Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].CN(C)[CH2:19][CH2:20]N(C)C>N1C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:19]([CH3:20])[CH2:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[C:3]#[C:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH3:14]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Reactant: CN(C)CCN(C)C
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Yield: 81.8 %

Procedure:
In a 1-l three-necked and round-bottomed flask 10.5 g of 3,7,11-trimethyldodeca-1-yne-3-ol, 5.0 g of cuprous chloride, 12.0 g of tetramethylethylenediamine and 675 ml of pyridine were placed and the mixture was subjected to oxydative coupling reaction at 50° ~ 55° C for 6 hours under an oxygen atmosphere. After completion of the reaction, there remained no unreacted starting alcohol. The pyridine was distilled off the reaction system and 300 ml of benzene and 200 ml of water were added to the residue and decanted. The organic layer was washed with 3N--H2SO4 and water, and dried. The benzene was distilled off to afford 8.55 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol. A 5.0 g portion of this product was dissolved in 10 ml of n-hexane and 0.25 g of 3 % palladium on active carbon was added thereto. The mixture was subjected to hydrogenation at a temperature of 60° C of under a hydrogen pressure of 3 ~ 5 kg/cm2 to give 4.6 g of the product consisting of the compounds (V) and (VI) in the ratio of 95.0 : 5.0 % respectively.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([SH:33])[CH2:31][CH3:32].C(OCC)(=O)C>C(#N)CCC>[CH3:16][O:15][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([S:33][CH2:30][CH2:31][CH3:32])=[C:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:4]=[N:5]2)=[CH:8][CH:9]=1)=[O:14]
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(C(=O)OC)cc1

Procedure:
tert-butyl 5-chloro-1-(4-methoxycarbonylphenyl)pyrazole-4-carboxylate (Intermediate #9) (2.016 g, 6.0 mmol) was dissolved in butyronitrile (30 mL), potassium carbonate (2.48 g, 18 mmol) and propanethiol (678 μL, 7.5 mmol) were added and the mixture heated to reflux for 5 h. Ethyl acetate (150 mL) was added and the mixture washed with water (4×25 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (120 g silica 0-25% EtOAc/isohexane) to give the title compound as a clear pale yellow oil that slowly crystallised on standing to a white solid. (2.01 g, 89%)
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 80 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (Intermediate 29, 100 mg) in chloroform (4 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (0.5 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:9]3[CH2:10][CH2:11][CH:6]([O:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]([F:1])([F:16])[F:17])[CH2:7][CH2:8]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Yield: 44 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-(2-trifluoromethylphenoxy)piperidine in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 44% yield. 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=9.5 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.00-6.96 (m, 3H), 4.78 (t, J=4.7 Hz, 1H), 4.03-3.95 (m, 2H), 3.83-3.74 (m, 2H), 3.56-3.50 (m, 2H), 2.00-1.98 (m, 4H), 1.51-1.45 (m, 2H), 0.75-0.70 (m, 1H), 0.46-0.40 (m, 2H), 0.09-0.04 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.2, 159.9, 154.9, 144.4, 133.2, 127.5, 127.4, 126.8, 120.2, 113.5, 112.1, 71.35, 41.1, 39.6, 34.6, 29.5, 8.7, 4.2 MS (ES+) m/z 457 (M+Na).
Reaction SMILES: C([N:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1)[CH2:9][CH3:10])(OC(C)(C)C)=O.Cl.O1CCOCC1>>[CH2:9]([NH:8][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1)[CH3:10]
Reactant: CCOC(=O)Cc1cccc(N(CC)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1cccc(CC(=O)OCC)n1

