Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH:48]1[CH:53]=[N:52][CH:51]=[C:50]([C:54]([NH:56][CH2:57][C:58](O)=[O:59])=[O:55])[CH:49]=1>CN(C=O)C>[Cl:19][C:14]1[C:13]2[C:12]3[C:11](=[C:22]([CH3:23])[O:21][N:20]=3)[C:10](=[O:24])[N:9]([CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:58]([CH2:57][NH:56][C:54](=[O:55])[C:50]4[CH:49]=[CH:48][CH:53]=[N:52][CH:51]=4)=[O:59])[CH2:4]3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CNC(=O)c1cccnc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Agent: I
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CNC(=O)c3cccnc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one hydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol), 1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethyl amine (0.10 mL, 0.58 mmol), (5 mg, cat.), and nicotinuric acid (44 mg, 0.24 mmol) in DMF(6 mL) and the mixture stirred overnight at rt. The mixture was then concentrated in vacuo and the residue taken up in water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was loaded onto a silica gel column and eluted with MeOH/CH2Cl2 which allowed for the recovery of 87 mg (92%) of the title compound as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:21]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:20]=3[CH2:19][CH:18]([CH3:29])[NH:17][N:16]=2)=[CH:11][CH:10]=1.[CH:30](O)=[O:31]>>[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:21]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:20]=3[CH2:19][CH:18]([CH3:29])[N:17]([CH:30]=[O:31])[N:16]=2)=[CH:11][CH:10]=1)=[O:3]
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Product: CC1Cc2cc3c(cc2C(c2ccc(NC=O)cc2)=NN1C=O)OCO3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6.0 ml (0.104 mol) of acetic anhydride 3.0 ml (0.08 mol) of 100% formic acid were added dropwise at 0° C. during 5 minutes while constant stirring. The stirring was continued at 50° C. for 15 minutes. Thereafter 1 g (3.3 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine was added to the thus-prepared mixed anhydride. The reaction mixture was stirred at 25° C. for 1.5 hours, then poured into ice-water, the precipitate formed was filtered, washed with 4×5 ml of distilled water and dried at 80° C. to give 0.80 g of raw product. After crystallization from 3 ml of ethyl acetate 0.65 g (56.2%) of the aimed product was obtained, m.p.: 193°-195° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138–140° C.; 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1 H), 6.76 (d, J=2.2 Hz, 1 H), 4.34–4.24 (m, 2 H), 4.10–4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.94–1.74 (m, 2 H), 1.06–0.98 (m, 1 H), 0.95–0.86 (m, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.44 (m, 2 H), 0.35–0.22 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2BrCl (M+H)+: 438.0584; found m/z 438.0605.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH2:70])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH:70][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (28.7 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (37.8 mg, purity 98.5%). MS m/z [M+H]+ calc'd for C29H25ClN4O8, 593.14. found 593.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2.C[O-].[Na+]>CO.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2
Reactant: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](COC(C)=O)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 198.1 %

Procedure:
2,5,6-Trichloro-3-propionyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.44, 90 mg, 0.21 mmol) was dissolved in dry MeOH (15 mL) to which was added sodium methoxide (14 mg, 0.26 mmol). The solution was stirred at room temperature for 40 min, and the solvent was then removed under vacuum. The residue was suspended in brine (50 mL) and water (5 mL), and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in 10% MeOH/CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from boiling EtOAc to yield 170 mg (81%) of 4.47 as a white crystalline solid: mp 239-240 C; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.44 (s, 1H), 6.06 (d, 1H), 5.44-5.41 (m, 2H, D2O exch.), 5.29 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.17 (s, 1H), 3.74 (m, 2H), 3.04 (dd, 2H), 1.12 (t, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 195.17, 132.45, 132.41, 126.13, 125.91, 125.84, 122.09, 115.39, 112.60, 88.90, 86.36, 71.58, 69.54, 60.97, 35.05, 7.98. HRMS (EI) m/z calcd. for C16H16Cl3NO5 407.0094. found 407.0089. Anal calcd for C16H16Cl3NO5: C, 47.02; H, 3.95; N, 3.43. Found: C, 46.85; H, 3.96; N, 3.47.
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:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[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[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1N1CCOCC1)[NH2:38]>>[CH2:2]1[C:35]2[C:41](=[CH:40][CH:39]=[C:37]([NH:38][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-fluoro-4-(4-morpholinyl)aniline by a procedure similar to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.97 (t, 4H, J=4.5 Hz), 3.76 (t, 4H, J=4.5 Hz), 6.61 (d, 1H, J=5.2 Hz), 6.96 (t, 1H, J=9.4 Hz), 7.17 (t, 1H, J=6.8 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.37 (d, 2H, J=7.9 Hz), 7.48-7.55 (m, 2H), 7.63 (t, 1H, J=8.3 Hz), 7.73 (d, 1H, J=15.5 Hz), 7.85 (d, 1H, J=8.8 Hz), 8.06 (s, 1H), 8.32 (d, 1H, J=5.2 Hz), 8.47 (d, 1H, J=8.0 Hz), 8.90 (d, 1H, J=6.9 Hz), 9.63 (s, 1H), 10.97 (s, 1H); ESIMS (M+H)+=622.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][C:25]=3[F:27])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 102.5 °C
Yield: 94.8 %

