Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:28](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc2ccccc12)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2-tert-Butoxycarbonylamino-3-(1-naphthyl)propionic acid (5.0 g; 0.01 5 mol) was dissolved in tetrahydrofuran (40 mL). Iodomethane (7.6 mL; 0.12 mol) was added. The reaction mixture was cooled to 0° C. and sodium hydride was added. The reaction mixture was stirred for 48 hours. Ethyl acetate (50 mL) and water (20 mL) were added dropwise. The solvent was removed in vacuo and ether (30 mL) and water (20 mL) were added. The organic phase was washed with an aqueous solution of sodium hydrogen carbonate (pH 8; 30 mL). To the aqueous phases was added citric acid (5%) to pH 3. The aqueous phase was extrated with ethylacetate (3×30 mL). The combined organic phases were washed with water (2×40 mL), an aqueous solution of sodiumthiosulfate (5%; 40 mL) and water (40 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and ether (10 mL) and dicyclohexylamine (8.5 mL) were added. The precipitated crystals were filtered off and dissolved in water (20 mL). Hydrochloric acid was added to pH 2. The reaction mixture was extrated with ethyl acetate (4×40 mL), dried (magnesium sulfate) and evaporated in vacuo to afford 3.97 g of (2R)-2-(tert-butoxycarbonyl methylamino)-3-(1-naphthyl)propionic acid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:15]1(=[O:20])[N:3]([CH2:4][CH2:5][C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1nc2ccccc2[nH]1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
2-Aminoethylbenzimidazole dihydrochloride (Bull. Soc. Chim. Fr. 1991, 128, 255-259; 2.34 g, 10 mmol), phthalic anhydride (1.63 g, 11 mmol) and triethylamine (2.79 ml, 20 mmol) in chloroform (25 ml) were heated at reflux overnight, and the mixture was then cooled to room temperature, diluted with ethyl acetate and filtered off. The filtrate was washed with saturated sodium carbonate solution, buffer (pH=7) and saturated sodium chloride solution and dried over sodium sulphate. Chromatography (dichloromethane:methanol 10:1, Rf=0.4) gave 2.08 g of 2-(2-phthalimidylethyl)-benzimidazole (71.4% of theory) as a colourless foam. MS (DCI, NH3)=292 (M+H+). 1H-NMR (DMSO-d6): 3.15 (2H, t); 4.0 (2H, t); 7.05-7.2 (2H, m); 7.4-7.5 (2H, m); 7.8-7.9 (4H, m); 12.4 (1H, br s).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 48.9 %

Procedure:
A mixture of methyl 6-chloronicotinate (5.14 g), 1-benzyl-4-aminopiperidine (6.84 g) and K2CO3 (5.38 g) in DMF (30 ml) was stirred at 100° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (98:2). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.77 g)
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S([N:34]=[C:35]=[O:36])(C1C=CC(C)=CC=1)(=O)=O.[CH2:37](N)[CH3:38]>CN(C=O)C.C1COCC1>[CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:35]([NH:34][CH2:37][CH3:38])=[O:36])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN
Reactant: Nc1nc2cc(-c3cccnc3)cc(NC3CCCCC3)n2n1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(NC3CCCCC3)n2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Step 1 (256 mg, 0.83 mmol) was taken up in DMF (2 mL) and cooled on an ice/water bath. TosNCO (0.18 g, 0.91 mmol) was added all at once. The solution was allowed to stir at room temperature for 1.5 h. Ethylamine (3 mL of a 2 M solution in THF) was added and the resulting solution was microwaved at 120° C. for 10 min. The solution was cooled in the refrigerator overnight and the resulting precipitate was collected by filtration yielding 1-(5-cyclohexylamino-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea. MS m/z 380 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:18]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>ClCCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:18]2[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.