Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Br[C:50]1[CH:55]=[CH:54][N:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:50]2[CH:55]=[CH:54][N:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(C(=O)NC2CCN(c3ccnc(C(F)(F)F)c3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 100 °C
Reaction time: 23 h
Yield: 34.6 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.59 mmol), potassium carbonate (204 mg, 1.5 mmol) and triethylamine (0.082 mL, 0.59 mmol) in DMF (3.0 mL) was heated to 80° C., 4-bromo-2-(trifluoromethyl)pyridine (133 mg, 0.59 mmol) was added, and the mixture was stirred at 100° C. for 23 hr. The reaction mixture was diluted with water, and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (126 mg, 35%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[N:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CO>[NH2:24][C:22]1[CH:21]=[N:20][N:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:10]([NH:9][CH2:8][CH:7]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:18]=2)[CH:23]=1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
The title compound is prepared by dissolving N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP2) in methanol (˜1.0M), adding a 2:1 mixture by weight of activated carbon and ferric chloride and an excess of hydrazine monohydrate, and stirring the resulting mixture at 65° C. for four hours. Filtration through Celite™, removal of the volatile components under reduced pressure, and purification by column chromatography/crystallisation, affords the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:21](I)([CH3:23])[CH3:22].[Cl-].[NH4+]>CN(C)C=O>[CH:21]([N:11]1[C:12](=[O:15])[CH:13]=[CH:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[C:10]1=[O:16])([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (135.0 mg) in N,N-dimethy formamide (5.0 ml) were added at room temperature sodium hydride (25.3 mg) and isopropyl iodide (265 μl) and the resulting mixture was stirred at 110° C. for two hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (30.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 3-isopropyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (122.5 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:3]([N:8]2[C:14]([OH:15])=[CH:13][C:12]([C:11]([F:21])([F:20])[F:10])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cc1cccnc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccnc1-n1nc(C(F)(F)F)cc1O
Temperature: 60 °C
Yield: 10.1 %

Procedure:
A mixture of 3-methyl-2-pyridylhydrazine (1.0 g, 8.13 mmol), acetic acid (7.0 mL) and ethyl trifluoroacetoacetate (1.2 mL, 8.13 mmol) was heated at 60° C. for 9 hours. The reaction mixture was neutralized with NaHCO3 and then was extracted with EtOAc (3×). The EtOAc extracts were combined, dried over MgSO4, filtered and concentrated to afford crude product which was purified by column chromatography on silica gel to afford 200 mg of 1-(3-methyl-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4ccccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), and 2-hydroxynaphthalene (40 mg, 0.28 mmol) in DMF (1.5 ml) containing potassium carbonate (48 mg, 0.35 mmol) was stirred at 100° C. for 3.5 hours. After cooling, methylene chloride (4.5 ml) was added and the mixture was poured onto a column of silica (SiO2 Isolute®) and eluted with, successively, methylene chloride, methylene chloride/methanol (9/1), methylene chloride/methanol/3M ammonia in methanol (75/20/5). The fractions containing the product were evaporated under vacuum. The residues was triturated with ether, filtered and dried under vacuum to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline (80 mg, 83%).
Reaction SMILES: I[CH2:2][CH3:3].FC(F)(F)C(O)=O.[NH:11]1[CH2:15][CH2:14][C@@H:13]([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([N:11]1[CH2:15][CH2:14][C@@H:13]([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1)[CH3:3]
Reactant: CCI
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCN1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 31.4 %

