Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[N+](CC)([O-])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([F:19])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC[N+](=O)[O-]
Product: COC(=O)c1cc(Br)cc2c1c(F)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 20.7 %

Procedure:
To a 20 ml vial was added methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (50.0 mg, 0.169 mmol), (selectfluor) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (78 mg, 0.219 mmol) followed with a magnetic stir bar and nitroethane (2 ml). The vial was capped and the reaction stirred at room temperature. Reaction progress was monitored by LCMS. After reaction completion the reaction solvent was removed in-vacuo. The residue was dissolved with DCM(1.4 ml). The DCM solution was charged onto an analogix Si35 SF10−8 gram column. The compound was eluted with EtOAc/Hexanes, 5-15%, 20 min. The desired product and side MW629 co-eluted. The mixture was dissolved with DMSO (1 ml) and purified by reverse phase HPLC using a Gemini 5 g 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient. The desired product eluted at 6.8 minutes and the side product MW 629 at 9.5 minutes. The desired fractions were concentrated to a residue. LCMS and NMR support the desired structure and analytical HPLC showed 100% purity. The product, methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (11 mg, 0.035 mmol, 20.53% yield), was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (t, J=1.77 Hz, 1H), 7.78 (d, J=1.77 Hz, 1H), 7.47 (d, J=2.53 Hz, 1H), 4.76-4.84 (m, J=1.64, 6.65, 6.65, 13.36 Hz, 1H), 3.96 (s, 3H), 1.50 (d, 6H). MS(ES)[M+H]+315.1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[S:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:44]=2N=N1.C(N(CC)CC)C.C[O-].[Na+].Cl>ClCCl.CO>[CH3:44][O:22][C:21](=[O:23])[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:33][CH:32]=2)=[CH:19][CH:18]=1)=[CH:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc(C)cc1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 41 (0.1 g, 0.218 mmol) and BOP [Castro's Reagent, Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate] (0.144 g, 0.326 mmol) in 5 mL dichloromethane was added triethylamine (0.067 mL, 0.477 mmol). The mixture was stirred for 1 h, and then sodium methoxide (0.5 M solution in methanol, 0.07 mL, 0.035 mmol) was added with 5 mL MeOH. The reaction was allowed to stir at room temperature for 16 h. 5% HCl was added to pH 0 and the mixture was extracted with 25 mL dichloromethane three times. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was loaded onto silica gel column as a solution in dichloromethane. The product was eluted with hexanes-ethyl acetate (3:2). Fractions were concentrated in vacuum to a white solid (0.037 g, 36.4%). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (br s, 1H), 7.75 (s, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 4.91 (dd, J=4.8 and 9.6 Hz, 1H), 3.72 (s, 3H), 3.39 (dd, J=4.0 and 13.6 Hz, 1H), 3.13 (dd, J=9.2 and 14.0 Hz, 1H), 2.25 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:28]=2[C:29]([OH:44])=[C:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:31]=12)=[O:21])([O:10]C1C=CC=CC=1)=[O:9])[CH3:6])C.O.[OH-].[Na+]>C(#N)C>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[C:34](=[O:35])[C:30]3[C:31](=[C:22]([C:20]([NH:19][CH2:18][CH2:17][P:8]([OH:10])([O:7][CH:5]([CH3:6])[C:4]([OH:45])=[O:3])=[O:9])=[O:21])[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:28]=4[C:29]=3[OH:44])[CH2:32]2)=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(C)OP(=O)(CCNC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(OP(=O)(O)CCNC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To 2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester 221 (15 mg, 0.024 mmol) dissolved in acetonitrile (0.10 ml) and water (0.05 ml) was added 1.0 M NaOH (0.072 ml). The reaction mixture was stirred at room temperature for 3 hours, cooled to 0° C., and quenched with 1.0 M HCl (0.1 ml). The mixture was concentrated in vacuo and the resulting residue was redissolved in dimethylsulfoxide, filtered through a glass plug, and purified by reverse phase preparatory HPLC to afford 2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-hydroxy-phosphinoyloxy]-propionic acid 315 (9 mg, 0.014 mmol, 60%). 1H NMR (CD3OD) δ 9.0 (d, 1H), 8.80 (d, 1H), 7.80 (m, 1H), 7.42 (M, 2H), 7.10 (t, 2H), 4.80 (d, 2H), 4.62 (s, 2H), 3.75 (m, 2H), 2.20 (m, 2H), 1.46 (d, 3H). 3P δ 27.8. 19F δ −78.0, −118.0. MS: 532.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[N:30]=[CH:31][CH:32]=[N:33]2)=[CH:27][CH:28]=1