[Cl:1][C:2]1[N:3]([C@@H:18]2[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc2nc(Cl)[nH]c2c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc([N+](=O)[O-])ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc([N+](=O)[O-])cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3.952 g (20 mmole) of 19 in 100 mL of 1,2-dichloroethane, was added 5 mL (20 mmole) of BSA. The reaction mixture was stirred at 75° C. for 15 min to give a clear solution. This solution was cooled to ~20° C. and treated with 7.0 g (22 mmole) of 1,2,3,5-tetra-O-acetyl-b-D-ribofuranose and 4.638 mL (24 mmole) of TMSOTf at room temperature for 2 h. The reaction mixture was diluted with 200 mL of CHCl3. The CHCl3 solution was washed with sat. NaHCO3 solution (200 mL×2), sat. NaCl solution (200 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (5×35 cm, eluted with CHCl3 and 0.5% MeOH/CHCl3). Evaporation of the appropriate fractions gave 6.50 g (71%, one spot on TLC) of 74 and 75 as a white foam. Fractional recrystallization of this foam (5 times from MeOH) give 1.59 g (17%) of the pure 6-nitro isomer 75. MP 127°-129° C. MS (El) m/e 455.0750 (2%, M+ =455.0732). 1H NMR (DMSO-d6): d 8.68 (d, 1, 7-H, J7-5 =2.0 Hz), 8.21 (dd, 1, 5-H, J5-4 =9.0 Hz), 7.88 (d, 1, 4-H), 6.41 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.58 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.45 (dd, 1, 3'-H, J3'-4' =4.0 Hz), 4.50, 4.40 (2×m, 3, 4'-H and 5'-H), 215, 2.12, 2.03 (3×s,9, 3×Ac). 13C NMR (DMSO-d6): d 170.12, 169.49, 169.25 (3×OCOCH3), 145.60 (C3a), 143.96 (C2), 143.65 (C6), 132.46 (C7a), 119.65 (C4), 118.92 (C5), 108.47 (C7), 86.96 (C1'), 79.67 (C4'), 71.12 (C2'), 68.75 (C3'), 62.56 (C5'), 20.39, 20.31, 20.03 (3×OCOCH3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-tert-butoxycarbonyl-5-hydroxyindan-2-amine (0.42 g), potassium carbonate (0.34 g), ethyl bromoacetate (0.24 ml), and N,N-dimethylformamide (4.2 ml) was stirred at ambient temperature for 20 hours. An additional portion of ethyl bromoacetate (0.12 ml) and potassium carbonate (0.17 g) was added to the mixture, and stirring was continued for an additional 12 hours. The mixture was diluted with ethyl acetate and the precipitates were filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; 5:1 n-hexane-ethyl acetate) to give N-tert-butoxycarbonyl-5-ethoxycarbonylmethoxyindan-2-amine (0.44 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([O:30]CC2C=CC=CC=2)=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2].CCOCC>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([OH:30])=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21

Procedure:
1-Ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepine-2-one (isomer B of Example 20, 1.1 g) in ethanol (150 ml) was hydrogenated at room temperature and atmospheric pressure using palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had terminated, the catalyst was filtered off, and the solvent removed under reduced pressure to give a semi-solid. Trituration with ether (30 ml) yielded isomer B of the title compound, m.p. 175°-177° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Cl)=[O:3].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[FH:19]>>[F:19][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:3]
Reactant: F
Reactant: O=C(Cl)Oc1ccccc1CCl
Reactant: c1ccccc1
Product: O=C(F)Oc1ccccc1Cc1ccccc1
Yield: 52 %

Procedure:
105 g (0.5 mol) of 2-chloromethylphenyl chloroformate are warmed to 40° C with 195 g (2.5 mols) of benzene in 100 ml of hydrogen fluoride for one hour and to 100° C for a further hour. After distillation in vacuo, 60 g (yield: 52%) of 2-benzylphenyl fluoroformate are obtained. 2nd reaction stage
