Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:14][C:15]1[CH:16]=[C:17]([NH3+:21])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=1)=[O:6]
Reactant: [NH3+]c1cccc(F)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Fluoro-5-nitro benzoic acid (1.48 g, 8 mmol) and 3-Fluoro-phenyl-ammonium (920 μl, 8.5 mmol) in methylene chloride/DMF (10:1) 20 ml was added 10 g PS-resin (1.54 mmol/g). The reaction mixture was stirred at room temperature for overnight and then PS-resin was moved by filtration. The filtrate was evaporated to yield the title compound as a yellow solid. (1.11 g, 50%). MS (ESI) m/z=279 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 10.89(s, 1H), 8.58-8.47(m, 1H), 7.72-7.67 (m, 1H), 7.45-7.42 (m, 1H), 7.00-6.98 (m, 1H), 6.37-6.28 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[C:11](=[C:15]([CH3:17])[CH3:16])[CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH:15]([CH:11]1[C:12](=[O:14])[C:13]2[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][C:9]=2[CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(C)=C1Cc2ccc3nc(C)oc3c2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc3c(c2o1)C(=O)C(C(C)C)C3
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.9 %

Procedure:
To a solution of 2-methyl-7-(1-methylethylidene)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (677 mg, 2.98 mmol) in methanol/ethyl acetate (5/15 mL) was added a palladium-carbon powder (68 mg), and the mixture was stirred at room temperature for 40 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (662 mg, yield 97%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]12[CH3:4])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH3:8][C@@H:7]1[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]2([CH3:4])[C:2]1=[O:1])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)C1=O
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
A solution of 4.58 g of 17β-hydroxy-16α-methyl-4,9(10)-estradien-3-one (prepared according to 1[e]) in 200 ml of acetone is combined under ice water cooling dropwise with 8.5 ml of Jones reagent (J. Chem. Soc. [London] 1946, 39). The mixture is stirred, after this addition, at room temperature for 20 minutes, thereafter poured into water, and extracted with methylene chloride. The methylene chloride extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Crystallization from ethyl acetate/diisopropyl ether yields 4.3 g of 16α-methyl-4,9(10)-estradiene-3,17-dione, m.p. 140°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
(+)-1,2-bis((2S,5S)-2,5-Diethylphospholano) benzene (cyclooctadiene) rhodium(I) trifluoromethanesulfonate (0.22 g) was dissolved in 2 mL of DCM and added to a solution of 2-tert-butoxycarbonylamino-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]-dioxin-6-yl}-acrylic acid methyl ester (1.8 g) in 20 mL EtOAc. The mixture was then degassed and flushed with hydrogen and stirred under hydrogen atmosphere (balloon) for 1 hour. The solvent was then evaporated and the residue was purified by silica gel flash chromatography (DCM to 5% EtOAC in DCM) to get pure product 1.7 g. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.24-7.37 (m, 2H), 7.00-7.06 (m, 2H), 6.92-6.97 (m, 1H), 6.90 (d, 1H), 6.70 (d, 1H), 6.61-6.70 (m, 1H), 5.08 (m, 1H), 5.03 (d, 2H), 4.99 (d, 1H), 4.50-4.60 (m, 1H) 4.34 (m, 1H), 3.98 (m, 1H) 3.74 (s, 3H), 2.80-3.20 (m, 2H), 1.44 (s, 9H). LCMS (m/z): 589.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)CC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(Br)ccc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Temperature: 112.5 °C
Yield: 78.1 %

Procedure:
A stirred suspension of 7-bromoquinolin-4-ol (162 g, 0.723 mol) in propionic acid (1500 mL) was brought to 110° C. 70% Nitric acid (85 g) was added dropwise over 1 h such that the temperature was maintained between 110-115° C. After half of the nitric acid had been added, stirring became difficult due to the formation of solids and an additional 200 mL of propionic acid was added. Upon complete addition, the reaction was stirred for 1 h at 110° C., cooled to room temperature, and the solid was collected by filtration. The filter cake washed with ice cold ethanol until the washings were nearly colorless (800 mL), and the product was dried at 60° C. under vacuum to afford 152 g of 7-bromo-3-nitro-quinolin-4-ol as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:12]2[CH2:13][CH2:14]3)=[CH:5][CH:4]=1)#[CH:2].I[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.C(N(CC)CC)C>[O:17]=[C:16]1[CH:15]2[CH2:18][CH2:19][CH:12]([CH2:13][CH2:14]2)[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(OCCCN3C(=O)C4CCC3CC4)cc2)cc1