Reactant: ClCc1ccc(-n2nccn2)cc1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.3 mmol) of the compound of Stage 3.7 in 10 ml of DMF, 0.8086 g (4.175 mmol) of 2-(4-chloromethyl-phenyl)-2H-[1,2,3]triazole, 0.0555 g (0.33 mmol) of KI and 0.646 g (4.68 mmol) of K2CO3 are added successively at r.t. After stirring for 18 h, the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give a solid which is washed with diethylether and MeOH to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24])[C:15]([NH:17]O)=[NH:16]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[N:17]=[C:4]([C:3]3[CH:7]=[CH:8][N:9]=[CH:10][C:2]=3[Cl:1])[O:5][N:16]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Reactant: O=C(Cl)c1ccncc1Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccncc3Cl)n2)cc1Cl
Temperature: 100 °C
Yield: 70.4 %

Procedure:
To a solution of 3-chloroisonicotinoyl chloride (about 2.6 mmol) (prepared by General procedure F) in pyridine (5 mL) was added 3-chloro-4-isopropoxy-N-hydroxy-benzamidine (300 mg, 1.31 mmol) (prepared by General procedure B). The mixture was heated at 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified via normal phase silica gel chromatography (0-50% ethyl acetate/heptane gradient over 30 min) to give 3-(3-chloro-4-isopropoxyphenyl)-5-(3-chloropyridin-4-yl)-[1,2,4]-oxadiazole (323 mg, 70.3%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.[N+]([O-])([O-])=O.[Na+].[I-:23].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>Cl.O.CCOCC>[I:23][C:8]1[CH:10]=[CH:11][C:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: CC(C)=CCC[C@H](C)CCc1ccc(N)cc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CC(C)=CCC[C@H](C)CCc1ccc(I)cc1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
A suspension of 4-[(3S)-3,7-dimethyl-6-octenyl]aniline (10.0 g, 43.2 mmol, Example 4) in concentrated HCl (9 mL) and water (100 mL) was cooled to 0° C. and then a solution of sodium nitrate (NaNO2, 2.96 g, 43.2 mmol) in water (22 mL) was added dropwise. To the resulting arenediazonium salt a solution of potassium iodide (7.11 g, 43.2 mmol) in water (22 mL) was added dropwise and the mixture was heated at 40° C. for 2 hours. Sodium thiosulfate was added and the suspension was extracted with ether (3×50 mL) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a dark oil. The crude material was dissolved in ether and filtered through a plug of silica gel to give 1-iodo-4-[(3S)-3,7-dimethyl-6-octenyl]benzene as a colorless oil (9.27 g, 27.1 mmol, 62.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]([CH3:17])[CH2:14][CH:15]=O.N1CCCC1.Cl>CCOC(C)=O.CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([CH2:14][CH:13]([CH3:17])[CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)CC=O
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC1CC(=O)c2cc(Br)ccc2O1
Reaction time: 72 h
Yield: 68.5 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (10.0 g, 46.5 mmol) and MeOH (0.20 L) were added 3-methylbutanal (7.54 mL, 69.8 mmol) and pyrrolidine (5.77 mL, 69.8 mmol) at ambient temperature, and the mixture was stirred for 3 days at the same temperature. After concentration of the reaction mixture at reduced pressure, the residue was diluted with EtOAc, acidified to pH 3-4 with 1M aqueous HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, and filtered. After concentration of the filtrate at reduced pressure, purification of the residue with column chromatography on silica gel (EtOAc-hexane, a linear gradient of EtOAc from 0 to 10%) afforded 6-bromo-2-isobutyl-2,3-dihydro-4H-chromen-4-one (9.02 g).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:16]=[C:17]([S:26][C@H:27]([CH3:31])[C:28](Cl)=[O:29])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:22]([C:19]1[CH:18]=[C:17]([S:26][C@H:27]([CH3:31])[C:28]([N:9]2[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]2=[O:10])=[O:29])[CH:16]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:20]=1[OH:21])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@@H](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of 60% sodium hydride (665 mg, 19.0 mmol) and toluene (40 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (2.0 g, 18.0 mmol) in toluene (20 mL) over a 30 min period. The cooling bath was removed and the solution was allowed to warm to room temperature and stir there for a 30 min period to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl chloride (29, 6.21 g, 19.0 mmol) in toluene (20 mL) over a 20 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 2:1). Water (100 mL) was added to the reaction and the phases were separated. The aqueous phase was extracted with t-butyl methyl ether (2×100 mL). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution (1×250 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×24 cm length) using hexane and ethyl acetate (10:1) afforded 2.32 g (32%) of (5S)-N-((2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl)-5-ethenylpyrrolidin-2-one (33a) as a white crystalline material: mp 105°-106° C.; 1H NMR (CDCl3) δ1.37-1.42 (m, 21 H), 1.79-1.86 (m, 1 H), 1.97-2.05 (m, 1 H), 2.32-2.41 (m, 1 H), 2.57-2.67 (m, 1 H), 4.71-4.75 (t, J=6.8 Hz, 1 H), 5.03-5.17 (m, 3 H), 5.33 (s, --OH, 1 H), 5.78-5.87 (m, 1 H), 7.23 (s, 2 H); 13C NMR (CDCl3) δ174.7, 172.6, 154.7, 136.3, 135.7, 132.7, 120.9, 115.3, 58.8, 44.1, 34.3, 31.9, 30.2, 23.9, 16.4; IR (KBr) 3581 (s), 2964 (s), 1748 (vs), 1684 (vs), 1426 (s), 1345 (s), 1227 (vs), 1198 (s), 917 (w), 885 (w) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:19][C:26](=[O:28])[CH3:27])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Bromo-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine (1.06 g, 3.19 mmol) was dissolved in dichloromethane (15.9 ml) and pyridine (0.28 ml, 3.51 mmol) was added. The solution was cooled to 0° C. and then, acetyl chloride (0.23 ml, 3.19 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 1 hour. Water and dichloromethane were added and the organic phase was separated, dried and concentrated under reduced pressure to afford N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide as a beige powder. 1H NMR (400 MHz, Acetone-d6) δ 9.37 (s, 1H), 9.32 (s, 1H), 8.83 (d, J=6 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.27 (d, J=6 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br>>[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1
Reactant: Fc1c(Cl)cccc1CBr
Reactant: Oc1cc(O)nc(S)n1
Product: Oc1cc(O)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The subtitle compound was prepared by the method of Example 19 step i) using 2-mercaptopyrimidine-4,6-diol (20.0 g) and 3-chloro-2-fluorobenzyl bromide to afford the subtitle compound as a white solid. Yield: 36.2 g.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH:18]=[CH:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 38.4 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.115 g, 0.620 mmol) was reacted with (3-azido-propenyl)-benzene (0.119 g, 0.748 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1Himidazol-2-ylamine hydrochloride (0.082 g, 43%) as a pale yellow solid. 111 NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 6H), δ 6.67 (d, 1H), δ 6.34 (q, 1H), δ 6.25 (s, 1H), δ 5.08 (d, 2H), δ 2.72 (t, 2H), δ 2.47 (t, 2H), δ 1.91 (m, 2H) ppm; 13C (75 MHz, CD3OD) 149.1, 137.9, 133.5, 129.5, 128.9, 128.7, 128.3, 128.2, 127.7, 126.8, 54.8, 48.9, 31.3, 29.6, 27.5 ppm; FIRMS (ESI) calcd for C17H21N6(M+) 308.1822, found 308.1821.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH:11]1[CH2:15][CH:14]([CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:17])[N:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[NH:11]1[CH:15]=[C:14]([CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:17])[N:13]=[CH:12]1
Reactant: CC(c1ccnc2ccccc12)C1CNC=N1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(c1c[nH]cn1)c1ccnc2ccccc12
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
To oxalyl chloride (0.85 μl, 0.976 mmol) in 5 ml of anhydrous dichloromethane at −78° C., dimethylsulfoxide (0.14 ml, 1.95 mmol) was added over a five minute period. After stirring for 5 minutes at the same temperature, 4-[1-(4,5-Dihydro-1H-imidazol-4-yl)-ethyl]quinoline (0.200 g, 0.888 mmol) was added slowly and the reaction mixture was stirred for a further 20 minutes at −78°. Triethylamine (0.62 ml, 4.44 mmol) was added and the reaction mixture was stirred for 5 minutes at −78° C. and then 20 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc (10 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified [EtOAc:MeOH:Methanol NH3 (1.0 M); 3.5:1:0.5) to give 0.100 g (51%) of the product as a syrup.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]([CH3:16])([CH3:15])[C:13]2[CH:12]=[C:11]([CH:17]=[O:18])[C:10]([Br:19])=[CH:9][C:8]=2[C:7]([CH3:21])([CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:22](O)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.ClCCl>[C:1]([O:4][CH:5]1[C:14]([CH3:15])([CH3:16])[C:13]2[CH:12]=[C:11]([CH:17]3[O:24][CH2:23][CH2:22][O:18]3)[C:10]([Br:19])=[CH:9][C:8]=2[C:7]([CH3:21])([CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC(C)(C)c2cc(Br)c(C=O)cc2C1(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC1CC(C)(C)c2cc(Br)c(C3OCCO3)cc2C1(C)C

