5 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.67 mL, 1.21 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2, then taken up in CHCl3 and washed with a saturated solution of Na2CO3, dried over Na2SO4, filtered, and concentrated in vacuo to give CBX003(32 mg, 0.077 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46-2.58 (m, 4H), 2.60 (s, 3H), 2.78 (t, J=6.8 Hz, 2H), 2.81 (s, 3H), 3.69 (t, J=4.5 Hz, 4H), 4.47 (t, J=6.8 Hz, 2H), 6.91-7.02 (m, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.43 (dd, J=7.9 Hz, 1.4 Hz, 1H), 7.45-7.52 (m, 2H), 7.58 (td, J=7.6 Hz, 1.1 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.26 (dd, J=4.7 Hz, 1.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.83, 19.93, 39.55, 53.99, 57.68, 66.93, 113.29, 118.10, 119.85, 124.42, 125.76, 125.78, 126.06, 126.24, 126.66, 129.10, 130.36, 132.90, 137.15, 138.40, 143.02, 146.42, 147.59, 193.21. MS m/z 415.5 [M+H]+.