Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.ClCCl.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: OC1CCOCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In a dry 25 mL round bottom flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (from Example 1, 614 mg, 2.51 mmol), dichloromethane (10 mL) and tetrahydro-4H-pyran-4-ol (0.50 mL, 5.01 mmol). The solution was stirred at 25° C. and then rhodium (II) acetate dimer (22 mg, 0.05 mmol) was added. Gas evolution began immediately and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for 1 h, it was poured into water (10 mL) and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL) and the combined organic layers were dried over sodium sulfate and in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) to furnish rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid methyl ester (598 mg, 75% yield) as a clear colorless oil: EI-HRMS m/e calcd for C14H15Cl2O4 (M+) 318.0426, found 318.0412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:15])([Cl:14])[C:11](Cl)=[O:12]>>[Cl:9][C:10]([Cl:15])([Cl:14])[C:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)cc1
Product: O=C(Oc1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 120 °C

Procedure:
A 25.6 gram (g) (0.2 mole) sample of 4-chlorophenol was mixed with 40 g of trichloroacetyl chloride at room temperature. The resulting solution was heated under reflux conditions at 120° C. for 10 hours. The temperature was gradually increased to 180° C. over a period of 16 hours. The reaction mixture was then allowed to cool to room temperature. An insoluble solid product was collected by filtration and dried in vacuo. The solid was identified by vapor phase chromatography as 4-chlorophenyl trichloroacetate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:10]2[CH2:12][CH2:11]2)[C:7]=1[Cl:8]
Reactant: OB(O)C1CC1
Reactant: Clc1c(Br)cncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1c(Br)cncc1C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3,5-dibromo-4-chloropyridine (X, 0.5 g, 1.84 mmol) and cyclopropylboronic acid (0.17 g, 2.02 mmol), cesium carbonate (1.19 g, 3.68 mmol) in the mixture of 1,4-dioxan (10 mL) and water (2 mL). The reaction mass was purged with nitrogen for 15 min. Then catalyst Pd (dppf)2Cl2 (0.075 g, 0.09 mmol) was added and allowed to stir at 100° C. for 4 h. The reaction mixture was filtered through Mite bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts were concentrated under vacuum to afford the crude compound, which was purified by column chromatography using 10-40% ethyl acetate/hexane as an eluent to obtain title compound. MS (M+1): 233.0.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH3:39])[C:35](=[O:40])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH2:42]([NH2:46])[CH:43]([CH3:45])[CH3:44]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:40])[NH:46][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:38][CH3:39])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
24 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (106i) (0.51 mmol) in isobutylamine (0.99 ml) (10.2 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=3/1-2/1) to obtain 267 mg of the title compound (yield: 92%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[OH-].[K+].[CH3:26]C(C)=O.CI>O>[CH3:26][S:20][C:19]1[N:6]2[C:7]3[C:12]([S:13][C:14]4[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]=42)=[CH:11][CH:10]=[CH:9][C:8]=3[C:17](=[O:21])[N:18]=1
Reactant: CC(C)=O
Reactant: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(=O)c2cccc3c2n1-c1cc(C(F)(F)F)ccc1S3
Reaction time: 18 h

Procedure:
10-Trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-3-one-1(2H)-thione (53.6 g., 0.152 mol.) was added to a stirred solution of 8.95 g. (0.160 mol.) of potassium hydroxide in 1680 ml. of acetone and 720 ml. of water. After all the solid had dissolved and a clear yellow solution formed, 22.8 g. (10 ml., 0.160 mol.) of methyl iodide was added in one portion. The reaction mixture was stirred at 25° for 18 hours, diluted with 1000 ml. of water and chilled in an ice-bath for several hours. The resulting light yellow solid was collected by filtration and washed with water to give 1-methylmercapto-10-trifluoromethyl-3H-pyrimido[5,4,3-kl]phenothiazine-3-one, m.p. 229°-231° (ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]([C:11](=[O:31])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>[Pt].CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]([C:11](=[O:31])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[N:14]=1)[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)Nc1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2)n1)N(C)C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C(=O)Nc1ccc(N)c(NCc2ccc(Cl)cc2)n1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