Procedure:
Iodoethane (4.1 g) was added to a cooled mixture of benzyl N—((R)-pyrrolidin-3-ylmethyl)carbamate trifluoroacetate salt (Intermediate 171, 7.6 g) and potassium carbonate (12.2 g) in DMF (10 mL) while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give benzyl N—((S)-1-ethylpyrrolidin-3-ylmethyl)carbamate (1.8 g) as a colourless oil, which was used without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Br:33][C:34]1[N:39]=[C:38]([NH:40][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])[CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1cccc(Br)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 1.0 g, 2.65 mmol) was diluted with dichloromethane (10 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (1.46 mL, 2.92 mmol) and DMF (1 drop). After stirring for 20 minutes, 6-bromopyridin-2-amine (0.505 g, 2.92 mmol) and diisopropyl ethylamine (1.16 ml, 6.64 mmol) were added and the reaction was stirred overnight at ambient temperature, then heated to 70° C. for 4 hours. The reaction mixture was cooled, then loaded directly onto a Biotage 40 cartridge, eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (500 mg, 0.940 mmol, 35.4% yield).
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([O:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of (S)-methyl 2-hydroxypropanoate (1.00 g, 9.61 mmol) in DMF (10 mL) at rt, were added imidazole (0.981 g, 14.41 mmol) and TBS-Cl (1.737 g, 11.53 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was diluted with hexanes. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% ethyl acetate/hexanes) to give 17A (1.73 g, 7.92 mmol, 82% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.34 (q, J=6.7 Hz, 1H) 3.72 (s, 3H) 1.40 (d, J=6.8 Hz, 3H) 0.90 (s, 8H) 0.09 (d, J=10.8 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>Br>[BrH:1].[BrH:1].[Br:1][C:2]1[C:3]([CH2:9][S:15][CH2:14][CH2:13][NH2:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(CO)c1Br
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1ccnc(CSCCN)c1Br

Procedure:
A mixture of 3-bromo-2-hydroxymethyl-4-methylpyridine (5.8), cysteamine hydrochloride (3.5 g) and hydrobromic acid (48%, 50 ml) was refluxed for 6 hours and evaporated to dryness. The residue was crystallised from isopropanol/methanol to give 2-(3-bromo-4-methyl-2-pyridylmethylthio)ethylamine dihydrobromide (8.5 g) m.p. 203°-205°.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[N:14]=[C:13]([C:27]#[N:28])[C:12]=1[N+:29]([O-])=O)[CH3:9].[OH-].[K+]>Cl.CN(C=O)C>[NH2:29][C:12]1[C:13]([C:27]#[N:28])=[N:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[CH:16][C:11]=1[NH:10][CH2:8][CH3:9]
Reactant: CCNc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
At 0° C., a solution of tin chloride dihydrate (30.2 g) in concentrate aqueous HCl (150 mL) was added dropwise over 2 hours to a solution of 4-ethylamino-3-nitro-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (5.0 g) in DMF (100 mL). The mixture was further stirred for 1 hour at 5° C., then poured to a mixture of ice (900 g) and potassium hydroxide (440 g), extracted with ethyl acetate (2×1.4 L). The combined organic layers were washed with brine (700 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (4,56 g) as a solid. 1H NMR (DMSO-d6) δ: 8.30-8.20 (m, 2H); 7.75-7.60 (m, 2H); 7.08 (s, 1H); 6.11 (t, J=6 Hz, 1H); 5.95 (br. s, 2H); 3.4-3.3 (m, 2H); 1.27 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.ClC(Cl)C>[Br-].[Zn+2].[Br-].ClCCl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCc1ccc(F)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: Oc1ccc(Br)cc1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
To a solution of 4-bromophenol (13.84 gm, 0.08 Mol), 4-fluorobenzyl alcohol (8.68 gm, 0.08 Mol), and 120 mL of dichloroethane was added zinc bromide (21 gm, 0.09 Mol). The reaction mixture was stirred at 60° C. for 24 h, filtered and concentrated under reduced pressure. Pure product was obtained by flash chromatography using SiO2, dichloromethane/hexane [1:1] as eluant to give 4-bromo-2-(4-fluorobenzyl)phenol (9.25 g, 41%) as colorless oil: 1H NMR (200 MHz, DMSO-d6): δ 9.79 (s, 1H), 7.16 (m, 5H), 6.74 (d, J=8.8 Hz, 1H), 3.82 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=methylene chloride-hexanes (1:1); Rf=0.38.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)cc3)cn2)c1
Yield: 70.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) and 2-(chloromethyl)-4-methylpyridine hydrochloride (0.46 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:23](=[O:32])[N:24]([CH3:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C=1>>[CH3:13][C:11]([CH3:12])([CH3:14])[CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:23](=[O:32])[N:24]([CH3:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)=[O:15]
Reactant: CC(C)(C)CC(=O)Nc1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C)cc1)c1ccccc1
Yield: 77 %