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.ClC(Cl)(Cl)C[O:23][C:24](=O)[NH:25][C:26]1[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([C:29]1[CH:30]=[C:26]([NH:25][C:24]([NH:19][CH2:18][C:17]2[C:12]([O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:23])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1ncc2cc(Oc3ncccc3CN)ccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cccnc2Oc2ccc3c(cnn3C)c2)cc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
C-[2-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-methylamine (4n) (0.017 g, 0.067 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (5n) (0.035 g, 0.087 mmol) were placed in a 10 mL reactor vial and dissolved in DMF (5 mL). DIEA (0.058 mL, 0.334 mmol) was added to the reaction mixture and the system heated to 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography using Sep-pak 10 g (35 cc) silica cartridge (50% EtOAc/Hexanes) to furnish the desired product (6n) (0.034 g, 100% yield). 1H NMR (400 mHz, DMSO) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=4.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 2H), 6.26 (s, 1H), 4.37 (d, J=6.3 Hz, 2H), 4.06 (s, 3H), 2.36 (s, 3H), 1.25 (s, 9H); MS (ESI+) m/z 510 (M+H) detected.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][O:11][CH3:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:5]([CH2:9][CH2:10][O:11][CH3:12])=[C:4]([CH3:13])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCc1c(C)nc(N)nc1O
Product: COCCc1c(C)nc(N)nc1Cl
Reaction time: 5.5 h
Yield: 30.3 %

Procedure:
A mixture of 2-amino-5-(2-methoxyethyl)-6-methylpyrimidine-4-ol (600 mg, 3.27 mmol) and phosphorus oxychloride (6 ml) was kept at 90° C. for 5.5 hours. The reaction mixture was concentrated in vacuo. Was added to the residue and an aqueous ammonia solution was cautiously added. The mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried over sodium sulfate and the solvent was concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate=8:2) to give the object compound (200 mg, 30.3%).
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]([CH2:34][CH2:35][CH2:36][CH3:37])=[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]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.443 mmol) was reacted with N-(2-azidoethyl)-4-butylbenzamide (0.109 g, 0.443 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H0, δ 7.67 (d, 2H), δ 7.29 (s, 1H), δ 7.11 (d, 2H), δ 6.42 (s, 1H), δ 6.25 (s, 2H), δ 4.48 (s, 2H), δ 3.83 (s, 2H), δ 2.56 (t, 4H), δ 2.21 (s, 2H), 1.47 (m, 13H), δ 1.21 (m, 4H), δ 0.83 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ168.3, 140.6, 149.5, 148.2, 147.1, 138.4, 131.5, 128.7, 127.4, 122.2, 106.4, 84.9, 49.4, 40.2, 35.7, 33.5, 29.2, 28.9, 28.3, 28.1, 27.9, 25.5, 22.4, 14.1 ppm; HRMS (ESI) calcd for C28H41N7O3 (M+) 523.3271. found 523.3261, 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-butylbenzamide hydrochloride (0.191 g, 94% yield). 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), δ 7.69 (s, 2H), δ 7.22 (s, 2H), δ 6.44 (s, 1H), δ 4.73 (s, 2H), δ 3.89 (s, 2H), δ 3.34 (s, 2H), δ 2.59 (s, 4H), δ 2.41 (s, 2H), δ 1.54 (s, 4H), δ 1.29 (s, 4H), δ 0.88 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 165.1, 160.3, 158.1, 147.4, 141.4, 131.2, 128.5, 127.7, 127.3, 126.9, 92.9, 39.6, 36.3, 33.4, 30.9, 28.0, 27.7, 24.1, 22.2, 13.2, 12.1, 10.9, 8.9, 6.2, 2.5 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. found 423.2738.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH2:27][CH3:28].N1C=CC=CC=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH2:27][CH3:28]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CCC(=O)O
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 74.08 g (1.0 mole) of propionic acid, 500 g of toluene and 191.42 g (2.42 moles) of pyridine. After replacing the air in the container with nitrogen, 210.05 g (1.1 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 100° C. for 1 hour and then aftertreated in the same manner as in Example 2 to obtain 384.7 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monopropionate having a melting point of 108° to 110° C. Yield, 97%.