Procedure:
Bis(tricyclohexylphosphine)palladium (250 mg, 0.375 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (4.6 g, 12.5 mmol) and 2,4-difluorophenylboronic acid (3.92 g, 25 mmol) in 125 mL dioxane. Argon was bubbled through the solution for 5 min. H2O (12.5 mL) was then added followed by dried, powdered potassium carbonate (3.45 g, 25 mmol). The mixture was heated to 100-105° C. under argon for 1 hr, cooled and distributed between 100 mL ethyl acetate and 100 mL H2O. The ethyl acetate layer was washed with saturated NaCl, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to yield 4.2 g of 3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.O.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][C@H:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(=O)Oc1ccc([C@H](ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc([C@H](O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (20.3 g) in dimethylformamide (60 ml) was added 2-(2-amino-4-thiazolyl)glyoxylic acid (7.8 g). the mixture was allowed to stand until it reached room temperature, and stirred overnight. The reaction mixture was then poured into ice-cooled water (400 ml), and the pH of the resulting mixture was adjusted to 2.0 with 1 N hydrochloric acid. The mixture was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was dissolved in a small amount of chloroform. This solution was added dropwise to ether. The formed crystals were collected by filtration and washed with ether, giving 22.3 g of the objective compound as pale yellow crystals.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:46]=[CH:45][C:10](/[CH:11]=[CH:12]/[CH:13]([S:22]([CH:25](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:24])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([O-])=O.O.NN>[Pd].C(Cl)(Cl)Cl>[NH2:4][C:7]1[CH:46]=[CH:45][C:10](/[CH:11]=[CH:12]/[CH:13]([S:22]([CH:25](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:23])=[O:24])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(/C=C/c2ccc([N+](=O)[O-])cc2)S(=O)(=O)C(/C=C/c2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(/C=C/c2ccc(N)cc2)S(=O)(=O)C(/C=C/c2ccc(N)cc2)c2ccc(OC)cc2)cc1
Yield: 52 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser, 5% Pd/C (0.073 g) was taken and 20 mL ethanol was added slowly. Compound 6d (0.5 g, 1.4 mmol) and hydrazine hydrate (1.24 g, 38.7 mmol) were added to the content of the flask and refluxed for 6 h. Completion of the reaction was monitored by TLC (CHCl3 on silica gel plate), filtered the reaction mixture through celite and concentrated the reaction mixture to 50% volume. The concentrated mixture was poured onto crushed ice, the solid formed was filtered, washed with cooled water, dried to get the desired product 6e. Yield: 52%; light yellow solid mp 164-168° C. 1H NMR: δ 3.80 (s, 3H, OCH3), 4.22 (s, 2H, CH2), 4.04 (br s, 2H, NH2), 6.42 (d, 1H, J=15.6 Hz, ═CH), 6.60-7.31 (m, 9H, Ar—H+ vinylic). Anal. (C16H17NO3S): C, H, N.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>O1CCOCC1>[CH:3]1([O:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(F)cc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
Suspend sodium hydride (336 mg, 2.8 mmol, 60% suspension in mineral oil) in anhydrous 1,4-dioxane (10 mL) under nitrogen atmosphere. Add cyclopentanol (620 mg, 7.2 mmol) and stir the resulting solution for 30 min. Add the preformed solution (3.35 mL, 2.4 mmol) to neat 4-fluorobenzonitrile (240 mg, 2 mmol) in a microwave tube and heat the sealed mixture at 100° C. for 30 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate (300 mg, 80%). GC-MS m/z: 187 (M+).
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].[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][C@H:27]([C@@H:29]1[C@:47]2([CH3:48])[C@H:32]([C@H:33]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:36]([CH2:37][C@H:38]([CH2:40][CH2:41]2)O)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH3:23].OS(O)(=O)=O>C(Cl)Cl>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][C@@H:38]1[CH2:37][C:36]2[C@@:42]([CH3:43])([C@@H:44]3[C@@H:33]([CH2:34][CH:35]=2)[C@@H:32]2[CH2:31][CH2:30][C@H:29]([C@@H:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:21])[CH3:23])[CH3:28])[C@@:47]2([CH3:48])[CH2:46][CH2:45]3)[CH2:41][CH2:40]1)=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
DCPLA (1 g), cholesterol (1 g), CH2Cl2 (20 ml), and concentrated H2SO4 (1 μl) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the DCPLA-cholesteryl ester. Linoleic acid (1 g), cholesterol (1 g), CH2Cl2 (20 ml), and concentrated H2SO4 (20 μl) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the cholesteryl linoleate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][C:24]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:12][N:8]1[C:6](=[O:7])[CH:33]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:26])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: NCc1ccccc1
Product: COc1ccc(CON=C2C[C@@H](C(=O)NCc3ccccc3)N(C(=O)C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and benzylamine the title compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=548.4.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[N:8]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:19]#[N:20].C[Si](Cl)(C)C.[CH2:33]([Mg]Cl)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CCOCC>[F:15][C:16]1[CH:17]=[C:18]([C:19]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[N:8]=2)([NH2:20])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: COc1cccc(Br)n1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)n1
Temperature: -37.5 °C
Reaction time: 0.33 h