Procedure:
7-Acetoxy-3-bromo-2-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.3 g, 0.849 mmol) from the preceding reaction was dissolved in 2 mL of benzene. Ethylene glycol (0.104 mL, 1.87 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added. A Dean-Stark apparatus was attached to the reaction flask and the reaction was brought to reflux for several hours. When the reaction was judged complete by TLC (SiO2, 20% ethyl acetate/hexanes), dichloromethane (25 mL) and sodium bicarbonate solution (50 mL) were added and the layers were separated. The aqueous layer was extracted one more time with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give 7-Acetoxy-3-bromo-2-(1,3-dioxolane-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as an oily residue that was used directly in the next step.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH:48]2[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]2)(=O)=O)=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.O>[CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:48]4[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCS(=O)(=O)CC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OC3CCS(=O)(=O)CC3)cc12
Temperature: 100 °C
Reaction time: 14 h
Yield: 28.1 %

Procedure:
A solution of ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (400 mg) obtained in Example A194(4), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) synthesized above and tripotassium phosphate (223 mg) in N,N-dimethylformamide (4 mL) was stirred at 100° C. for 14 hr. 1,1-Dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) and tripotassium phosphate (112 mg) were further added to the mixture, and the mixture was stirred at 100° C. for 2 hr then at 120° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-34:66, v/v) to give a colorless amorphous form (200 mg). The colorless amorphous form (200 mg) was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 1N aqueous sodium hydroxide solution (0.64 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.64 mL) under ice-cooling and stirred at 0° C. for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (136 mg, 29%) as a colorless amorphous form.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[NH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30]>C1COCC1.CN(C=O)C.CN(C=O)C.CCOC(C)=O.CC(O)=O>[CH3:26][O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:30][C:22](=[O:24])[C@@H:17]1[CH2:18][CH2:19][C:20](=[O:21])[NH:16]1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.03 h

Procedure:
N-Methylmorpholine (2.02 g, 0.020 mol) and isobutyl chloroformate (2.73 g, 0.020 mol) were added to a solution of L-pyroglutamic acid (2.58 g, 0.020 mol) in 100 ml of THF/DMF (6:1) at -15° C. After a 2 minute coupling period, a mixture of L-phenylalanine methyl ester hydrochloride (4.31 g, 0.020 mol) (suspension) and N-methyl morpholine (2.02 g, 0.020 mol) in 50 ml of DMF was added to the reaction mixture. The reaction was allowed to proceed at this temperature for 30 minutes and then at room temperature for 1 additional hour. The reaction mixture was then filtered to remove fines and the filtrate was evaporated in vacuo to incipient dryness. The resulting yellow liquid was dissolved in 100 ml of ethyl acetate, and the ethyl acetate solution was washed with 5% citric acid saturated with sodium chloride (50 ml) and 5% sodium bicarbonate saturated with NaCl (50 ml). The separated organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield quantitative amounts of a pale yellow liquid which was used directly for the following step. TLC: Rf =0.22 in EtOAc/AcOH (100:1), detected by UV quenching; IR (neat, cm-1) 3300 (NH), 3020-3060 (C6H5), 2860-2960 (alkyl), 1650-1750 (C=O); NMR (Silanor C, δ from TMS) 7.25 (fused s, C6H5 --), 5.5-5.7 and 6.6-6.8 (broad, NH's), 4.6-5.1 (q, --NH--CH--C=O), 3.0-3.2 (q, --CH2 --C6H5), 1.6-2.5 (m, cycl. O=C--CH2 --CH2).