Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][CH3:27]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:26]([CH3:27])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CNCc1ccco1
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)Cc3ccco3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with furan-2-ylmethyl-methyl-amine as described in Step 5, Example 24 to give the title compound as a cream solid (78% yield). LC/MS: RT 3.03 min, n/e 393 (M+H); 1H NMR (δ, ppm): 11.85 (1H, s), 7.62 (2H, m), 7.35 (1H, s), 7.23 (1H, d), 6.40 (2H, dd), 4.27 (2H, s), 2.70 (3H, s), 2.41 (2H, q), 2.32 (3H, s), 1.10 (3H, t).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.CSC.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])([CH3:19])[CH3:18])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2([C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:30][CH:29]=3)([CH3:19])[CH3:18])[CH2:5][O:21]2)=[CH:23][CH:24]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 53.9 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C. in the course of about 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is subsequently stirred for 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and are further reacted directly. ##STR159##
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].C[O:12][C:13](=O)[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](OC)=[O:19].[OH-].[Na+]>CCOCC>[OH:19][CH2:18][C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[CH2:15][CH2:14][CH2:13][OH:12]
Reactant: COC(=O)CCc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a stirred solution of LAH (1.89 g, 49.77 mmol) in Et2O (40 mL) under N2 was cooled to 0° C. and was added AlCl3 (1.6 g, 11.8 mmol). The mixture was allowed to warm to room temperature and stirred for 30 minutes. A mixture of methyl 2-(3-methoxy-3-oxopropyl)benzoate (2 g, 9 mmol) in Et2O was added dropwise. The mixture was stirred overnight. Aqueous NaOH (1 N, 12 mL) was added at 0° C. The mixture was filtered and the cake was washed with EtOAc 3 times. The filtrate was dried and concentrated to give 3-(2-(hydroxymethyl)phenyl)propan-1-ol (1.46 g, 98%). 1H-NMR (CDCl3): 1.85 (m, 2H), 2.77 (m, 2H), 3.52 (m, 2H), 4.62 (s, 2H), 7.23 (m, 2H), 7.27 (m, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]=[O:19])[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([OH:19])[CH3:1])[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(C)O)c1C(=O)OCC
Temperature: 25 °C

Procedure:
0.5 ml of a 0.3 M tetrahydrofuran solution of methyl magnesium bromide was added to a 3 ml tetrahydrofuran solution of 0.050 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate at −70° C. under a nitrogen atmosphere, and the mixture was allowed to warm to room temperature. 10 ml of a 5% aqueous ammonium chloride solution was added to this solution, and the mixture was extracted with 30 ml of ethyl acetate. The organic layer was washed successively with 10 ml of water and 10 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.049 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
Reaction SMILES: F[C:2]1C(O)=C(F)C(F)=C(F)C=1F.C(O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][C:32]=1[S:33][CH3:34])[O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH2:28][NH2:29].C(N(CC)CC)C.B.C1COCC1>C(OCC)C.C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][C:32]=1[S:33][CH3:34])[O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH2:28][NH:29][CH3:2]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1cc(Oc2cnccc2CN)ccc1SC
Agent: B
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=CO
Product: CNCc1ccncc1Oc1ccc(SC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Pentafluorophenol (852 mg, 4.64 mmol) was dissolved in diethyl ether (15 mL) and the solution cooled to 0° C. Formic acid (209 μL, 5.56 mol) was added followed by DCCl (956 mg, 4.64 mmol) and the mixture was stirred for 10 min. The white suspension was filtered off and the filtrate was cooled to 0° C. and treated with a solution of the product from Example 1 (640 mg, 2.32 mmol) in DCM (10 mL) and triethylamine (323 μL, 2.32 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. The solvents were then removed under reduced pressure and the residue was basified with water (10 mL)/880 NH3 (1 mL) and extracted with DCM (4×15 mL). The combined organic extracts were dried (MgSO4) and evaporated to an oily-solid residue (844 mg, ca. 100%); δH (CDCl3, 400 MHz) 2.42 (3H, s), 3.87 (3H, s), 4.55 (2H, s), 5.98 (1H, brs), 6.50 (1H, dd), 6.59 (1H, d), 7.17 (1H, d), 7.31 (1H, d), 8.21 (1H, s), 8.29 (1H, s), 8.38 (1H, d). This material was carried on directly to the reduction stage without further purification. The crude formamide was dissolved in THF (10 mL) and treated with borane-THF complex (1M in THF, 7 mL, 7 mmol). The resulting pale yellow solution was heated at reflux under nitrogen for 3.5 h. After cooling to room temperature, the reaction was quenched by the careful addition of 6 M HCl (7 mL) and the mixture was subsequently heated to reflux for 3 h. Most of the THF was removed by evaporation and the resulting aqueous solution was washed with diethyl ether (2×10 mL) and then basified by the addition of 880 NH3. Extraction with DCM (4×10 mL) followed by drying of the combined extracts (MgSO4) and evaporation afforded a clear oil. Purification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (95:5:0.5)] gave the desired compound as a colourless oil. A portion of this material (300 mg) was dissolved in DCM (5 mL) and treated with 1M HCl in diethyl ether (5 mL) and the resulting mixture was evaporated to dryness twice from DCM. The resulting yellow oil was dissolved in DCM (5 mL) and treated with diethyl ether dropwise to induce precipitation. The solvents were removed under reduced pressure and the resulting pale yellow solid was dried under vacuum (345 mg); Bis HCl salt: δH (CD3OD, 400 MHz) 2.39 (3H, s), 2.87 (3H, s), 3.85 (3H, s), 4.58 (2H, s), 6.87 (1H, dd), 6.95 (1H, d), 7.29 (1H, d), 8.06 (1H, d), 8.28 (1H, s), 8.58 (1H, d); MS m/z (TS+) 291 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.Br[C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:16]1[C:12]([C:8]2[N:6]3[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: Brc1cc2ccccc2s1