Procedure:
A solution of ethyl 2-(N-Boc-N-ethylamino)-6-pyridylacetate (1.5 g, 4.87 mmo)l) and 4M HCl/dioxane (5 mL, 20 mol) was stirred at RT overnight, then was concentrated. Reconcentration from toluene gave the title compound as white solid: MS (ES) m/e 209 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[NH2:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
6-[1-(3-Amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (25 ml) and with the addition of aqueous 1N-sodium hydroxide (20 ml), the mixture was stirred at 25° C. for 2 hours. With the slow addition of 3N-hydrochloric acid for neuturalization (pH=˜5), water (25 ml) was slowly added to the mixture for precipitate. After a 1-hour stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 2.53 g (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Br)c2ncccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
8-Bromoquinoline (25.00 g, 120.2 mmol) was dissolved in sulfuric acid (82.5 mL) at rt and then cooled to 0° C. HNO3 (fuming, 32.5 mL) was then slowly added over a 10 minute period. The reaction was then warmed to rt and then to 65° C. After 48 h at 65° C., the reaction was cooled to rt and poured onto 500 g of ice. This solution was extracted with methylene chloride (5×200 mL). The organic layers were washed once with brine and dried over anhydrous sodium sulfate. Concentration gave the crude compound 464A as a light yellow solid (28.6 g, 94%). HPLC: 98% at 2.717 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>C(O)C.Cl>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([F:30])[CH:32]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)C(F)(F)F
Temperature: 80 °C

Procedure:
To a mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (2.27 g, 5.4 mmol) in ethanol (60 mL) was added 3-fluoroaniline (0.62 mL, 6.48 mmol) and 5 drops of conc. HCl. The reaction was heated to 80° C. for 16 h, allowed to cool to rt and concentrated. The mixture was partioned between DCM and saturated aq. NaHCO3. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated to give, after trituration of the residue, the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.78 (s, 1H), 8.83 (d, 1H, J=7.2), 8.43 (d, 1H, J=9.2), 8.30 (d, 1H, J=5.2), 7.97 (s, 1H), 7.79-7.72 ((m, 2H), 7.52-7.40 (m, 4H), 7.22 (q, 1H, J=7.6), 7.12 (t, 1H, J=6.8), 6.69 (m, 1H), 6.56 (d, 1H, J=5.2).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:26][O:27][C:28]([C@H:30]([NH2:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].Cl.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CO.C(Cl)(Cl)Cl>[CH3:26][O:27][C:28](=[O:29])[C@@H:30]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:38][C:13](=[O:14])[C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH:1][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Z-D-Trp-OH (3.62 g, 10.7 mmoles), H-D-Phe-Ome.HCl (2.3 g, 10.7 mmoles) and 1-hydroxybenzotriazole (2.89 g, 21.4 mmoles) in dry DMF (25 ml) is cooled to 0° C and N-ethylmorpholine (1.37 ml, 10.7 mmoles) is added. A cold (0° C) solution of DCC (2.27 g, 11 mmoles) in DMF (6 ml) is added dropwise and the reaction mixture is stirred for 1 hr at 0° C and 1 hr at room temperature. The reaction mixture is then cooled to 0° C, filtered, the filtrate evaporated under reduced pressure and taken upon in EtOAc. The EtOAc solution is washed with saturated NaHCO3 solution, water, cold citric acid (2N), water, saturated NaHCO3 solution and saturated NaCl solution, dried with MgSO4, and evaporated under reduced pressure to afford the crude title product which is subjected to chromatography on a column of silica gel (500 g) with CHCl3 containing MeOH (1%) as eluent. The eluates are evaporated under reduced pressure and the residue is crystallized from EtOAc-petroleum ether to give the title compound; mp 130° - 131° C, [α]D25 = +34.1° (c = 1, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.CC(O[Na])=O.[Br:18]Br.Cl>C(O)(=O)C.C(OCC)(=O)C>[Br:18][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[OH:9]
Reactant: BrBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-Methoxy-2-nitro-phenol (10 g) was dissolved in glacial acetic acid (60 mL) and CH3CO2Na (8.2 g) was added. Next, bromine (3 mL) dissolved in glacial acetic acid (12 mL) was added drop wise to the stirring solution at room temperature. After complete addition of bromine, the mixture was stirred for 30 min at room temperature and then placed in an oil bath at 75° C. for 2 h. After reaction mixture cooled to room temperature, concentrated HCl (500 mL) was slowly added to the mixture followed by addition of ethyl acetate (500 mL). The layers were separated and the organic layer was washed with water, brine, dried (Na2SO4). Flash chromatography on silica gel eluting with 5% ethyl acetate-hexane afforded 8.8 g (60%) of the title compound as a solid. MS: 218 (MH+−30), HPLC tR: 2.40 min.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2>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.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21

