Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=[C:20]3[O:19][CH2:17][CH3:18])[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (example 17a, 41.4 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a light brown solid: 46.6 mg (61.7%), MS: m/e 472 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].S(OOS([O-])(=O)=O)([O-])(=O)=[O:13].[Na+].[Na+]>[OH-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:13])=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(O)ccc(F)c1C(=O)O

Procedure:
2-amino-6-fluorobenzoic acid (5.00 g, 32.2 mmole) was dissolved in 30 ml of 2N sodium hydroxide. To this was added dropwise a solution of sodium persulfate (7.67 g, 32.2 mmole) in 80 ml of water. After stirring over night the resulting black solution was extracted with 2 L of ether and 1 L of ethylacetate. Evaporation of the water gave a black solid that was used with no purification.
Reaction SMILES: N1C=CN=C1.[CH3:6][CH:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:8][OH:9].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[O:9]([CH2:8][CH:7]([CH3:6])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(CO)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of imidazole (27.2 g) in DMF (100 ml) was added to a stirred solution of 2-methyl-3-(4-bromophenyl)propanol (37.4 g) and tert-butyldimethylsilyl chloride (28.9 g) in dry DMF (100 ml) at 0° C. The reaction mixture was allowed to stir, warming to ambient temperature, over 21 hours and was then poured onto ice (500 g). The reaction mixture was extracted with diethyl ether (3×500 ml), the combined organic layers were dried (MgSO4) and the solvent was evaporated to give 1-(tert-butyldimethylsiloxy)-2-methyl-3-(4-bromophenyl)propane as a yellow oil (53.3 g), mass spectrum (+ve CI): 343 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][OH:18]>C(O)C.[OH-].[Na+].C1CCCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:17][OH:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccccc1)c1ccccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
This compound was prepared by suitable modification of the procedures described by Niemers and Hiltman, Synthesis, 1976, 593 as follows. To a solution of 1-(2-pyridinyl)-2-phenylethanone (Case and Buttle, J. Org. Chem., 1961, 26, 4415) (49.05 g, 0.249 mol) in 95% ethanol (400 ml) was added a solution of hydroxylamine hydrochloride (51.91 g, 0.747 mol) in 10% sodium hydroxide (200 ml). The solution was heated to reflux under nitrogen for 1.25 hours, and stirred at room temperature for 48 hours. The majority of the solvent was removed and the residue was added to water (500 ml). The aqueous solution was extracted with ether (1×1000 ml, and 3×250 ml). The combined ether extracts were washed with saturated NaCl and dried over MgSO4. Removal of solvent gave 55.61 g of the crude product as a brown solid. The above solid was dissolved in cyclohexane (400 ml) and ether (500 ml) and filtered while hot. The filtrate was concentrated to a volume of 500 ml and cooled to room temperature. The solid which formed was isolated by filtration to yield 20.77 g of 1-(2-pyridinyl)-2-phenylethanone oxime; mp 151°-153° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]Br>S([O-])([O-])(=O)=O.[Ag+2].OS(O)(=O)=O>[Br:12][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: Cc1cccc2cccnc12
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of 8-Metyl quinoline (30 g, 0.209 mol) in Conc.H2SO4 (300 ml) was added Silver sulphate (97.98 g, 0.314 mol) in lots at 0° C. and followed by Bromine (10.74 ml, 0.209 mol) drop wise for 10 min. After addition of Bromine, the reaction mixture was stirred at RT for 4 h and the reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was quenched with ice and basified with NH4OH solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous sodium sulphate and concentrated to afford (43 g, 92.4% yield) as dark brown liquid. The crude product was as such taken for next step without further purification. 1H NMR (DMSO-d6 400 MHz): δ 8.97-8.96 (dd, J=4.16, 5.8 Hz, 1H), 8.45-8.42 (dd, J=8.56, 10.2 Hz, 1H), 7.81-7.79 (d, J=7.68 Hz, 1H), 7.67-7.64 (dd, J˜8.52, 12.64 Hz, 1H), 7.53-7.51 (dd, J=7.64, 8.52 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>CO.O>[NH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[N:7]=[C:6]([NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([NH2:9])[CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1N
Solvent: O
Solvent: CO
Product: Cc1ccc(Nc2ccnc(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60 (dd, 2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%; MS (m/e): 321.09 (M+, 100).