Procedure:
To an oven-dried round bottomed flask was added nBuLi (2.5 M in hexanes, 3.6 mL, 9.0 mmol, 1.1 eq) at −45 to −40° C. under N2. An Et2O solution (12 mL) of 2-bromo-6-methoxypyridine (1 mL, 8.14 mmol) was added dropwise at the above temperature. The resulting light brownish yellow solution was stirred at −40 to −35° C. for 20 min. The mixture was cooled to −78° C., an Et2O solution (3 ml) of 3-fluoro-5-trifluoromethyl-benzonitrile (1.50 g, 7.94 mmol) was added dropwise at −78 to −70° C. The resulting solution was stirred at this temperature for 1 h. Pretreated TMSCl (1.08 mL, 8.55 mmol, 1.05 eq) was added dropwise at −78° C. The mixture was allowed to warm to room temperature for 30 min, and then stirred at room temperature for 30 min. The reaction mixture was cooled back to −78° C., and benzyl magnesium chloride (4.1 ml, 8.2 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 0.8 h, and then warmed up to room temperature for 1 h. The reaction mixture was quenched by adding sat'd NH4Cl and 1N HCl, and stirred for 10 min. The resulting solution was extracted with EtOAc, washed with 1N NaOH, saturated NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(6-methoxypyridin-2-yl)-2-phenylethanamine as light brownish gum (1.42 g, yield: 44.7%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=3.20 min, 391.12 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (s, 1 H), 7.47-7.57 (m, 2 H), 7.11-7.21 (m, 4 H), 6.99 (d, J=7.6 Hz, 1 H), 6.80 (dd, J=7.6, 2.0 Hz, 2 H), 6.61 (d, J=8.1 Hz, 1 H), 3.93 (s, 3H), 3.92 (d, J=13 Hz, 1 H) 3.40 (d, J=13 Hz, 1 H).
Reaction SMILES: [CH2:1]1[S:4][CH:2]1[CH3:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>>[SH:4][CH:2]([CH3:3])[CH2:1][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CC1CS1
Reactant: CN1CCNCC1
Product: CC(S)CN1CCN(C)CC1

Procedure:
1-(2-Mercaptopropyl)-4-methylpiperazine is prepared by heating a mixture of propylene sulphide (19 cc) and N-methylpiperazine (29 cc) at 100° C. for 16 hours. In this manner, a colourless oil (32 g) which distils at 105° C. at 1.3 kPa is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C1(C)C=CC=CC=1>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:28][C@@H:26]2[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:30][C@@:18]4([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:19][C:20](=[O:29])[C@@H:21]3[CH2:27]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: C1CN2CCN1CC2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Reaction time: 0.25 h

Procedure:
A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (22.1 g, 44.8 mmol) and DABCO (8.5 g, 76.7 mmol) in toluene (88 mL) may be stirred at room temperature. To this solution may be added a solution of 4-bromobenzene-1-sulfonyl chloride 17.2 g, 67.2 mmol) in toluene (44 mL). After the addition is complete the reaction mixture can be quenched with 10% aqueous sodium carbonate (110 mL) and the mixture stirred for 15 min. Tetrahydrofuran (44 mL) can be added and the mixture is washed with 0.5 M HCl, water, and then saturated aqueous sodium chloride. The organic layer may be dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure and dried to provide the title compound (27.7 g, 87% yield), which may be used without further purification.