Reaction SMILES: O[C@@:2]12[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:20])[CH2:13][CH2:12]4)[C@H:9](C)[CH2:8][C:7]1=[CH:6][C:5](=[O:22])[CH2:4][CH2:3]2.S(=O)(=O)(O)O.P(=O)(O)(O)O.O>ClCCl.C(Cl)(Cl)Cl>[CH3:16][C@:15]12[CH2:17][CH2:18][C:19]3[C@@H:10]([CH2:9][CH2:8][C:7]4[C:2]=3[CH2:3][CH2:4][C:5](=[O:22])[CH:6]=4)[C@@H:11]1[CH2:12][CH2:13][C:14]2=[O:20]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A mixture of the products (III) and (IV) from example 18 (210.3 Mmoles) was slurried in 130 ml of dichloromethane and added over 30 minutes to a mixture of 103 ml of 96% sulfuric acid and 1.7 ml of 85% phosphoric acid which had been precooled to 2° C. The reaction was complete 90 minutes after the addition was finished. The mixture was added to 200 grams of ice and 100 ml of water; this was extracted with several portions of dichloromethane. The organic phase was concentrated to about 100 ml and 400 ml of isopropyl alcohol was added. This solution was concentrated to about 300 ml volume and cooled slowly to −20° C. The crystalline mass was filtered, washed with 2×30 ml of cold isopropanol and dried to give the product. The m.p. was 138.6-139.0° C., and the optical rotation [α]D=−132.5° (Cl, chloroform). NMR (CDCl3); 1.02 ppm (3H, s), 1.3-3.0 ppm, several multiplets, 5.70 ppm (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])/[C:7](=[CH:15]/[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]([NH:24][CH3:25])=[O:23])/[CH2:6]2.[CH2:26]([Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:33].[CH2:26]([N+:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[C:7]2/[C:8](=[O:14])[C:9]3[C:5]([CH2:6]/2)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)=[C:17]([C:22]([NH:24][CH3:25])=[O:23])[CH:18]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNC(=O)c1cnccc1/C=C1\Cc2cc(OC)c(OC)cc2C1=O
Reactant: BrCc1ccccc1
Product: CNC(=O)c1c[n+](Cc2ccccc2)ccc1/C=C1\Cc2cc(OC)c(OC)cc2C1=O
Product: [Br-]

Procedure:
The title compound 151 is prepared according to the procedure reported in Example 38.1 with compound 98 (50 mg, 0.148 mmol) and benzyl bromide (36 μL, 2 equiv) as reactants. Pale yellow solid. (Yield 55.2 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:28]1([CH2:33][C@@H:34]2[CH2:39][CH2:38]CN[CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=[N:46][C:44]=2C=1.C(Cl)CCl>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([N:46]2[CH2:44][CH2:35][CH:34]([CH2:33][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:39][CH2:38]2)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: On1nnc2ccccc21
Reactant: C1CNC[C@H](CN2CCCC2)C1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2CCC(CN3CCCC3)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 70 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (108 mg, 0.3 mmol) was coupled with (R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL), acetonitrile (1 mL) at rt for overnight to give 107 mg (70%) of the titled compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:18][S:15]([C:11]1[N:10]([C:8]2[CH:7]=[CH:6][C:5]([O:19][CH3:20])=[C:4]([CH:9]=2)[C:3]([OH:21])=[O:2])[CH:14]=[N:13][N:12]=1)(=[O:16])=[O:17]
Reactant: COC(=O)c1cc(-n2cnnc2S(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2cnnc2S(C)(=O)=O)cc1C(=O)O
Yield: 83 %

Procedure:
Stir a mixture of 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid methyl ester (1.0 g, 3.2 mmol), lithium hydroxide (0.042 g, 3.6 mmol), and 25% water in tetrahydrofuran (30 mL) at reflux overnight. Cool and add 1N hydrochloric acid (3.6 mL) dropwise via syringe. Concentrate to remove the tetrahydrofuran and collect the precipitate by vacuum filtration. Wash the filter cake twice with water and hexane, and dry in vacuo overnight to give 0.79 g of 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid as a solid.
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][CH2:11][C:12]#[CH:13].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: C#CCBr
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (11 g; 70.41 mmol) in ethyl acetate (60 mL) was added dropwise at room temperature to a mixture of 3-bromoprop-1-yne (15.2 mL; 141 mmol), sodium bicarbonate (11.95 g; 141 mmol), ethyl acetate (400 mL), and water (4 mL). The mixture was stirred at room temperature for 24 h and the solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to give 14.38 g (87%) of ethyl 5-(bromomethyl)isoxazole-3-carboxylate as a white solid.