EtOAc (15 mL) was added to {1-[6-(4-chloro-benzylamino)-5-nitro-pyridin-2-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (300 mg, 0.65 mmol) and 10% Pt/C (80 mg). The mixture was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give {1-[5-amino-6-(4-chloro-benzylamino)-pyridin-2-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester which was used immediately in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([C:12]2[C:17]3[C:18](=[O:24])[N:19]4[CH:23]([C:16]=3[N:15]=[C:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:13]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22][CH2:21][CH2:20]4)=[CH:8][CH:7]=1)=[O:5])C>O1CCOCC1.[OH-].[Na+]>[CH2:36]([O:35][C:33]([C:13]1[C:14]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[N:15][C:16]2[CH:23]3[N:19]([C:18](=[O:24])[C:17]=2[C:12]=1[C:9]1[N:10]=[N:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1)[CH2:20][CH2:21][CH2:22]3)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1ccc(-c2c(C(=O)OCC)c(Cc3ccc(F)cc3)nc3c2C(=O)N2CCCC32)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)nn1)C(=O)N1CCCC21
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the ethyl 4-[6-(ethoxycarbonyl)-3-pyridazinyl]-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate (F, 145 mg, 0.29 mmol) in 2.5 ml dioxane, 1.2 ml 1N NaOH was added and the resulting mixture was stirred overnight. Acidified with 2N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent and purification of the resulting residue with flash chromatography afforded 125 mg off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 8.17 (d, 1H), 7.20 (t, 2H), 6.95 (t, 2H), 4.79 (m, 1H), 4.42 (m, 2H), 3.98 (q, 2H), 3.62 (m, 1H), 3.39 (m, 1H), 2.45 (m, 1H), 2.32 (m, 2H), 1.41 (m, 1H), 0.92 (t, 3H) ppm. ESI-MS m/z 475 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.C1COCC1.C1C(=O)N([O:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=O)C(=O)C1>C([O-])(O)=O.[Na+]>[CH:42]1[C:43]2[CH:31]([CH2:30][O:29][C:27]([N:1]3[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]3)=[O:26])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C(O)/C=C/C=C/C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)/C=C/C=C/C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The above solid (24) was taken up in saturated NaHCO3 (50 mL)/THF (50 mL). To this was added Fmoc-Osu (3.0 g, 9.0 mmol) at room temperature. The suspension became clear within 30 min. After stirring at room temperature overnight, the solution was concentrated to remove organic solvent, the resulting white suspension was acidified with 1 N HCl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give a white solid (25) (3.63 g, >100%). 1H NMR (500 MHz, CDCL3) δ 7.77 (d, J=7.5 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34 (dd, J=15.0, 11.0 Hz, 1H), 7.32 (t, J=7.5 Hz, 2H), 6.21 (dd J=15.0, 11.0 Hz, 1H), 6.09 (dd, J=15.0, 7.0 Hz, 1H), 5.85 (d, J=15.5 Hz, 1H), 4.45 (br s, 2H), 4.18 (m, 3H), 2.83 (br s, 2H), 2.31 (m, 1H), 1.72 (m, 2H), 1.26 (m, 2H); MS (ES+) m/z 404.81 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35]3)=[C:3]([O:14][CH2:15][CH2:16][CH3:17])[C:4]=1[O:12][CH3:13]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CCCOc1c(Br)ccc(OC(F)F)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1c(-c2ccc3c(c2)CNC3=O)ccc(OC(F)F)c1OC
Temperature: 85 °C
Yield: 14.3 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (300 mg, 1.115 mmol) in acetonitrile (10 mL) was added potassium carbonate (495 mg, 2.334 mmol) and propyl bromide (411 mg, 3.34 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-3-methoxy-2-propoxybenzene (Int14-F2) as a solid. A stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-propoxybenzene (300 mg, 0.964 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (625 mg, 1.926 mmol), tetrakis(triphenylphosphine) palladium(0) (37 mg, 0.032 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (199 mg, 0.771 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (40 mg, 11%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][NH:13][CH2:12]1.CCN(CC)CC>O>[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:12]1
