Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C([Mg]Cl)(C)C>O1CCCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[CH:5][C:6]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: -30 °C
Yield: 88 %

Procedure:
4-Bromo-3-methyl-benzoic acid methyl ester (6 g, 26.19 mmol) was dissolved into anhydrous tetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (3.81 g, 39.29 mmol) was then added to the solution in one portion. Isopropyl magnesium chloride (39 mL, 2M soln. in THF, 78.6 mmol) was slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride was added with stirring. The reaction was diluted with diethyl ether and extracted. The organic layer was collected and washed with cold water (2×) and brine. The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated. The 4-Bromo-N-methoxy-3,N-dimethyl-benzamide (5.94 g, 23.05 mmol) was obtained in purified form after flash column chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:12][CH2:13][CH2:14][Cl:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12>>[Cl:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[N:5]=[CH:4][N:3]=[C:2]2[NH:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]2[O:26][CH2:27][O:28][C:20]=12
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCl
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: COc1cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c2cc1OCCCl
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 59% yield; NMR Spectrum: (CDCl3) 3.95 (t, 2H), 4.05 (s, 3H), 4.4 (t, 2H), 6.1 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.75 (s, 1H); Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([NH:24]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[CH:10]=[CH:9]2>[Pd].CO>[CH3:1][O:2][C:3](=[O:35])[CH:4]([NH2:24])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[CH:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a flame dried 500 mL of round bottom flask was added 2-benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-acrylic acid methyl ester (2.24 h, 4.36 mmol), methanol (100 mL) and 10% palladium on charcoal (0.52 g). The mixture was degassed and purged with hydrogen five times. It was stirred at room temperature for 1 h and filtered through a pad of celite. Solvents were removed and the residue was subjected to flash chromatography using ethyl acetate/hexanes (1:1 and 2:1) containing 1% triethylamine to afford the tile compound as a colorless viscous liquid (1.27 g, 76%), which solidified upon cooling. 1H-NMR (CD3CN, 500 MHz) δ 7.82 (d, J=8.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.22 (dd, J=8.6, 1.5 Hz, 1H), 6.72 (d, J=3.7 Hz, 1H), 3.70 (dd, J=7.3, 6.1 Hz, 1H), 3.65 (s, 3H), 3.38-3.34 (m, 2H), 3.08 (dd, J=13.4, 5.8 Hz, 1H), 2.95 (dd, J=13.4, 7.3 Hz, 1H), 0.82-0.79 (m, 2H), −0.05 (s, 9H). 13C-NMR (CDCl3, 125 MHz) δ 176.0, 134.4, 133.4, 131.1, 127.9, 126.4, 122.4, 113.1, 107.7, 56.6, 51.7, 50.8, 41.3, 10.1, −2.7. Mass spec. 383.16 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](C(OC)=O)=[CH:8][CH:9]=2)[N:4](S(C(F)(F)F)(=O)=O)[N:3]=1.[C:22]([O-])([O-:24])=[O:23].[K+].[K+]>CO.O.CCOC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([OH:24])=[O:23])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(C)nn(S(=O)(=O)C(F)(F)F)c2c1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a solution of methyl 3-methyl-1-[(trifluoromethyl)sulfonyl]-1H-indazole-6-carboxylate (590 mg, 1.83 mmol) in methanol/water (3:1, 72 mL) was added K2CO3 (1.01 g, 7.31 mmol) and the mixture was heated at reflux for 2 hours. The reaction was cooled to room temperature and the methanol was removed under reduced pressure. The aqueous solution was acidified to pH 3-3.5 with KHSO4. The solid was isolated by filtration, dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to provide the title compound (259 mg, 80%).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38](=[O:39])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:69][CH2:70][CH3:71])[O:72][CH2:73][CH3:74])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq), DIEA (2.5 eq) and HBTU (1.1 eq). The resulting mixture was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][O:13][CH3:14].Cl.CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
10 g of 6-chloro-pyridine-2-carboxylic acid are dissolved in 50 ml of thionyl chloride and heated under reflux for 3.5 h. The solution is cooled and freed from excess thionyl chloride under reduced pressure. The crude product is taken up in 60 ml of methylene chloride and treated with 7.22 g of N,O-dimethyl-hydroxylamine•hydrochloride. 25 ml of NEt3 in 30 ml of CH2Cl2 are added while cooling with ice and the solution is stirred at RT for 1.5 h., the suspension is filtered and the filtrate is washed with dilute sodium hydroxide solution and saturated sodium chloride solution and dried. After concentration of the solution 13.12 g of 6-chloro-pyridine-2-carboxylic acid methoxy-methyl-amide are obtained as the crude product. 6.7 g of this amide in 40 ml of THF are added dropwise at −78° C. to a solution of 40 ml of n-BuLi (1.6M in hexane) and 15 g of 1,4-dibromobenzene in 140 ml of THF. The solution is stirred at −78° C. for 2 h. and at 0° C. for 1 h. and then treated with 60 ml of 2M HCl. The phases are separated, the inorganic phase is extracted with 50 ml of ether and the organic phases are washed with sat. NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified over silica gel with ethyl acetate:hexane (6:1) and recrystallized from ethyl acetate/hexane. There are obtained 6.75 g of (4-bromo-phenyl)-(6-chloro-pyridin-3-yl)-methanone, m.p 127.4° C., MS: m/e 295 (M, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]([CH2:33][C:34](Cl)=[O:35])[N:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:34](=[O:35])[CH2:33][N:23]2[C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[N:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
1.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 3.2 g (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 1 g triethylamine in 50 mL dichlormethane. The reaction was stirred 1 day at RT, evaporated and purified by chromatography on silica gel (petrolether/diethylether:1/1) to yield 3.1 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26]([NH2:28])[CH3:27].O1CCCC1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([OH:24])[CH2:25][NH:28][CH2:26][CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@H]2CO2)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC[C@@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 13b) (110 mg), ethylamine (70% aqueous solution, 2 mL) and tetrahydrofuran (10 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The resulting white solid was filtered off to give the titled compound (109 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1.C(OC(N1CCOC[C@H]1C(O)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Agent: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Agent: Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
Using the same procedure for the preparation of 16A, reaction of compound 2A with (S)-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (19A) afforded the title compound 20A as a white powder in similar yield. Its 1H NMR and LCMS data are identical with those of compound 16A.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[CH3:1][Si:2]([CH3:17])([CH3:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Reactant: Cc1cccc(CO)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1cccc(C)c1