Procedure:
The title compound (262 mg, 77% yield) was prepared from N-(4-hydroxyphenyl)-3,3-dimethyl-butyramide (275 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=341 (M+1); Rt=4.15 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]#[CH:21])[C@H:14]2[CH3:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=1[O:36][CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]#[C:21][C:26]3[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=3[O:36][CH3:37])[C@H:14]2[CH3:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1Br
Reactant: C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(F)c(C(C)C)cc1C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-prop-2-yn-1-yl-1,3-oxazolidin-2-one (100 mg, 0.285 mmol), 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (27.4 wt % in toluene, 233 mg, 0.259 mmol), bis(triphenylphosphine)palladium dichloride (18.2 mg, 0.0259 mmol), copper (I) iodide (4.9 mg, 0.0259 mmol), triphenylphosphine (13.6 mg, 0.0518 mmol), and diethylamine (283 mg, 406 μL, 3.88 mmol) in dry DMF (0.5 mL) was degassed and subjected to microwave irradiation (120° C., 60 min). The reaction mixture was diluted with 0.1N HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)prop-2-yn-1-yl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.38 (20% EtOAc/hexanes). LCMS calc.=518.2; found=518.2 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H); 7.78 (s, 2H); 7.26 (d, J=8.4 Hz, 1H); 6.56 (d, J=12.0 Hz, 1H); 5.76 (d, J=8.3 Hz, 1H); 4.70 (d, J=17.8 Hz, 1H); 4.53-4.47 (m, 1H); 4.08 (d, J=17.8 Hz, 1H); 3.82 (s, 3H); 3.17-3.09 (m, 1H); 1.22 (d, J=6.9 Hz, 6H); 0.90 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31].I[CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[N:19]([CH2:36][CH3:37])[N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31]
Reactant: CCI
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnn[nH]3)cc12
Product: CCn1nnnc1-c1cc2c(C)c(C)n(Cc3cccc(Cl)c3)c2c(N2CCc3ccccc3C2)n1
Yield: 34 %

Procedure:
In accordance with the same procedures as in Example 853, except for using 2-[1-(3-chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline prepared in Example 852 and iodoethane, the titled compound was obtained as a white solid. (Yield: 34%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([CH2:9][CH:10]([CH:15]=O)[CH2:11]2)[CH2:7]1.[CH2:27]([NH:30][C:31]1[CH2:35][S:34][C:33](=[O:36])[N:32]=1)[C:28]#[CH:29].C([O-])(=O)C.[NH2+]1CCCCC1.C(=O)([O-])O.[Na+]>CC(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:7][CH:8]2[CH2:14][CH:12]([CH2:11][CH:10](/[CH:15]=[C:35]3/[C:31]([NH:30][CH2:27][C:28]#[CH:29])=[N:32][C:33](=[O:36])[S:34]/3)[CH2:9]2)[CH2:13]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To a solution of 3-[2,4-bis(trifluoromethyl)benzyl]-3-azabicyclo[3.3.1]nonane-7-carbaldehyde (173.9 mg) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (141 mg) in 2-propanol (2.29 mL) was added piperidinium acetate (66.6 mg). The reaction mixture was stirred at 60° C. overnight, allowed to cool to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (36.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[N:6][CH:7]=1.C(O)C.O.[NH2:21][NH2:22]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:21][N:22]=2)=[N:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cn1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Cl)cn2)=NN1
Yield: 81.1 %

Procedure:
To a dry 200 mL flask equipped with magnetic stirrer, and reflux condenser was charged 3.7 g ethyl 4-(5-chloropyridin-2-yl)-4-oxobutanoate (0.0153 mol), 75 mL ethanol, and 0.8 g of hydrazine hydrate (0.0168 mol). The reaction was heated at reflux for about 2 hours. An aliquot was analyzed by GC which indicated no remaining starting material, and one major product. The reaction was cooled and poured into about 200 mL of water to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried overnight in vacuo at 40° C. Isolated 2.6 g of a tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.65 (t, 2H); 3.22 (t, 2H), 7.75 (d, 1H); 8.00 (d, 1H); 8.60 (s, 1H); 8.70 (bs, 1H). The sample was stored in the refrigerator and had 81% isolated yield.