Reactant: CC1(C)CCNC1
Reactant: Nc1cccc(F)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCN(c2cccc(N)n2)C1
Temperature: 205 °C
Yield: 78.5 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol), 3,3-dimethylpyrrolidine hydrochloride (0.73 g, 5.35 mmol) and Et3N (1.08 g, 10.7 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-amine (0.67 g, 78%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.187 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (12.82 mmol; 1968 mg) in Dichloromethane (50 mL) was added N,N-Diisopropylethylamine (38.45 mmol, 6.7 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (19.22 mmol; 3205 mg; 3.40 mL) was then added dropwise at room temperature. The resulting mixture was stirred overnight. The mixture was partitioned between DCM and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (590 mg, 13%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]#[C:16]C2C=CC(Br)=CC=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[Si](C#C)(C)C>>[C:1]1([C:7]#[C:8][C:12]2[CH:13]=[CH:14][C:9]([C:15]#[CH:16])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(C#Cc2ccccc2)cc1
Reactant: C#Cc1ccccc1
Agent: C#C[Si](C)(C)C
Product: C#Cc1ccc(C#Cc2ccccc2)cc1

Procedure:
In an especially contemplated arm extension strategy depicted in FIG. 4, in which AD represents an adamantane or diamantane group. Phenylacetylene is a starting molecule that is reacted (A1) with TBPA (supra) to yield 1,3,5,7-tetrakis[3′/4′-(phenylethynyl)phenyl]adamantane. Alternatively, phenylacetylene can be converted (B1) to 4-(phenylethynyl)phenylbromide that is subsequently reacted (C1) with trimethylsilylacetylene to form 4-(phenylethynyl)phenylacetylene. TBPA can then be reacted (with phenylethynylphenylacetylene to 1,3,5,7-tetrakis{3′/4′-[4″-(phenylethynyl)phenylethynyl]phenyl}-adarnantane. In a further extension reaction, phenylethynylphenylacetylene is reacted (2) with 1-bromo-4-iodobenzene to form 4-[4′-(phenylethynyl)phenylethynyl]phenylbromide that is further converted (C2) to 4-[4′-(phenylethynyl)phenylethynyl]acetylene. The so formed 4-[4′-(phenylethynyl)phenylethynyl]acetylene may then be reacted (A3) with TBA to yield 1,3,5,7-tetrakis-{3′/4′-[4″-(4′-(phenylethynyl)phenylethynyl)phenylethynyl]phenyl}adamantane.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([NH:16][CH:17]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:18]1=[O:37])=O)C>>[CH:1]1([CH2:6][C:7]([NH:16][C@H:17]([C:23]([C:17]2([NH2:16])[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:18]2=[O:37])=[O:24])[CH3:18])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.50 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH3:32][N:6]1[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][O:19][C:18]3[CH:21]=[C:22]4[C:26](=[CH:27][C:17]2=3)[CH2:25][CH2:24][O:23]4)[C:9]1=[O:28]
Reactant: O=C1CC[C@@H](CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.235 g, 0.623 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.04 g, 1.04 mmol) at ambient temperature. The mixture was stirred for 15 min, and iodomethane (0.28 g, 2.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 1 h, and concentrated to dryness. The residue was purified by flash chromatography (hexanes/ethyl acetate; gradient 0% to 30%) to afford 1′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (0.15 g, 62%) as colorless solid: mp 72-76° C.; 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.5, 7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.46-6.38 (m, 2H), 4.77 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.03-3.75 (m, 3H), 3.11-2.83 (m, 5H), 2.61-2.42 (m, 1H), 2.42-2.27 (m, 1H), 2.26-2.07 (m, 1H), 2.03-1.84 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.4, 178.4, 175.1, 175.0, 161.8, 161.3, 161.2, 142.1, 141.9, 132.5, 132.4, 128.9 (2C), 124.3, 124.2, 123.7 (2C), 120.0, 119.9, 119.7, 119.6, 118.6, 118.5, 108.0, 93.2, 80.5, 72.3, 58.1, 58.0, 57.5 (2C), 43.0, 42.9, 29.3, 29.2, 28.9, 28.7 (2C), 22.6 (2C); MS (ES+) m/z 391.1 (M+1).
