Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[C:23]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([CH2:12][C@@H:13]1[O:14][C:15]2[C:23]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:22][CH:21]=[CH:20][C:16]=2[CH2:17][CH2:18][CH2:19]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
A solution of [(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl 4-methylbenzenesulfonate (381 mg, 0.798 mmol) and sodium azide (208 mg, 3.192 mmol) in anhydrous dimethyl sulfoxide (10 mL) was heated at 70° C. under nitrogen for 19 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a colorless syrup. Purification by flash chromatography using 3% ethyl acetate in hexane as eluant gave 240 mg (86%) of (2R)-2-azidomethyl-9-(2,6-dichloro-phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepine as a colorless syrup.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7](O)=[O:8].O>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Yield: 97.8 %

Procedure:
10.0 g of 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid were dissolved in 50 ml tetrahydrofuran under an atmosphere of argon. 69.7 ml of boran-tetrahydrofuran complex (1 molar solution in tetrahydrofuran) was added and the mixture refluxed for three hours. Water was added to the cooled reaction mixture and the solvent removed in vacuo. The residue was extracted five times with 50 ml portions of ethyl acetate. The combined extracts were dried over MgSO4. The solvent was removed in vacuo to obtain 9.3 g of [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol as a yellow solid.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)c1ccccc1
Product: CON=C1C[C@@H](c2noc(-c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and benzoic acid, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=439.2.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[S:25][C:26]([Cl:40])=[C:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=2)[CH:28]=1)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:40][C:26]1[S:25][C:24]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([CH2:19][OH:20])[O:7]2)=[CH:28][C:27]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(OC(C)=O)cc3)c(Cl)s2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](c2cc(Cc3ccc(O)cc3)c(Cl)s2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a suspension of acetate 28 (413 mg, 0.617 mmol) in MeOH (15 mL) was added NaOMe (25 wt % in MeOH, 0.2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 29 (130 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (3.0 g, 12.5 mmole) and N-(benzyloxycarbonyloxy)-succinimide (3.42 g, 13.7 mmole) were mixed in 15 ml of dichloromethane. The mixture was stirred at room temperature overnight and then concentrated under vacuum to provide the crude product The residue was purified by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.29-7.43 (m, 5H) 5.13 (s, 2H) 4.15-4.33 (m, 1H) 3.39-3.74 (m, 5H) 3.20-3.37 (m, 1H) 2.84-2.96 (m, 1H) 1.92-2.03 (m, 1H) 1.66-1.82 (m, 1H) 1.46 (s, 9H). MS: (M+H)+=347.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 114.4 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in dichloromethane (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.23 g) was obtained by concentrating under a reduced pressure (yield: 99.0%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:26]4[CH:30]=[CH:29][O:28][N:27]=4)[O:21][C:20]3=[O:31])=[CH:15][C:14]=2[F:32])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:26]4[CH:30]=[CH:29][O:28][N:27]=4)[O:21][C:20]3=[O:31])=[CH:15][C:14]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC(O)C2)c(F)c1

Procedure:
3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxy methyl)oxazolidin-2-one (230 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 ml), and cooled under nitrogen to 0°. A solution of tetra-n-butylammonium fluoride (1 M, 1 ml, 1 mmol) was added and the mixture allowed to come to ambient temperature. Water (2 ml) was added, and the mixture evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut(D column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane. Relevant fractions were combined and evaporated, then redissolved in EtOAc and the desired product (96 mg) precipitated by addition of isohexane.
Reaction SMILES: [O:1]1[C:10]2[S:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[O:11][CH2:12][CH2:13]Br.[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]1[C:10]2[S:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[O:11][CH2:12][CH2:13][N:29]1[CH2:28][CH2:27][CH:26]([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]1
Reactant: BrCCOC1CCC2=C(O1)SCC=C2
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOC2CCC3=C(O2)SCC=C3)CC1

