Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2].[OH-].[Na+].[CH3:25]OS(OC)(=O)=O>CO.O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2]
Reactant: O=Cc1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide (2.2 g, 6.6 mmol) in methanol (11 mL) is treated with a solution of sodium hydroxide (275 mg, 6.9 mmol) in water (2.4 mL). To this is added dimethylsulfate (0.64 mL, 6.8 mmol). The reaction is stirred at rt overnight, evaporated, and chromatographed on silica gel in 5% and 10% ethyl acetate-methylene chloride. The product fractions are further purified by crystallization from toluene-hexane to afford N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide in 68% yield.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CN(C)C=O.Br[CH:18]([CH3:20])[CH3:19]>O>[CH3:19][CH:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:20]
Reactant: CC(C)Br
Reactant: CC(=O)C1=CNCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1=CN(C(C)C)CCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry dimethylformamide (50 ml) stirring at 0° C. and stirring was continued for 15 minutes. 2-Bromopropane (21.5 g, 0.175 mole) was then added dropwise over 15 min, stirring continued for a further hour at 0° C. then overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was extracted with water (150 ml), dried over magnesium sulphate, concentrated under reduced pressure to give methyl 1-(1-methylethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (1). The product was distilled as a pale yellow oil (b.pt 97°-98° C./0.5 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:14])=[CH:4][N:3]=1.[CH2:15]([O:17][C:18](=[O:30])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25](O)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][O:12][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C@H:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:30])[CH2:21][CH2:22]3)[C:5]([CH3:14])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N(C)CCCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 341, 785 mg, 3.64 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 401 mg, 1.82 mmol) in THF (17 mL) were added PPh3 (954 mg, 3.64 mmol) and ADDP (918 mg, 3.64 mmol). The reaction mixture was vigorously stirred at rt for 24 h after which additional PPh3 (954 mg, 3.64 mmol) and ADDP (918 mg, 3.64 mmol) were added. After an additional 24 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (3:1 hexanes/EtOAc) to give the product (586 mg, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H), 1.71-1.76 (m, 1H), 2.06-2.11 (m, 2H), 2.26 (s, 3H), 2.34-2.42 (m, 2H), 2.67-2.88 (m, 3H), 3.15 (s, 3H), 3.49-3.50 (m, 1H), 3.70 (t, 2H), 3.94 (t, 2H), 4.13 (q, 2H), 6.64 (d, 1 H), 6.70 (s, 1H), 7.02 (d, 1H), 7.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.[I:26][C:27]1[CH:42]=[CH:41][C:30]([CH2:31][NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(I)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (1.38 g, 3.92 mmol), tert-butyl 2-((4-iodobenzyl)amino)acetate INT-35 (1.36 g, 3.92 mmol) and TEA (0.82 ml, 5.88 mmol) in DMF (8 mL) was added HATU (1.56 g, 4.11 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EA (150 mL) and washed successively with NaHCO3 (100 mL) and brine (100 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 2.05 g (75%) of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36. LCMS-ESI (m/z) calculated for C30H30F3IN2O5: 682; found 627 [M−tBu+H]+, tR=2.90 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 7.76-7.68 (m, 2H), 7.62 (dd, J=7.0, 1.8 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.27-7.13 (m, 3H), 7.12-6.97 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 3.92 (m, 2H), 3.85 (s,2H), 3.83 (s, 3H), 1.41 (s, 4.5H), 1.31 (s, 4.5H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:7][C:8](=[O:12])[O:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[O:7][C:8](=[O:12])[O:9][C:10]=1[CH2:11][Br:13])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCc1oc(=O)oc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1oc(=O)oc1CBr
Temperature: 80 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-Acetoxymethyl-5-methyl-2-oxo-1,3-dioxolene (159 mg, 0.92 mmol) was dissolved in carbon tetrachloride (5.0 mL). Thereto were added N-bromosuccinimide (164 mg, 0.92 mmol) and benzoyl peroxide (11 mg, 0.046 mmol). This mixture was stirred at 80° C. for 1 hours. Through the ordinary post-treatment, crude Compound S-31 (220 mg, yield 95%) was obtained.
Reaction SMILES: [Br-:1].[Li+].C[Si](Cl)(C)C.[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]O)[C:11]=2[O:10]1>C(#N)C.C(OCC)C>[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][Br:1])[C:11]=2[O:10]1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Reactant: [Br-]
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)Cc2cccc(CBr)c2O1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 8.7 grams (0.1 mole) of lithium bromide in 100 mL of acetonitrile is stirred, and 13.5 grams (0.125 mole) of trimethylsilyl chloride is added. Upon completion of addition, a solution of 8.9 grams (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol in 50 mL of acetonitrile is added. Upon completion of addition, the reaction mixture is warmed to reflux, where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature and then is taken up in 200 mL of diethyl ether. The mixture is then washed with 25 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, yielding 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>C(C1C=CC=CC=1)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:11]([S:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCc1ccccc1
Product: CSC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Temperature: 130 °C
Yield: 6.7 %