Reactant: Clc1ccc2nccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Clc1ccc2ncc(-c3cc4ccccc4s3)n2n1
Yield: 56 %

Procedure:
To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (1.59 g, 10.3 mmol, 1.1 equiv) in 28.0 mL of toluene was added 2-bromobenzo[b]thiophene (2.00 g, 9.38 mmol, 1.0 equiv), potassium carbonate (2.59 g, 18.8 mmol, 2.0 equiv), triphenylphosphine (592 mg, 1.88 mmol, 0.2 equiv) and palladium acetate (211 mg, 0.938 mmol, 0.1 equiv). The solution was stirred to reflux for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 1.50 g of the yellow solid, 56%.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:22][C:23]([CH3:25])=O>CO.C(#N)C>[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][O:2][N:1]=[C:23]([CH3:25])[CH3:22])[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]=2[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CC(C)Cn1c(CON)nc2c(N)nc3c(c21)CCCC3
Reactant: CC(C)=O
Solvent: CC#N
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3

Procedure:
A solution of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (700 mg, 2.42 mmol) in methanol (12 mL) and acetone (12 mL) was stirred at room temperature for 1 day, then was concentrated under reduced pressure to yield an oil. The oil was diluted with acetonitrile and concentrated under reduced pressure to yield a solid that was recrystallized from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 379 mg of acetone O-{[4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as white crystals, mp 176-177° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2cccc(C#N)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from the 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 23 and 3-cyanophenylboronic acid, 5-(3-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=59%).
Reaction SMILES: C(C(C)C(O)=O)#N.[CH3:8][C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH:18](C)[C:19]#[N:20])=[CH:15][C:14]([O:22][CH3:23])=[CH:13][CH:12]=2>>[CH3:8][C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]#[N:20])=[CH:15][C:14]([O:22][CH3:23])=[CH:13][CH:12]=2
Reactant: COc1ccc2c(c1)C(C(C)C#N)=C(C)C2
Agent: CC(C#N)C(=O)O
Product: COc1ccc2c(c1)C(CC#N)=C(C)C2

Procedure:
When α-cyanopropionic acid is used in place of cyano acetic acid in the above example, then the product is α-(2-methyl-5-methoxy-3-indenyl)-propionitrile.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:20])[CH2:18][NH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1([CH:27]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:21]1([CH2:27][NH:19][CH2:18][C:17]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:7]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: O=CC1=CCCCC1
Reactant: NCC(=O)N1CCc2ccccc2C1C1CCCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: O=C(CNCC1=CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (695 mg) was dissolved in methylene chloride (12 mL), and titanium tetraisopropoxide (1.1 mL) and 1-cyclohexene-1-carboaldehyde (309 mg) were added thereto, followed by stirring at room temperature for 3 hours. Thereafter, the solvent was evaporated, and MeOH (15 mL) and then sodium cyanotrihydroborate (190 mg) were added to the mixture, followed by stirring for 14 hours. The solvent was evaporated, and water and EtOAc were added to the mixture. The mixture was filtered through celite and extracted with EtOAc. The extract was washed with saturated brine and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain N-(cyclohexa-1-en-1-ylmethyl)-2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanamine (585 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18](=[O:24])[CH2:19][Si](C)(C)C)([CH3:16])([CH3:15])[CH3:14].[CH3:25][C:26]1([C:29](N2C=CN=C2)=[O:30])[CH2:28][CH2:27]1.Cl>O1CCCC1>[CH3:25][C:26]1([C:29](=[O:30])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:24])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Reactant: CC1(C(=O)n2ccnc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C1(C)CC1
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium (2.5M in hexane, 36 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (9.09 g) in dry tetrahydrofuran (i.e. tetrahydofuran) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred for 0.25 hour and t-butyltrimethylsilylacetate (16.9 g) was added dropwise with stirring whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour. A suspension of 1-(1-methylcyclopropylcarbonyl)-imidazole (13.5 g) in dry tetrahydrofuran (120 ml) was added dropwise whilst maintaining the temperature below -60° C. The mixture was stirred at -78° C. for 3 hours and the temperature was allowed to rise to room temperature. Hydrochloric acid (2M, 100 ml) was added cautiously and the mixture was extracted with ether (2×100 ml). The combined extracts were washed with hydrochloric acid (2M, 3×50 ml) and water (3×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 3-(1-methylcyclopropyl)-3-oxopropionate as an orange oil NMR (CDCl3) 0.65(m,2H), 1.1(m,2H), 1.25(s,3H), 1.4(s,9H), 3.2(s,2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (24.61 g, 96 mmol) was dissolved in acetic acid (100 ml) and the mixture was cooled to 10° C. Nitric acid fuming (Fluka ID 84392, 100%, 10 ml, 240 mmol) was added dropwise to the cooled solution over 2 hours. The reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction mixture was poured into water (400 ml). The precipitate was filtered, washed with water, then taken up in sodium hydrogencarbonate saturated aqueous solution (300 ml) and stirred for 2 hours. The precipitate was filtered, washed with water and dried. The raw product was recrystallized from ethyl alcohol (1000 ml) to give 18.25 g of product [B]. Yield 65%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (442 mg, 1.19 mmol) (obtained as described in Reference Example 40(4)) in methylene chloride (15 ml) were added methanesulfonyl chloride (0.12 ml, 1.49 mmol) and triethylamine (0.20 ml, 1.49 mmol) in an ice bath. The mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (517 mg, yield 97%) as a pale yellow solid.
