Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[N:27](COCC[Si](C)(C)C)[CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[NH:27][CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c(N)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (35 mg, 0.062 mmol) in DCM (6 ml) was added TFA (3.0 mL) and the reaction mixture was stirred for 3 hours at RT. The solvent was removed and the crude material was purified via reverse phase HPLC and neutralized to give N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (9.0 mg, 0.021 mmol, 33% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70 (s, 1H), 7.20-7.42 (m, 2H), 6.58 (d, 1H), 6.49 (d, 1H), 4.62 (s, 2H). LC-MS (ES+) m/z 438.13, [M+H].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[CH2:19][CH2:18][CH2:17][C:11]=3[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1.[Mg].C(O)(=O)C.Cl>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1
Reactant: O=c1[nH]c2cc(-c3ccco3)ccc2c2c1CCC2
Agent: Cl
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.5 %

Procedure:
A solution of 1.32 g (5.3 mmol) of 7-(2-furanyl)-1,2,3,5-tetrahydrocyclo-penta[c]quinolin-4-one in 300 ml of methanol is mixed with 2.58 g (10.6 mmol) of magnesium and 0.06 ml of acetic acid. After 15 hours at room temperature, another 1.29 g (5.3 mmol) of magnesium is added to it. The batch is stirred for 15 hours at room temperature, treated with 10% hydrochloric acid (500 ml) and extracted with ethyl acetate (3×300 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.49 g of product.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:4].[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:4])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
2-Bromo-N-(4-bromophenyl)-acetamide (3.083 g, 10.522 mmol), prepared according to J. Med. Chem., 1996, 4(2), 197-203, benzimidazole (1.24 g, 10.52 mmol) and K2CO3 were combined and dissolved in DMF (60 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight before filtering and purifing by SCX cartridge. The crude product thus obtained was washed with EtOAc to remove excess benzimidazole, yielding the pure product (2.20 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.17 (2H, s), 7.19-7.28 (2H, m), 7.51 (2H, d, J=12 Hz), 7.51-7.56 (1H, m), 7.57 (2H, d, J=12 Hz), 7.66 (1H, d, J=8 Hz), 8.22 (1H, s), 10.57 (1H, s). MS (ES) m/z: 332.5 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(OC([N:28]1[CH2:34][C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:32][C@H:29]1[CH:30]=[O:31])=O)(C)(C)C.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:12])[C:9]([CH2:10][CH:30]([C@@H:29]1[CH2:32][C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:34][NH:28]1)[OH:31])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: CC(=O)N(C)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Under a nitrogen atmosphere, a solution of N-benzyl-N-methylacetamide (280 mg, 1.67 mmol) in tetrahydrofuran (1 ml) was dropwise added at -78° C. to a solution comprising a 2.0M lithium diisopropylamide--tetrahydrofuran solution (835 μl, 1.67 mmol) and tetrahydrofuran (15 ml). The mixture was stirred at -78° C. for 10 minutes, and then a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (500 mg, 1.52 mmol) in tetrahydrofuran (1 ml) was dropwise added thereto. The reaction mixture was stirred at the same temperature for 10 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and then the reaction mixture was poured into a mixture of ethyl acetate--water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained oily residue was subjected to silica gel column chromatography (heptane-ethyl acetate=2:1) to give the title compound (549 mg, yield: 73.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]CCCC)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 10-mL sealed tube, was placed (S)-butyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (74 mg, 1.85 mmol, 5.02 equiv), water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 75% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 60 mg (46%) of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[O:9]=[C:10]1[NH:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH:24]=[CH2:25])=[N:13][CH:12]=[C:11]1[C:26]#[N:27].Cl>O.O1CCCC1>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[NH:15][C:10](=[O:9])[C:11]([C:26]2[NH:27][N:7]=[N:6][N:5]=2)=[CH:12][N:13]=1)[CH:24]=[CH2:25]
Reactant: C=CCOc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 18 h
Yield: 36.9 %