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1.C(O)C.[Na].[CH3:17][SH:18]>O>[CH3:17][S:18][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1
Reactant: O=C1c2ccccc2OCC1Br
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSC1COc2ccccc2C1=O
Reaction time: 2 h
Yield: 17 %

Procedure:
After 10.4 g of 3-bromo-4-chromanone [synthesized in accordance with procedures described in W. S. Johnson, et al., J. Am. Chem. Soc., vol.66, p.218 to 220 (1944)] was dissolved into 42 ml of ethanol, 21.3 ml of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After the stirring for 2 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. An organic layer was extracted with 200 ml of ether, and the ether layer was sequentially washed with a sodium chloride aqueous solution and water. After the ether layer was dried with magnesium sulfate, the solvent was removed by evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=3/1) to provide 1.52 g of 3-methylthio-4-chromanone (yield: 17%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:22]=[N:23][N:24]=[C:6]2[C:5]([CH2:9][CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH3:12])=[C:4]([CH3:21])[N:3]=1
Reactant: CC(=CCc1c(C)nc(N)nc1Cl)c1cc(Cl)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=CCc1c(C)nc(N)n2nnnc12)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Yield: 85.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 2.0 grams (0.006 mole) of 2-amino-4-chloro-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, 0.4 gram (0.006 mole) of sodium azide, and 0.3 gram (0.006 mole) of ammonium chloride in 15 mL of dimethyl sulfoxide is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is poured into ice-water. The mixture is stirred until the ice melted, and the resultant solid is collected by filtration. The solid is dissolved in methylene chloride, and the solution is dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residual solid. The solid is recrystallized from methylene chloride/petroleum ether, yielding 1.8 grams of 5-amino-7-methyl-8-[3-(2,5-dichlorophenyl)-2-butenyl]tetrazolo[1,5-c]-pyrimidine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[C:13]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccc(-c2cccc(S(C)(=O)=O)c2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(3-Bromo-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-methylsulfonylphenylboronic acid in analogy to Example 1b): MS (ISP): 551.5 ((M+NH4)+, MS (ISN): 532.2 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:10]([C:9]3([CH3:16])[CH2:13][CH2:14][CH2:15][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)-2-methylproline (425 mg), triethylamine (0.425 ml) and tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.2 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (337 mg) produced in Example 1, step D, was added, and the mixture was stirred at 60° C. overnight. Thereafter, the mixture was stirred in a microwave reactor at 120° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), 2M aqueous sodium hydroxide solution (2.04 mL) was added, and the mixture was stirred at 60° C. for 1 hr and at 80° C. for 1 hr. Ethanol (4 mL) was added to the reaction mixture, and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (109 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 4-formylphenylboronic acid. Colorless crystals (170 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3cnccc3c2n1CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.5 g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted three times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene then purified by flash chromatography (silica gel eluting with 20% methanol in dichloromethane with a trace of ammonium hydroxide) to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 164-166° C. Analysis: Calculated for C17H27N5+0.5H2O: %C, 65.77; %H, 9.09; %N, 22.56; Found: %C, 65.99; %H, 8.71; %N, 22.23.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[K+].OO.O.CC[O:29]C(C)=O>CCO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]([NH2:19])=[O:29])[N:17]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a solution of 0.56 g (6.83 mmol) of sodium acetate in 10 mL of water was added 1.29 g (4.78 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone. The resulting solution was warmed for 30 minutes and then cooled in an ice/water bath. A solution of 4-(fluorophenoxy)benzaldehyde (789 mg, 3.65 mmol) in MeOH was added, followed by 10 mL of a concentrated aqueous NH4OH solution. Additional MeOH was added until a homogenous solution formed. After stirring at room temperature overnight, the reaction was diluted with water. The precipitate that formed was collected, washed with water and dried. Column chromatography (gradient from 8/2 to 2/3 hexane/EtOAc) afforded 0.6 g of a solid. A mixture of 0.5 g of the solid and 80 mL of a concentrated aqueous NH4OH solution was diluted with MeOH until a solution formed. The reaction was heated in a sealed tube for 1.5 days. After cooling to room temperature, the mixture was added to a water/EtOAc mixture. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (1:1 hexane/EtOAc) gave 2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carbonitrile as a solid. 1H NMR (DMSO-d6): δ13.37 (br s, 1H), 8.23 (s, 1H), 7.95 (d, 2H, J=8.7 Hz), 7.27 (t, 2H, J=8.9 Hz), 7.15 (dd, 2H, J=9.3, 4.5 Hz), 7.08 (d, 2H, J=8.7 Hz). To a solution of the nitrile in EtOH was added 1 g of KOH dissolved in 5 mL of water and 1.5 mL of a 30% aq. H2O2 solution. After heating at reflux for 3 hours, the reaction was added to water/EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (100% EtOAc) affording the title compound as a white solid, TLC Rf 0.34 (5% MeOH/EtOAc). 1H NMR (CDCl3): δ12.90 (br s, 1H), 8.08 (br s, 1H), 7.97 (d, 2H, J=9.0 Hz), 7.70 (s, 1H), 7.63 (br s, 1H), 7.26 (t, 2H, J=8.7 Hz), 7.15-7.10 (m, 2H), 7.07 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NNC(=O)CS(=O)(=O)c1ccccc1
Yield: 78 %

Procedure:
To a stirred solution of 1.50 g (7.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 5 mL of acetic acid, 1.44 g (14.0 mmol, 2 eq) of acetic anhydride were added, and the solution was heated at reflux for 1 hour. The reaction mixture was diluted with water, extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated, to afford 1.40 g (78%) of acetic acid N′-(2-benzenesulfonyl-acetyl)-hydrazide as a white solid, MS: 274 (MNH4+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[F:44])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Mg].[CH:13]1[C:34]2[C:17](=[CH:18][C:19]3[C:20](=O)[C:21]4[C:30](C(=O)[C:32]=3[CH:33]=2)=[CH:29]C2[C:23](=[CH:24][CH:25]=CC=2)[CH:22]=4)[CH:16]=[CH:15][CH:14]=1.[I-].[K+]>O1CCCC1.C(O)(=O)C>[CH2:25]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:7]3[C:2](=[CH:3][C:4]4[C:5]([CH:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:13]([C:34]3[CH:33]=[CH:32][C:19]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=3)=[C:18]3[C:19]=2[CH:32]=[C:33]2[C:34](=[CH:17]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:30][CH:29]=1)[CH2:16][CH2:15][CH3:14]
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Reactant: CCCCc1ccc(Br)cc1
Agent: [I-]
Agent: [K+]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2c3cc4ccccc4cc3c(-c3ccc(CCCC)cc3)c3cc4ccccc4cc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
6,13-bis(4-butylphenyl)pentacene was synthesized as follows. A solution of 1-bromo-4-butylbenzene (about 5.09 grams, about 32.40 mmol) in about 20 milliliters of anhydrous tetrahydrofuran (THF) was added over a period of about 1 hour to a stirred suspension of magnesium turnings (about 0.79 grams, about 32.40 mmol) in about 10 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at about 60° C. for about 2 hours. A solution of 6,13-pentacenequinone (about 1.0 grams, about 3.24 mmol) in about 20 milliliters of THF was added and the resulting mixture was stirred at about 60° C. for about 2 hours. Subsequently, the reaction mixture was cooled to about 22° C. to about 25° C. and quenched with ice. The reaction mixture was extracted with toluene and the organic layer was separated and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed and a solution of potassium iodide (KI) (about 2.00 grams, about 12.0 mmol) in about 50 milliliters acetic acid (AcOH) was added to the solid residue. The resultant mixture was then refluxed for about 1 hour and then cooled to about 22° C. to about 25° C. A purple precipitate, obtained after filtration, was washed with water and methanol, yielding about 0.83 grams of 6,13-bis(4-butylphenyl)pentacene as a dark purple solid (about 47% yield). Further purification was conducted by sublimation. An overview of this process is set forth below in Scheme 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19]>CO>[OH:17][CH:16]([NH2:19])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:18]
Reactant: CC(CC=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: N
Solvent: CO
Product: CC(CC(N)O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A mixture of 24.2 g of 3-(4'-fluoro-4-biphenylyl)butanal [obtainable by oxidation of 3-(4'-fluoro-4-biphenylyl)-butanol with CrO3 ], 40 g of liquid ammonia and 400 ml of methanol is heated at 100° for 12 hours. In the course thereof, 1-hydroxy-3-(4'-fluoro-4-biphenylyl)butylamine and 3-(4'-fluoro-4-biphenylyl)-butylidene-imine, which are not isolated, are probably formed as intermediate products. 30 g of Raney nickel are then added and the mixture is hydrogenated for about 20 hours at 100 m and 100°, and is filtered and evaporated to give 3-(4'-fluoro-4-biphenylyl)-butylamine. Hydrochloride, m.p. 222°-224°.