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[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)=[O:28])=[N+:22]=[N-:23]>>[CH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[C:27]([NH:26][CH2:25][CH2:24][N:21]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=2)[N:23]=[N:22]1)=[O:28]
Reactant: [N-]=[N+]=NCCNC(=O)c1ccc2ccccc2c1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc4ccccc4c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.095 g, 0.344 mmol) was reacted with N-(2-azidoethyl)-2-naphthamide (0.083 g, 0.344 mmol) following the general click procedure to give tert-butyl 4-(5-(1-(2-(2-naphthamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), δ 8.01 (s, 1H), δ 7.72 (m, 4H), δ 7.39 (m, 2H), δ 7.26 (s, 1H), δ 6.33 (s, 1H), δ 6.04 (s, 2H), δ 4.51 (s, 2H), δ 3.88 (s, 2H0, δ 2.48 (t, 2H), δ 2.12 (s, 2H), δ 1.47 (m, 13H), δ 1.17 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 150.4, 149.5, 148.3, 138.6, 134.9, 132.7, 131.4, 129.2, 128.5, 128.1, 127.9, 126.8, 124.0, 122.3, 106.5, 84.9, 49.4, 40.4, 29.9, 29.2, 28.9, 28.6, 28.2, 27.9, 28.6, 27.9, 27.8, 25.6 ppm; HRMS (ESI) calcd for C28H35N7O3(M+) 517.2801. Found 517.2792, 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)-2-naphthamide hydrochloride (0.140 g, 90% yield). 1H NMR (300 MHz, CD3OD) δ ppm; 13C NMR (75 MHz, CD3OD) δ ppm; HRMS (ESI) calcd for C23H27N7O (M+) 417.2277. Found 417.2274.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:5]2[OH:16].C([O-])([O-])=O.[K+].[K+].[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:5]2[OH:16]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(Br)cc12
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a flask with 6-bromo-4-hydroxy-2-trifluoromethyl-quinoline (1.00 g, 3.42 mmol) was added K2CO3 (8.55 mL, 1.0 M in H2O, 8.55 mmol) followed by dioxane (85.5 mL). Benzofuran-2-boronic acid (0.665 g, 4.10 mmol) was then added followed by PdCl2(dppf) (0.028 g, 0.0342 mmol). The reaction mixture was stirred at room temperature for 0.5 hour and then heated to 65° C. for 18 hours. After concentration, the reaction was diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl, (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from EtOAc to afford the product (0.770 g, 68%) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 330. 1H NMR (500 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.37 (d, 1H, J=9.3 Hz), 8.07 (d, 1H, J=9.3 Hz), 7.65-7.75 (m, 3H), 7.38 (t, 1H, J=7.7 Hz), 7.30 (t, 1H, J=7.7 Hz), and 7.06 ppm (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.1020 g, 0.345 mmol) in 3 mL of DCM, isopropyl isocyanate (0.0400 mL, 0.407 mmol) was added. The solution was stirred for 1 h. Solvent was evaporated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) then again with 10-40% EtOAc in hexanes to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 381.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.48 (t, J=7.75 Hz, 1H) 7.19-7.32 (m, 2H) 7.01-7.14 (m, 2H) 6.55 (s, 1H) 4.30 (s, 1H) 3.98-4.13 (m, 1H) 3.38-3.63 (m, 2H) 2.69-2.98 (m, 2H) 1.13-1.25 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([F:27])[CH2:23]1)=[O:21])=O)(C)(C)C>ClCCl>[F:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][NH:15]2)=[O:21])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@@H]1CCCN1)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (S)-2-((R)-3-fluoro-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 2.4 mmol) in dichloromethane (5 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated. The residue was dissolved in methanol-water (1:1), neutralized to pH>10 with OH− formed resin. After concentration, 400 mg (89%) of ((R)-3-fluoro-pyrrolidin-1-yl)-(S)-pyrrolidin-2-yl-methanone was obtained.