Procedure:
Aluminum chloride (1.71 g., 0.0128 mole) followed by sodium azide (2.5 g., 0.0384 mole) was cautiously added to ice-cold, stirred tetrahydrofuran (100 ml.). The mixture was heated under reflux for 0.5 hour. To the mixture was added 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carbonitrile (3.23 g., 0.0128 mole) and refluxing was continued for 18 hours. The cooled reaction mixture was diluted with water and acidified with 6N hydrochloric acid. The precipitate was collected and recrystallized from 95% ethanol to give the title compound (1.4 g., 37%), m.p. 221°-225°. Two recrystallizations from acetic acid gave analytical material, m.p. 230.5°-232° (decomp).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCSCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and methyl thioglycolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[CH:17]=[CH2:18])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.5 g, 2.122 mmol) (prepared as in Example 5, Part B) in THF (25 mL) at −70° C. was added vinylmagnesium bromide (1.0 M in THF) (6.37 mL, 6.64 mmol) dropwise and the solution was stirred at this temperature for 45 min. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was used without purification in the next step. LCMS (ESI) m/e 264 [(M+H)+, calcd for C14H12ClFNO 264.0]; LC/MS retention time (Method C): tR=1.59 min.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24])([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10])(=[O:25])=[O:24])([O-:13])=[O:12]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(=O)ccn1C
Yield: 23 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.10 g, 0.73 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (0.3 g, 1.1 mmol) in 10 mL of pyridine to afford PZBG-3d in 23% yield (0.07 g, 0.2 mmol). 1H NMR (400 MHz, CDCl3) δ=8.83 (d, J=2.8 Hz 1H), 8.37 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 3.68 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ=169.35, 154.98, 144.00, 142.61, 141.42, 140.76, 138.54, 129.69, 122.24, 118.15, 116.78, 59.63, 13.29.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([Br:38])[CH:32]=1>>[Br:38][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:36]=[CH:35][C:34]=1[OH:37]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1ccc(O)c(Br)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1Br

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2-bromo-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.8 (m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H) 6.9 (m, 1H) 3.7 (m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H) 1.8 (m, 2H) 1.5 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](OC(C)C)(C)[CH3:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:27]=[CH2:28])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)CC2

Procedure:
The compound is obtained by following the procedure described in Preparation I step b) but starting from the product obtained in step b) above. Yield: 7 g. M.p. 89°-91° C. (isopropyl ether). [α]D20 =+40° (c=0.3%, CH2Cl2).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:17]2[S:18][CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:9][C:8]=1[C:29]([F:32])([F:31])[F:30])C>[OH-].[Na+].C(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:16]([C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH3:28])=[CH:15][CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[C:8]([C:29]([F:31])([F:32])[F:30])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2sccc2C)c2sccc2C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C(=CCSc1ccc(OCC(=O)O)c(C(F)(F)F)c1)c1sccc1C

Procedure:
A solution of {4-[3,3-bis-(3-methyl-thiophen-2-yl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester (75 mg, 0.15 mmol) in 1N NaOH (0.02 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours. The reaxtion mixture was evaporated and the residue dissolved in 1 N HCl (0.03 ml). The aquous phase was extracted with methylene choride (3×25 ml), dried (MgSO4) and evaporated to give the title compound in 70 mg (99%) yield.
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[NH:7])C=CN=C1.NC1[C:19]([OH:20])=[CH:18]C=CN=1>C1COCC1>[O:20]1[C:19]2[C:9](=[N:10][CH:11]=[CH:12][CH:18]=2)[N:8]=[C:6]1[NH2:7]
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncccc1O
Solvent: C1CCOC1
Product: Nc1nc2ncccc2o1

Procedure:
An oven dried round bottom flask was charged with di(1H-imidazol-1-yl)methanimine (500 mg, 3.10 mmol), 2-aminopyridin-3-ol (171 mg, 1.551 mmol) and anhydrous THF (20 ml) at room temperature. The resulting suspension was refluxed under N2 for 1 hr. LC/MS indicated complete consumption of starting material. The solvent was removed in vacuo and the residue was used in the next step without further purification. MS (LC/MS) R.T.=0.235; [M+H]+=136.09.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH3:18][CH:16]1[NH:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:14]=2[N:15]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1
Reactant: Cc1nc2cccc(OCc3ccccc3)c2n1Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC1Nc2cccc(O)c2N1Cc1ccc2ccccc2c1