Reaction SMILES: Br[C:2]1C(Br)=C(NC([C@@H]2C[C@H]2C)=O)SN=1.[Br:15][C:16]1[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:18][CH:17]=1.O>O1CCCC1.C(OCC)(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]([OH:24])([CH3:2])[CH3:23])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cccc(Br)n1
Yield: 98 %

Procedure:
Add a solution of methyl magnesium bromide (3.0; M, 9.7; mL, 29.09; mmol) in tetrahydrofuran dropwise over 20; min to a cooled solution of 1-(6-bromo-pyridin-2-yl)-ethanone (5; g, 24.25; mmol) in anhydrous tetrahydrofuran (48.5; mL) at 0° C. Upon completion of the reaction, add water (exothermic), dilute with ethyl acetate (50; mL) and separate the layers. Extract the aqueous layer once with ethyl acetate (50; mL). Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (5.69; g, 98%) that is used without further purification. 1H NMR (CDCl3) δ 1.55; (s, 6H), 4.07; (s, 1H), 6.59; (t, 1H), 7.37; (t, 2H), 7.55; (t, 1H).
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.CCOC(C)=O.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1
Reactant: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Galactal 7' (0.100 g, 0.304 mmol) in 5 mL dry CH2Cl2 at 0° C. under a N2 atmosphere was treated with 10 mL Murray solution (freshly prepared) and stirred at 0° C. for 40 min. TLC (1:1 EtOAc:hex) showed no trace of 7'. Solvents were evaporated using a dry N2 stream. The residual epoxide of 7' was kept on a vac. line ~2 h. To the epoxide under a N2 atmosphere was added a solution of glucal derivative 3' (0.150 g, 0.496 mmol) in 3 mL dry THF. On cooling to -78° C., 1.0M ZnCl2 in Et2O (0.50 mL, 0.50 mmol) was added. The mixture was allowed to slowly warm to r.t. (over ~2 h) and stirred overnight. TLC (1:1 EtOAc:hex) showed that the reaction was complete. Saturated aq. NaHCO3 (20 mL) was added, and the mixture was then extracted with EtOAc (3×20 mL). The organic layer was dried over MgSO4. Column chromatography on silica (1:3 EtOAc:hex) afforded diol 18' as a colorless solid. Yield: 173 mg (89%). [α]D23 -9.8° (c 1.0, CH2Cl2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][C:33]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)=[O:28])=[C:22]([F:45])[CH:21]=1)[CH3:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:31]=[N:32][C:33]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=3)=[O:28])=[C:22]([F:45])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cnc(C(C)(C)CO)c(C(F)(F)F)c2)c(F)c1
Yield: 53.1 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (20 mg, 0.032 mmol) in TFA in DCM (5 mL, 3.72 mmol) was stirred at 25° C. After LCMS analysis showed the starting material was consumed, the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC (under neutral condition) to yield a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (8.8 mg, 0.017 mmol, 54% yield): 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.24-7.21 (m, 2H), 5.98 (s, 1H), 4.13-4.08 (m, 2H), 3.82 (s, 4H), 1.37 (t, J=7.0 Hz, 9H); ES-LCMS m/z: 508.2 (M+H).