Procedure:
A mixture of 3.9 g (0.0303 mole) of 5-amino-2-chloropyridine, 5.0 g of 1,1-bis(methylthio)-2-nitroethylene and 80 ml of ethylbenzene was heated at 130° C. for 2 hours. The ethylbenzene was distilled off under reduced pressure and the crystalline residue was washed with AcOEt and subjected to silica gel column chromatography using EtOH-CHCl3 (1:30) as the eluent to recover crude crystals. These crystals were recrystallized from AcOEt, washed with ether and dried. The procedure gave 0.5 g of 1-(6-chloro-3-pyridyl)amino-1-methylthio-2-nitroethylene as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1I
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-iodotoluene according to the general procedure C. Obtained as a yellow oil (755 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:8]1[CH:7]=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1cc(C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 12.6 %

Procedure:
With 22.3 g of 3-methoxy toluene and 33.1 g of 5-chloroisatin as starting materials, 6.98 g of the title compound (colorless solid) was obtained by a similar method to Step 239-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].ClC[C:24](Cl)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:25]=[C:24]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Reactant: O=C(Cl)CCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCNCC2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TEA (1 eq) was added dropwise to a solution of tert-Butyl (2-{[2-(5-cyanopyridin-2-yl)ethyl]amino}ethyl)carbamate (1 eq) and chloroacetyl chloride (1 eq) in 200 mL of DCM at 0° C. The mixture was stirred at room temperature for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum. The resulting solid (1.0 g, 2.7 mmol) was added to the mixture of 10 mL TFA and 10 mL of DCM and stirred at RT for 1 hour then concentrated by vacuum. The residue was re-dissolved in CH3CN, K2CO3 was added and the mixture was stirred at RT for 2 hours. The mixture was poured into water and extracted with EtOAc twice. The combined organic layers were concentrated and the residue was purified by flash chromatography (DCM:MeOH=10:1) to afford the title compound 1H-NMR (400 MHz, CDCl3) δ ppm 8.74 (d, J=1.6 Hz, 1H), 7.81-7.83 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.71 (t, J=7.2 Hz, 2H), 3.42 (d, J=7.2 Hz, 2H), 3.24 (t, J=5.6 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C

Procedure:
To a solution of 2-butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.34 g) in methanol (100 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at ambient temperature over the weekend to give a suspension. The reaction mixture was concentrated to a small volume (thick slurry) before being diluted with ethyl acetate (50 mL). The resultant slurry was filtered and washed with a small volume of ethyl acetate until the filtrate was colourless. The solid remaining was dried by air and then in vacuo to give the title compound as a solid (6.20 g). The filtrate obtained previously was concentrated to give a slurry which was diluted with a small volume of ethyl acetate (10 mL) and then filtered and dried as above. This second crop was isolated as a white solid (0.276 g). Both crops were identical by NMR.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[C:29]([C:31]([NH:33]O)=[NH:32])[CH:28]=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:33]=[C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([NH2:24])[CH:30]=4)[N:32]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccnc(N)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccnc(N)c4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH/dichloromethane/hexane) as an off-white solid (140 mg, 64%). MS (EI) 436.1 [(M)+]; mp 264° C.
Reaction SMILES: C([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1)=O.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[O:13]=[C:5]1[CH2:4][C:3](=[C:18]2[C:19](=[O:20])[O:21][C:14]([CH3:15])=[N:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cc(=O)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1=NC(=C2CC(=O)Nc3ccccc32)C(=O)O1

Procedure:
17 Grams of 4-formylcarbostyril, 18 g of N-acetylglycine, 7 g of anhydrous sodium acetate and 100 ml of acetic anhydride were heated at 110° C. to make a homogeneous solution, further the solution was refluxed for 1.5 hours. After cooled the reaction mixture, the reaction mixture was poured in a cold water and the crystals precipitated were collected by filtration. The crystals were washed with cold water, then recrystallized from ethanol-chloroform to obtain 10 g of 4-(1,2-dihydro-2-oxo-4-quinolyliden)-2-methyl-5-oxazolone.1/2-hydrate.
Reaction SMILES: C[O-].[Na+].[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=O)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[Br-].[CH3:33]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1COCC1>[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=[CH2:33])=[CH:7][C:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1
Reactant: COC(=O)c1csc(C(=O)COc2cc3c(cc2I)C(C)(C)CCC3(C)C)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1cc(C(=O)OC)cs1