Procedure:
This compound was prepared according to a process similar to that described in step 5.1 by reacting ethyl 6-trimethylsilyl-1H-indole-2-carboxylate prepared according to the process described in step 9.2 with (3-methylphenyl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel to give the expected product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:16][C:17](=[O:31])[CH:18]([NH2:30])[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:32][C@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.CCCCCC.ClCCl>[CH2:22]([NH:21][C:19](=[O:20])[CH:18]([NH:30][C:34](=[O:35])[C@H:33]([Br:32])[CH:37]([CH3:39])[CH3:38])[C:17]([NH:16][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(C)[C@@H](Br)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](Br)C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reaction time: 18 h
Yield: 67 %

Procedure:
Combine N,N′-diphenethyl-2-aminomalonamide trifluoroacetic acid salt (0.285 g, 0.655 mmol) and dichloromethane (5 mL). Add (R)-2-bromo-3-methylbutyric acid (0.118 g, 0.655 mmol), N-methylmorpholine (0.10 mL, 0.983 mmol), and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloric acid salt (0.14 g, 0.725 mmol), and 1 -hydroxybenztriazole hydrate (0.10 g, 0.72 mmol). After 18 hours, evaporate the reaction mixture in vacuo, dilute the concentrated reaction mixture with ethyl acetate, extract with an aqueous 5% sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Saturate each of the aqueous layers with sodium chloride and extract four times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound (67%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C@H](C(O)=O)CCC(=O)N.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:45]([O:49][C:50](=[O:58])[C@H:51]([CH2:53][CH2:54][C:55](=[O:57])[NH2:56])[NH2:52])([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.C(N(CC)CC)C>[C:45]([O:49][C:50](=[O:58])[C@H:51]([CH2:53][CH2:54][C:55](=[O:57])[NH2:56])[NH:52][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(=O)CC[C@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NC(=O)Cc1ccccc1