Procedure:
In the a) route of scheme 3, compound 5 is reacted with ethyl 4-iodo-benzoate in the presence of triethylamine (Et3N), trimethyl-benzylammonium chloride (Me3N (Bn) Cl) and tetrakistriphenylphosphine palladium (Pd(PPh3)4) to give ethyl 4-[4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylethynyl]-benzoate (compound 15), then 4-[4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylethynyl]-benzoic acid (compound 16 ) is provided by hydrolysis of compound 15.
Reaction SMILES: C([O:8][C:9]1[CH2:13][N:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:11](=[O:35])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH2:13][N:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:11](=[O:35])[CH:10]=1
Reactant: O=C1C=C(OCc2ccccc2)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1C=C(O)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 15.2 %

Procedure:
A mixture of the 7-(4-benzyloxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (8 mg, 0.017 mmol) prepared in Example 1-8 and palladium hydroxide (2 mg) was dissolved in methanol. The obtained mixture was stirred in a hydrogen atmosphere for 1 hour. Thereafter, the reaction solution was filtered through celite, and the concentrated residue was then preparatively separated by preparative HPLC (column: Combi ODS (φ: 28.0 mm×50 mm), manufactured by Wako; developing solvent: 0.05% trifluoroacetic acid-containing water: 0.05% trifluoroacetic acid-containing acetonitrile=90:10 to 5:95), so as to obtain 7-(4-hydroxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (1 mg, 15%) in the form of a colorless oil substance.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][S:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(O)(C)C>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:15][CH2:14][CH2:13][S:12][CH3:11])[C:7]=1[NH2:8]
Reactant: CSCCN
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSCCNc1nc(C)nc(Cl)c1N
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Heat a solution of 4,6-dichloro-2-methyl-pyrimidin-5-amine (46.0 g, 0.258 mol), 2-(methylthio)ethyl amine (40.05 g, 0.439 mol) and triethylamine (53.3 g, 0.517 mol) in isopropanol (500 mL) at 90° C. for 30 h. Cool the reaction mixture to room temperature and concentrate. Dissolve the residue in dichloromethane (2 L) and wash with water (2×500 mL) and brine (500 mL). Dry the organic layer over solid sodium sulfate, filter, and evaporate to afford a brown solid. Purify the residue on a silica gel column eluting with ethyl acetate to give the title compound (56 g). ES/MS (m/z) 233 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](Cl)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Yield: 127.3 %

Procedure:
The procedure described in Example 17, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford 1.01 g of the title compound, melting at 223°-227° C. (dec.).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13](Cl)=[O:14]>C(Cl)Cl>[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13]([N:2]([CH3:3])[CH3:1])=[O:14]
Reactant: O=C(Cl)C(Br)CCCBr
Reactant: CNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(Br)CCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of dimethylamine (0.91 ml, 7.18 mmol; 40% solution in water) and 2.75 ml (19.76 mmol) of Et3N in 6 ml of CH2Cl2 cooled at 0° C. was added dropwise a solution of 2,5-dibromo-pentanoyl chloride (1.00 g, 3.59 mmol) in 4 ml CH2Cl2. After stirring 1 h at RT, the reaction mixture was partitioned between CH2Cl2 and water. The organic phases were washed with water and brine and the aqueous layers extracted twice with CH2Cl2. The organic phases were dried over MgSO4, evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1) to afford 0.66 g (64%) of the title product as light yellow oil. MS: 288.1 (2Br, MH+).
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:21])=O>O1CCCC1>[Cl:21][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1.5 h