Procedure:
7-Benzyloxy-2-methyl-1-naphthalen-2-ylmethyl-1H-benzoimidazole (211 mg) in methanol (12 mL) and acetic acid (1.0 mL) was hydrogenated in presence of 10% Pd—C at 45 psi for 20 h. Reaction mixture was filtered through a pad of celite. The filtrate was concentrated to afford 2-methyl-3-naphthalen-2-ylmethyl-1H-benzoimidazol-4-ol, I-111 (211 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]=[CH2:11])[CH:3]=1>CO.[Pd]>[CH2:10]([C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:11]
Reactant: C=Cc1cc(F)ccc1C#N
Agent: [Pd]
Solvent: CO
Product: CCc1cc(F)ccc1C#N
Reaction time: 1 h
Yield: 77.1 %

Procedure:
800 mg 4-Fluoro-2-vinyl-benzonitrile were dissolved in 5 ml methanol. 80 mg palladium (10% on charcoal) were added and the reaction was stirred under a hydrogen atmosphere for one hour. The catalyst was filtered off trough a pad of celite. The filtrate was evaporated to obtain 625 mg 2-Ethyl-4-fluoro-benzonitrile.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[O:26][CH2:27][C:28]([F:29])([F:31])[F:30]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)c(OCC(F)(F)F)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(OCC(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H12F4N4O, 377. Found, 377.
Reaction SMILES: [C:1]([C:7]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]2[S:10][CH:11]=[CH:12][C:8]=12)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1COCC1.[Pd]>[CH2:1]([C:7]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]2[S:10][CH:11]=[CH:12][C:8]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1c2ccsc2c(C#CCCCC)c2ccsc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCc1c2ccsc2c(CCCCCC)c2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a solution of the above prepared 4,8-dihexynylbenzo[1,2-b:4,5-b′]dithiophene (3 grams, 8.6 mmol) in THF (150 milliliters) in a round-bottomed flask was added 10 percent Pd/C (0.90 gram, 0.86 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The solvent was removed by vacuum evaporation, and the residue with the catalyst impurity was purified by column chromatography on silica gel (eluent:hexane/dichloromethane, 2/1, v/v). Recrystallization of the product isolated from column chromatography from 20 milliliters of isopropanol in fridge afforded 1.54 grams (51 percent yield) of needle crystal after drying in vacuo.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1.[CH:20](O)=[O:21]>C(OC(=O)C)(=O)C>[CH:20]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:17][CH2:18][Cl:19])[CH2:3][CH2:2][Cl:1])=[CH:16][CH:15]=1)=[O:21]
Reactant: O=CO
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
A solution of 4-[bis(2-chloroethyl)amino]-(L)-phenylalanine (150 mg) in formic acid (1.82 ml) and acetic anhydride (0.64 ml) is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and partitioned between water (3 ml) and ethyl acetate (2×50 ml). The organic phase is dried over sodium sulfate and solvent is evaporated off under vacuum to give N-formyl-4-[bis(2-chloroethyl)amino]-(L)-phenylalanine (160 mg) as a yellow foam, [α]D =+67° C. (c=2 ethanol)
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH:3]1[CH2:9][C:7]2([CH2:10][CH3:11])[CH:6]2[CH:4]1O2.[S-:12]C#N.[NH4+]>O1CCCC1>[S:12]1[CH:6]2[CH:4]1[CH:3]1[CH2:9][C:7]2([CH2:10][CH3:11])[CH:8]2[CH:2]1[O:1]2
Reactant: N#C[S-]
Reactant: CCC12CC(C3OC31)C1OC12
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC12CC(C3OC31)C1SC12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