Procedure:
Using the procedure of Example I step B and starting from (8-thiachromanyloxyethyl) bromide and 4-(N-phenyl N-propionylamino) piperidine, N (8-thiachromanyloxyethyl) 4-(N'-phenyl N'-propionylamino) piperidine is obtained and isolated as its oxalate which melts at 182°-184°.
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[C:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[C:8]=3[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.B.FC(F)(F)C(O)=O>C1COCC1>[CH:1]1([NH:4][CH:5]2[CH:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[CH:8]3[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Agent: B
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccc(O)cc2C2CCC(NC3CC3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (8.7 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A 1M solution of borane in THF (540 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back down to 0° C. and trifluoroacetic acid (119 ml) was added in a dropwise manner. The solution was stirred for 15 minutes and THF was removed in vacuo. The mixture was neutralized with 10% NaOH solution, extracted with methylene chloride (4×500 ml), dried (Na2SO4) and concentrated to give 3-(N-cyclopropyl)amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (8.8 g).
Reaction SMILES: O.[CH:2]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:14]([O-])([OH:16])=[O:15].N([O-])=O.[Na+]>CCOCC>[CH:2]1([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(C2CCCC2)ccc1O
Reaction time: 120 h

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 4-cyclopentylphenol was added dropwise 2.1 ml of 61% nitric acid and further was added a catalytic amount of sodium nitrite, then the mixture was reacted with stirring at room tempeature for 5 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried wih anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform-n-hexane (1:1)] to give 3.60 g of 4-cyclopentyl-2-nitrophenol.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:41]=[CH:40][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:23]=2)=[O:20])=[CH:40][C:41]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:132-133° C.; 1H NMR (300 MHz, CDCl3) δ: 9.53 (1 H, s), 8.10 (1 H, s), 8.00 (2 H, m), 7.85-7.87 (1 H, d, J=6.0 Hz), 7.66-7.69 (1 H, d, J=9.0 Hz), 7.43-7.45 (1 H, d, J=6.0 Hz), 7.33-7.36 (1 H, d, J=9.0 Hz), 6.58-6.61 (1 H, d, J=9.0 Hz), 5.56 (1 H, s), 4.23-4.25 (1 H, m), 3.64 (2 H, s), 2.61 (8 H, brs),2.44 (3 H, s), 2.43 (2 H, m), 1.91-1.97 (2 H, m), 1.81-1.86 (1 H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H31ClF3N6O: 583.2194. found: 583.2174.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:30])[C@:4]1([OH:29])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][OH:28].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:30])[C@:4]1([OH:29])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][O:28][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCO)[C@]2(O)C(=O)CCl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOS(C)(=O)=O)[C@]2(O)C(=O)CCl

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione (7.6 mmoles) in 30 ml of pyridine is cooled to 0°C and 1 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.Cl[CH2:12][O:13][CH3:14]>>[CH2:9]([O:8][C:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:12][O:13][CH3:14])[CH:5]=1)=[O:7])[CH3:10]
Reactant: COCCl
Reactant: CCOC(=O)c1c[nH]cn1
Product: CCOC(=O)c1cn(COC)cn1

Procedure:
In analogy to Step (1) of Example 1, but using ethyl imidazole-4-carboxylate (26.3 g) and chloromethylmethylether (21.2 mL), the title compound (17.2 g) was afforded.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)=[C:2]=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([NH:1][C:2](=[O:3])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: Cc1ccc(N=C=O)cc1C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C)c(C)c3)cc2)o1)C(C)C
Yield: 82 %