Procedure:
To a refluxing solution of 0.63 g of N-[3-(1,6-dihydro-6-oxo-3-pyridazinyl)phenyl]propanamide in 100 ml of dry tetrahydrofuran was added 0.5 ml of phosphorus oxychloride. After 1.5 hours, 0.5 ml of phosphorus oxychloride was added and after 2 hours of refluxing 0.25 ml of phosphorus oxychloride was added. The solution was refluxed for an additional hour, then the solvent was removed, dichloromethane was added and the solution was poured into ice water. The mixture was neutralized with sodium bicarbonate and extracted with dichloromethane. The extracts were combined, washed with water, dried and the solvent removed giving an oil. This oil was chromatographed on thick layer silica gel preparative plates with dichloromethane:methanol (95:5), as solvent to give 0.33 g of solid. Recrystallization of 0.15 g from dichloromethane-acetone-hexane gave the desired compound as white crystals, mp 188°-189° C.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: F[C@H]1CCNC1
Reactant: [C-]#[N+]CC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CC[C@H](F)C1
Yield: 79.1 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.18 g, 11.9 mmol) was slowly added (S)-(+)-3-fluoropyrrolidine hydrochloride (97%, 1.5 g, 11.9 mmol), triethylamine (1.67 mL, 11.9 mmol) and MeOH (3 mL). The mixture was stirred for 15 h at RT and concentrated. The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((S)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01166 (1.47 g, 79% yield) as a brown oil which was used in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1.O.O1CCOCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[O:9])[CH2:2]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCNC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)C1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A solution of 3-pyrrolidinol (4.0 g) in dioxane-water (10:1, 50 ml) mixed solvent was cooled to 5° C., and into which a solution of 4-nitrobenzyl chloroformate (10.9 g) in dioxane (20 ml) was added dropwise, while maintaining the pH at 8-9, followed by 10 minutes' stirring at 5° C. Distilling the solvent off under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. Washing the residue with ethyl acetate, 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (6.6 g) was obtained as a pale yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:19]([C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[S:14][C:13]=1[C:15]1[N:16]=[C:30]([C:29]2[CH:33]=[CH:34][C:26]([O:25][C:24]3[CH:35]=[CH:36][CH:37]=[C:22]([F:21])[CH:23]=3)=[CH:27][CH:28]=2)[O:18][N:17]=1)[CH3:20]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(3-fluorophenoxy)benzoic acid (0.13 g, 0.55 mmol) that was obtained in Example 17 (17a), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 5:5) as the eluent to afford the title compound (0.15 g) in a yield of 73% as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 90.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclopropylmethylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide (0.35 g, 91%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]([CH3:18])[CH3:17].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1nc2ccccc2n1CCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc2ccccc2n1CCCCCBr
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Part C. A solution of the alcohol prepared in Part B above (4.18 g, 17.0 mmol) and carbon tetrabromide (6.75 g, 20.3 mmol) in methylene chloride (40 mL) was cooled to 0° C., and a solution of triphenylphosphine (5.34 g, 20.4 mmol) in methylene chloride (40 mL) was added dropwise. The mixture was stirred for 20 hours, then evaporated. The residue was separated by flash chromatography (1:2 ethyl acetate-hexane) to afford the product, 1-(5-bromopentyl)-2-(1-methylethyl)-1H-benzimidazole, as an oil (4.80 g, 15.5 mmol, 92%. 1H NMR (CDCl3): 7.79-7.72 (1H, m) ; 7.32-7.21 (3H, m); 4.14 (2H, t, J=7.5 Hz); 3.39 (2H, t, J=6.6 Hz); 3.18 (1H, heptet, J=7.0 Hz); 1.94-1.78 (4H, m); 1.63-1.50 (2H, m); 1.45 (6H, d, J=7.0 Hz).
Reaction SMILES: S([O-])(=O)(=O)C.[I-:6].[Na+].[CH3:8][C:9]([CH2:11][CH3:12])=O>>[I:6][CH2:8][C@H:9]1[CH2:12][CH2:11][C@H:9]([CH2:8][I:6])[CH2:12][CH2:11]1
Reactant: CCC(C)=O
Reactant: [I-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: IC[C@H]1CC[C@H](CI)CC1

Procedure:
Add 30 gms. of the mesylate prepared in step (a) to 300 ml. methylethyl ketone (MEK), then add 90 gm. sodium iodide and reflux for about 30 minutes. Remove the solvent and extract with methylene chloride to yield trans 1,4-bis iodomethyl cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[OH:13][C:8]1[N:3]2[N:4]=[C:5]([SH:7])[N:6]=[C:2]2[N:1]=[C:10]([CH3:12])[CH:9]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(O)n2nc(S)nc2n1
Yield: 37.6 %

Procedure:
A mixture of 3-amino-5-mercapto-s-triazole (10 g), ethyl acetoacetate (34 g), piperidine (10 ml) and ethanol (300 ml) was refluxed for four hours. After removing the solvent by distillation under reduced pressure, 150 ml water was added, the mixture was neutralized to pH 7.0 with hydrochloric acid and cooled, giving 5.9 g of the objective compound.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[CH:12][CH:11]=2.[N-:21]=[N+]=[N-].[Na+].CO>O>[CH3:6][O:7][C:8]1[C:9](=[O:20])[NH:21][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:19])[C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)c2c(C)cccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(=O)c2c(C)cccc2[nH]c1=O
Yield: 93 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (12 mL, Baker), there was added 2-methoxy-5-methylnaphthalene-1,4-dione (800 mg, 3.96 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (515 mg, 7.92 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (50 mL) to give a thick green suspension. This was diluted with H2O (30 mL) and vigorously stirred with 30% MeOH/70% CHCl3 (60 mL) until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (800 mg). Crystallization from 95% EtOH (dissolved in 30 mL, hot filtered, concd to 20 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (564 mg, 66%, pure by 1H NMR); mp 215.5° -217° C.; 1H NMR (DMSO-d6) δ2.32 (s, 3H), 3.71 (s, 3H), 6.32 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 11.00 (s, 1H); IR (KBr) 3195 (m), 3134 (m), δ3061 (m), 2999 (m), 2967 (m), 2939 (m), 1691 (s), 1649 (s), 1616 (s), 1212 (m), 834 (m), 783 (m); MS (m/z) 217 (M+, 100).