Procedure:
As shown in reaction scheme I, (FIG. 1) phenylacetic acid 1 (1250 mg; 1.84 mmol) was coupled to a protected glutamine 4 (protected in this case by a lower alkyl such as t-butyl group) by first dissolving the phenyl acetic acid in anhydrous dimethylformamide (8 ml). N-hydroxysuccinimide 2 (254 mg; 2.2 mmol) was added followed by addition of dicyclohexylcarbodiimide (456 mg; 2.2 mmol) to produce N-succinimidphenylacetate 3. The reaction mixture was stirred for ten hours and precipitated dicyclohexyl urea was filtered off. The filtrate containing 3 was returned to a reaction flask to which a carboxy-protected glutamine such as L-glutamine t-butyl ester hydrochloride 4 (439 mg; 1.84 mmol) was added. pH was adjusted to 9 with triethylamine, and the reaction mixture was stirred for 24 hours to produce phenylacetylglutamine t-butyl ester 5. Precipitated crystals were filtered off, and the filtrate containing 5 after concentration in vacuum was purified by column chromatoqraphy on silica gel using ethyl acetate-methanol (95:5) as an eluent. Yield 299 mg of desired material, mp. 132-133° C. 1H-NMR (60 MHz) (CDCl3) δppm: 1.4 (s,9H); 1.8-2.4 (mult,4H); 3.6 (s,2H); 4.5 (mult,1H); 5.5 (broad,1H); 6.3 (mult,2H); 7.3 (s,5H). Mass Spectrum (DEI/DIP): 321 (M+H)+, 320 M+, 264 (M-C4H8)+, 247 (M-OC4H9)+. The t-butyl ester 5 (295 mg; 0.924 mmole) of phenylacetylglutamine was deprotected (i.e., the t-butyl carboxy protecting group was removed) by dissolving 5 in methylene chloride (4 ml) and adding trifluoroacetic acid (4 ml). After 45 minutes, the reaction mixture was evaporated in vacuum and the oily residue crystallized from tetrahydrofurane (THF), to give colorless crystals of phenylacetyl glutamine 6. 1H-NMR(300 MHz)(CDCl3 /CD3OD) δ ppm: 1.9-2.05 (mult,1H); 2.13-2.36 (mult,3H); 3:58 (s,2H); 4.5 (mult,1H); 7.23-7.38 (mult,5H); Mass Spectrum (pos FAB, MeOH):265 (M+H)+ (100%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.CC(C[AlH]CC(C)C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH2:35]([OH:38])[CH2:36][OH:37]>C(Cl)Cl.C1C=CC=CC=1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:38][CH2:35][CH2:36][O:37]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: OCCO
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(I)ccc1C1OCCO1
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (1.89 g; 6.38 mmol, Note 1) in CH2Cl2 (15 mL) at −40° C. was added DIBAL-H (9.6 mL of a 1.0M solution in CH2Cl2; 9.6 mmol), dropwise over 5 min. The mixture was stirred 30 min, quenched by dropwise addition of MeOH and removed from the cooling bath. To the still-cold mixture was slowly added HCl (10 mL of a 6M solution), and after stirring 30 min at room temperature the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in PhH (15 mL), along with TsOH.H2O (0.12 g; 0.64 mmol) and ethylene glycol (3.5 mL; 63 mmol), and the solution was heated under reflux for 2 h using a Dean-Stark trap to remove water. Upon cooling, the mixture was diluted with <solvent>, washed (water, brine), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.00-4.11 (m, 2H), 4.11-4.24 (m, 2H), 6.06 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.99 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(Cl)Cl.[CH3:12][N:13](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.[Zn].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]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
The mixture of 2,5-dibromopyridine (4.74 g, 20.0 mmol), zinc cyanide (1.40 g, 12.0 mmol), zinc dust (0.059 g, 0.90 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.36 g, 0.44 mmol) in 25 ml of DMF was heated at reflux for 5 h, cooled to RT, diluted with H2O, extracted with EtOAc, the organic portion was washed with brine, the solvents were removed, the crude compound was purified by flash column chromatography (5 to 15% of EtOAc in hexanes), the titled compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH:12]([OH:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@@H:7]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC1CC(O)[C@@H](CCCCCC)C(=O)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC1CC(=O)[C@@H](CCCCCC)C(=O)O1

Procedure:
(M)(b) 3 g of a diastereomer mixture of tetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-2-one were dissolved in 300 ml of acetone. 3 ml of Jones' reagent were added dropwise while stirring in such a manner that the temperature did not exceed 25° C. After 3 hours the reaction mixture was poured into 700 ml of H2O. The lactone precipitated out and was filtered off. After recrystallization in ether/n-hexane there were obtained 1.7 g of tetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one, m.p. 112.5°-113.5° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:80])[NH:6][C:7]2[CH:78]=[CH:77][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:76]=[CH:75][C:24]([C:25]([N:27]([CH3:74])[CH2:28][C@@H:29]([O:66][Si](C(C)(C)C)(C)C)[C@H:30]([O:58][Si](C(C)(C)C)(C)C)[C@@H:31]([O:50][Si](C(C)(C)C)(C)C)[C@@H:32]([O:42][Si](C(C)(C)C)(C)C)[CH2:33][O:34][Si](C(C)(C)C)(C)C)=[O:26])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:79])[CH:8]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]1([NH:4][C:5](=[O:80])[NH:6][C:7]2[CH:78]=[CH:77][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:76]=[CH:75][C:24]([C:25]([N:27]([CH3:74])[CH2:28][C@@H:29]([OH:66])[C@H:30]([OH:58])[C@@H:31]([OH:50])[C@@H:32]([OH:42])[CH2:33][OH:34])=[O:26])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:79])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CN(C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 243 (250 mg, 0.228 mmol) in THF (5 mL) was added TBAF (1.0M in THF) (0.273 mL, 0.273 mmol) and the reaction mixture was stirred for 2 hr at RT before concentration. The residue was purified by Biotage, (MeOH/DCM, 20-50%, SNAP 25 g cartridge) and Gilson (Phenomenex, Luna, 15μ, C18(2) 100A, 250×50.00 mm, 15 μm, 0.05% of formic acid in both MeOH/H2O, 40-90%, flow=30 mL/min), to afford title compound 244 (10 mg, 0.016 mmol, 7% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.72 (d, 1H, J=3.9 Hz), 8.47 (s, br, 1H), 8.19-8.13 (m, 2H), 8.13-8.00 (m, 1H), 7.65 (dd, 1H, J1=2.5 Hz, J2=13.1 Hz), 7.29 (t, 1H, J=8.81 Hz), 7.20-7.17 (m, 1H), 6.64 (d, 1H, J=5.3 Hz), 4.20-4.18 (m, 0.45H), 4.07-4.04 (m, 0.55H), 3.83-3.53 (m, 7H), 3.17 (s, 3H), 2.62-2.57 (m, 1H), 0.78-0.73 (m, 2H), 0.54-0.50 (m, 2H). MS: 642.6 (MH+).