Procedure:
The title compound was synthesized analogous to Example 1, using 4-isocyanato-1,2-dimethylbenzene and intermediate 1. Yield: 82%; 1H NMR (DMSO-d6, 300 MHz): δ 8.97 (d, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.79 (s, 1H), 7.77 (d, 2H), 7.61 (d, 2H), 7.24 (dd, 1H), 7.19 (dd, 1H), 7.04 (d, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.28 (m, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 0.95 (d, 6H); MS (ES+): m/z 465 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([C:20]3[C:25](F)=[CH:24][C:23](C#N)=[CH:22][C:21]=3F)C(OCC)=O)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C[O:38][CH:39]([OH:41])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:20]3[CH:25]=[CH:24][C:23]([C:39]([OH:41])=[O:38])=[CH:22][CH:21]=3)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:31][CH:32]=1
Reactant: COC(C)O
Reactant: CCOC(=O)C(c1c(F)cc(C#N)cc1F)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cc2ccc(C(=O)O)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of ethyl 2-[5-(4-chlorobenzoyl)-1,4-dimethylpyrrol-2-yl]-2-(2,6-difluoro-4-cyanophenyl)acetate (0.05 g, 0.11 mmol) [prepared as described in Example 9, Step (a)] in methoxyethanol (4 ml) was added an aqueous solution of lithium hydroxide monohydrate (0.02 g in 0.5 ml H2O), and the reaction mixture was heated at reflux under an argon atmosphere. After 24 hr, the reaction mixture was cooled to room temperature and poured into a mixture of ice/water (40 ml) containing 1N HCl (1 ml). The solid was filtered to give crude {4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.037 g) as a tan solid. Flash chromatography on a silica gel column (0.5% acetic acid-30% acetone:hexane), followed by recrystallization from methanol-acetone gave pure {4-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.032 g, 70.2% yield) as a white solid, mp 245-246.8° C. ##STR48##
Reaction SMILES: [CH:1]1([C:4](=[O:20])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:20])[C:5](=[CH:24][O:23][CH2:21][CH3:22])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([F:15])([F:16])([F:17])([F:18])[F:19])=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1
Yield: 103.5 %

Procedure:
A mixture of 3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)-propan-1,3-dione (0.82 g) and triethylorthoformate (3.1 g) in acetic anhydride (40 ml) was heated at reflux temperature for 6 hours. The excess reagent and solvent were evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(4-pentafluorosulphanylphenyl)-propan-1,3-dione (1.0 g) as an orange oil. This was used directly in the subsequent reaction stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: Cc1ccc(Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nc1
Reaction time: 5 h
Yield: 58.1 %

Procedure:
A suspension of 5-chloro-2-methylpyridine (Reference Example 52, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90° C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2Cl2 at −78° C. was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, 1 h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M+H)+ (3.0 min).
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](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[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](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc(C(C)(C)C)cc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.070 g, 0.253 mmol) was reacted with N-(2-azidoethyl)-4-tert-butylbenzamide (0.062 g, 0.253 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-tert-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H), δ 7.64 (t, 1H), δ 7.36 (d, 2H), δ 7.27 (s, 1H), δ 6.42 (s, 1H), δ 5.99 (s, 2H), δ 4.51 (t, 2H), δ 3.88 (q, 2H), δ 2.58 (t, 2H), δ 2.22 (t, 2H), δ 1.52 (m, 13H), δ 1.21 (m, 11H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.3, 150.4, 149.6, 148.3, 138.9, 131.2, 127.3, 125.6, 122.2, 106.5, 84.8, 49.4, 40.2, 35.1, 31.3, 31.1, 29.3, 28.9, 28.3, 28.2, 28.1, 25.6 ppm; HRMS (ESI) calcd for C28H41N7O3 (M+) 523.3271. found 523.3270, 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-tert-butylbenzamide hydrochloride (0.105 g, 90% yield). 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), δ 7.76 (d, 2H), δ 7.48 (d, 2H), δ 6.50 (s, 1H), δ 4.84 (s, 2H), δ 3.95 (s, 2H), δ 2.85 (s, 2H), δ 2.46 (t, 2H), δ 1.73 (s, 2H), δ 1.57 (m, 2H), δ 1.39 (s, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 155.6, 147.3, 130.8, 129.9, 127.6, 127.2, 127.1, 126.7, 125.4, 125.3, 119.5, 108.6, 108.5, 52.3, 39.4, 34.6, 30.4, 27.9, 27.8, 27.6, 24.1, 23.2, 22.2 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. found 423.2741.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O-:27])=[O:26])=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>CCO.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS, 2SR, 3SR)-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2-carboxylate (650 mg, 1.68 mmol) in EtOH containing a few drops of THF was added 6M KOH (1.68 ml, 10.1 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as a solid (305 mg, 51%); m.p. 186-187° C.