6-Epoxyethyl-3-oxatricyclo [3.2.1.0 2.4 ] octane (42g, 0.28mol), ammonium thiocyanate (23g, 0.30 mol) and tetrahydrofuran (125 ml) were placed in a 200-ml egg-plant type flask, and stirred with a magnetic stirrer in a water bath of 50° C. Although first the reaction solution was completely uniform, a white precipitate was deposited about 30 minutes later. 5 hours later, the reaction mixture was suction filtered by a Nutsche to remove the white precipitate, and the filtrate was concentrated by a rotary evaporator. Toluene (250 ml) and water (80 ml) were added to the concentrate, and after separation of the water layer the toluene layer was washed (80 ml ×2). The toluene layer was dried over magnesium sulfate and the toluene was then distilled away by a rotary evaporator. The concentrate was simply distillated under reduced pressure to obtain 6-epithioethyl-3-oxatricyclo [3.2.1,02.4 ] octane (40g, yield 87%). Colorless oil; b.p. 90-93° C./2mmHg; nD 1.5294; IR (neat) 3030(m), 2968(s), 1446(m), 1375(m), 1319(m), 1035(m), 1007(m), 849(s) cm-1 ; 13C NMR(CDCl3) δ23.1, 23.3, 24.1, 24.3, 24.5, 25.3, 26.5, 26.9, 29.7, 30.2, 31.9, 32.3 (CH2); 35.6, 36.2, 36.5, 36.7, 36.9, 37.4, 38.2, 39.0, 41.1, 41.2, 42.1, 42.3, 44.1, 45.3, 47.2, 47.7, 48.5, 48.6, 50.2, 50.4, 50.6, 50.7, 51.0(CH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[N:14](OCCC(C)C)=[O:15]>CCOCC.O1CCCC1.Cl.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])/[C:10](=[N:14]/[OH:15])/[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: CC(C)CCON=O
Reactant: O=C1CCCCc2cc(Br)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1/C(=N/O)CCCc2cc(Br)ccc21
Temperature: 24 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
J.3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved in 2:1 ether/tetrahydrofuran (120 mL) and 1N HCl in ether (9 mL) was added. The solution was cooled to 0° C. before addition of isoamyl nitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 h at 24° C., concentrated, and applied to 25 (M) Biotage silica gel column. Gradient elution from 15-100% B (A=Hexanes; B=ethyl acetate) over 1 L and gave J.3a (E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1 g (64%). LC (Cond.-J1); RT=1.9 min; LC/MS: Anal. Calcd. for [M+H]+ C11H10NBrO2: 268; found: 268.
Reaction SMILES: Cl[CH2:2][CH:3]([N:5]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]1=[O:18])[CH3:4].[CH2:19]([C:22]1([CH2:26][CH2:27][CH3:28])[CH2:25][NH:24][CH2:23]1)[CH2:20][CH3:21]>C1C=CC=CC=1>[Cl:17][C:13]1[CH:12]=[C:11]([N:7]2[CH2:8][CH:9]([CH3:10])[N:5]([CH:3]([CH3:4])[CH2:2][N:24]3[CH2:25][C:22]([CH2:26][CH2:27][CH3:28])([CH2:19][CH2:20][CH3:21])[CH2:23]3)[C:6]2=[O:18])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1(CCC)CNC1
Reactant: CC(CCl)N1C(=O)N(c2cccc(Cl)c2)CC1C
Solvent: c1ccccc1
Product: CCCC1(CCC)CN(CC(C)N2C(=O)N(c3cccc(Cl)c3)CC2C)C1

Procedure:
A mixture of 7 g. of 3-(2-chloro-1-methylethyl)-1-(m-chlorophenyl)-4-methyl-2-imidazolidinone and 10 g. of 3,3-dipropylazetidine in 100 ml. of anhydrous benzene is heated in a bomb at 150°-160° C. for 8 hours. The solvent is evaporated under vacuum and the residue is taken up with water, alkalinized with aqueous sodium carbonate and extracted with diethyl ether. The residue obtained by evaporation of the organic layer is purified by column chromatography through silica gel, using as the eluent chloroform containing 8% of methanol. Yield 8.6 g., b.p. 220° C./0.5 mm Hg.