Procedure:
A 30% solution of sodium methoxide in methanol (1.68 ml) was added over 8 hours to a mixture of methyl 5-[(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetyl]-3-thiophenecarboxylate (4.1 g, 8 mmol) and methyltriphenylphosphine bromide (3.8 g, 10.8 mmol) in THF (50 ml).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][N:35]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:26]([NH:25][C:23](=[O:24])[C:22]1[CH:33]=[CH:34][N:35]=[C:20]([NH:19][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])[CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)C1CCCC1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)C2CCCC2)c1
Yield: 88 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with cyclopentanecarbonyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(cyclopentanecarboxamido)-isonicotinamide was obtained as a colorless solid in 88% yield: mp 55-57° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.49 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 7.49 (d, J=5.1 Hz, 1H), 7.23-7.18 (m, 6H), 4.54 (d, J=5.7 Hz, 2H), 2.82-2.80 (m, 1H), 1.22-0.82 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 175.7, 165.3, 152.2, 148.2, 144.1, 137.5, 128.7, 128.4, 127.9, 127.6, 118.2, 110.9, 46.4, 44.1, 30.3, 25.9; MS (ES+) m/z 324.6 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCCCBr)cc1

Procedure:
A solution of methyl 4-hydroxyphenylacetate (20.0 g, 0.12 mol), 1,3-dibromopropane (97.2 g, 0.48 mol) and cesium carbonate (43.1 g, 0.13 mol) in dry DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (2:1) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(OCC)(=O)C>[N:41]([C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[N+:33]([O-:35])=[O:34])[CH2:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[NH:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:22]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(N=[N+]=[N-])c5)CC4)cccc3[nH]2)cc1
Yield: 93 %

Procedure:
In a round bottom flask was combined 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (0.197 g, 0.40 mMol), dimethyl sulfoxide (3 mL), and sodium azide (0.029 g, 0.44 mMol) and the mixture stirred overnight. Upon arrival the mixture was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), washed with brine (50 mL), and the organics dried with magnesium sulfate and filtered. The organics were concentrated on a rotary evaporator to yield 190 mg (92% yield) of 4-[4-(3-Azido-4-nitro-benzyl)-piperazin-1-yl]-2-(4-tert-butyl-phenyl)-1H-benzoimidazole as a light yellow solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.04 (d, 2H, J=8.7 Hz), 8.01 (d, 1H, J=8.3 Hz), 7.57 (m, 1H), 7.54 (d, 2H, J=8.6 Hz), 7.39 (dd, 1H, J=8.5, 1.2 Hz), 7.03 (m, 2H), 6.50 (dd, 1H, J=5.5, 1.4 Hz), 3.70 (s, 2H), 3.60 (br s, 4H), 2.68 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.41 mins., purity=89.8%, calculated mass=510, [M+H]+=511, [M−H]−=509.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[S:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].IC>C(O)C>[C:14]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:11][CH:10]([S:12][CH3:20])[NH:9][C:8]2=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NC(=S)NC1(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSC1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Yield: 60 %

Procedure:
7.0 g of 5,5-diphenyl-2-thiohydantoin is dissolved in 50 ml of ethanol and 10 ml of 3N sodium carbonate added followed by 3 ml of iodomethane. The mixture is refluxed for 18 hours, then cooled and the solvent evaporated. The residual solid is recrystallized from ethanol to give 4.6 g (60%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=3)=[O:28])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: Cn1c(C(=O)NCCN=[N+]=[N-])cc(Br)c1Br
Product: Cn1c(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc(Br)c1Br

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.116 g, 0.417 mmol) was reacted with N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide (0.145 g, 0.417 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), δ 7.32 (s, 1H), δ 6.81 (s, 1H), δ 6.49 (s, 1H), δ 6.17 (s, 2H), δ 4.52 (s, 2H), δ 3.94 (s, 3H), δ 3.84 (s, 2H), δ 2.65 (t, J=7.2 Hz, 2H), δ 2.30 (m, 2H), δ 1.58 (m, 13H), δ 1.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.2, 149.6, 148.2, 138.8, 127.4, 122.2, 114.9, 111.9, 106.5, 98.2, 84.5, 49.5, 39.7, 35.9, 29.3, 28.9, 28.2, 28.0, 27.7, 25.6 ppm; HRMS (ESI) calcd for C23H32N8O3 (M+) 626.0964. found 626.0960, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (0.151 g, 64% yield). 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), δ 6.86 (s, 1H), δ 6.56 (s, 1H), δ 4.71 (s, 2H), δ 3.81 (s, 5H), 2.78 (s, 2H), δ 2.44 (t, J=7.2 Hz, 2H), δ 1.69 (s, 2H), δ 1.59 (s, 2H), δ 1.37 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 161.4, 150.2, 159.8, 159.4, 147.3, 127.6, 127.3, 114.9, 111.6, 108.4, 97.9, 51.3, 39.0, 35.2, 28.3, 28.0, 27.6, 24.2, 23.8 ppm; HRMS (ESI) calcd for C18H24Br2N8O (M+) 526.0439. found 526.0425.