Procedure:
Using Method C above, propargyl alcohol (0.11 g, 1.95 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.32 g, 0.78 mmol) (Starting Material 2 above) using (Ph3P)2PdCl2 (27.4 mg) and CuI (7.4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 0.12 g, 46%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3cccc(Cl)n3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,6-dichloro-pyridine (18.5 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.1 mg (2%) of the title compound. MS (ISP): 376.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]([CH3:53])([CH3:52])[C@H:49]([NH2:51])[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C@H:49]([CH3:50])[C:48]([CH3:53])([CH3:52])[CH3:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)C(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(-)-3,3-dimethyl-2-butylamine (Aldrich) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:31]1[S:35][C:34]([S:36]([N:39]2[CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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]>[N:39]1([S:36]([C:34]2[S:35][C:31]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:4][CH2:3][S:2](=[O:29])(=[O:1])[CH2:7][CH2:6]3)=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:40][CH2:41][CH2:42]1
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCC1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(S(=O)(=O)N3CCC3)s2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Reaction time: 0.3 h
Yield: 48.2 %

Procedure:
A mixture of 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (21 mg, 0.050 mmol), 1-[(5-bromo-2-thienyl)sulfonyl]azetidine (28.3 mg, 0.100 mmol), and K2CO3 (20.81 mg, 0.151 mmol) in 1,4-dioxane (0.22 mL) and water (0.110 mL) was degassed with argon in a Biotage microwave vial for 10 min. PdCl2(dppf) (3.67 mg, 5.02 μmol) was added, the vial was sealed, and the reaction was heated at 100° C. for 5 min in a Biotage microwave at high absorption. Additional PdCl2(dppf) (3.67 mg, 5.02 μmol) was added, and the reaction was heated at 130° C. in a Biotage microwave for 30 min on high absorption. The aqueous layer was removed via pipette, and the reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g), eluting with 1:1 DCM/MeOH (10 mL). The crude product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 11.9 mg of impure product. The impure product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC(YMC C18 S-5 mm/12 nm 50×20 mm preparatory column), eluting at 20 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) over 10 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 6.1 mg (25%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=2)[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(ethyl(3-hydroxyphenyl)amino)acetate (122 mg) in DMF (5.0 mL) were added potassium carbonate (75 mg) and 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (100 mg), and the mixture was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (107 mg) as a colorless oil.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(Cl)Cl.OS(O)(=O)=O>[C:1]([O:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCC/C=C\CCCCCCCC

Procedure:
Oleyl linoleate was prepared by refluxing linoleic acid (1 g) and Oeyl alcohol (1 ml) in CH2Cl2 (20 ml) and concentrated H2SO4 (10 μl) overnight. The product was slightly pink and was purified by flash chromatography. The resultant Oeyl linoleate was subjected to the Simmons-Smith procedure described above to generate DCPLA-oleyl ester.
Reaction SMILES: Cl.[N:2]1([CH2:12][C:13]([OH:15])=O)[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)CN1CCCC2CCCCC21
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCCC2CCCCC21)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(octahydroquinolin-1(2H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 45, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroquinolin-1(2H)-yl)acetamido)propanamide (20.1 mg, 44.9%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.84 (m, 1H), 7.59 (d, 2H), 7.28 (m, 7H), 7.02 (m, 4H), 4.69 (m, 1H), 4.51 (m, 2H), 3.73 (m, 2H), 3.34 (m, 2H), 3.33 (m, 2H), 2.97 (m, 1H), 2.75 (m, 1H), 2.17 (m, 1H), 1.42 (m, 11H). MS (EI) for C33H38FN3O4: 560.5 (MH+).