Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[C:6]([I:24])[CH:5]=1>C(O)C>[F:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH2:13])=[C:6]([I:24])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cnc(F)cc1I
Agent: NN
Solvent: CCO
Product: NCCOc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Add hydrazine (70 mg, 2.12 mmol) to a solution of 2-[2-(6-fluoro-4-iodo-pyridin-3-yloxy)-ethyl]-isoindole-1,3-dione (440 mg, 1.06 mmol) in ethanol (10 mL). Stir the solution at RT overnight. Filter to remove the solid and concentrate the filtrate to a light yellow solid. Purify by column chromatography (10% 2 M ammonia in methanol in methylene chloride) to afford the title compound as a light yellow oil (250 mg, 83.8%). 1H NMR (400 MHz, CD3CN) δ 2.12 (s, 2H), 3.03 (t, J=5.2 Hz, 2H), 4.10 (t, J=5.2 Hz, 2H), 7.47 (d, J=4.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][CH:38]([NH2:42])[CH2:39][O:40][CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:42][CH:38]([CH3:37])[CH2:39][O:40][CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxy isopropylamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.17 (d, J=8.6 Hz, 1 H), 8.56 (s, 1 H), 7.75 (s, 1 H), 7.22 (m, 2 H), 7.02 (t, J=8.7 Hz, 2 H), 4.43-4.33 (m, 3 H), 4.13 (s, 2 H), 3.48 (d, J=4.7 Hz, 2 H), 3.41 (s, 3 H), 3.38-3.33 (n, 4 H), 3.05 (t, J=6.5 Hz, 2 H), 2.17 (m, 2 H), 1.97-1.92 (m, 4 H), 1.31 (d, J=7.0 Hz, 3 H); HRMS C27H33FN4O6S (M+H)+ calcd 561.2105, found 561.2189.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13](C(OC(C)(C)C)=O)[NH2:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[ClH:22]>O1CCOCC1>[ClH:22].[NH:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH2:14]
Reactant: COC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NN)cc1OC
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
tert-butyl 1-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate #112) (4.86 g, 16.40 mmol) was added to a 4M solution of hydrogen chloride (61.5 mL, 246 mmol) in dioxane. The resulting solution was stirred at 20° C. for 5 hours. The reaction mixture was evaporated to dryness and the crude residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give methyl 4-hydrazinyl-2-methoxybenzoate hydrochloride (3.50 g, 92%) as a pale green solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)(C)OC(=O)OCI
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC(C)(C)C)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 95.9 %

Procedure:
In the same manner as in Example 81, 214 mg of the title compound was prepared from 176 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 135 mg of t-butoxycarbonyloxymethyl iodide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a mixture of 2-(3-bromo-5-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.3 g, 7.9 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×20 mL), washed with saturated aqueous sodium bicarbonate solution (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 16%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.2, 408.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][NH:14][CH3:15].O>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:15]
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 6-bromomethylnicotinate (350 mg) in tetrahydrofuran (5 ml) was added a 50% aqueous dimethylamine solution (3 ml), and the mixture was vigorously stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=100:1) to obtain methyl 6-(dimethylamino)methylnicotinate (276 mg) as brownish powder.
Reaction SMILES: [CH:1]1([C@H:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13][CH:12]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(C(O)=[O:25])=CN=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C@H:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:25])=[N:13][CH:12]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1ccc(C(=O)N[C@H](C)C2CCCCC2)cn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)c1ccc(CO)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of (R)-N-(1-cyclohexylethyl)-6-methylnicotinamide (2.28 g, 9.3 mmol prepared from the starting 6-methylnicotinic acid) in CHCl3 was added MCPBA (2.24 g, 1.4 eq) and stirred for 2 h at rt. Saturated aqueous NaHCO3 was added and the organics extracted with CH2Cl2, dried over Na2SO4 and concentrated under reduced vacuum. The residue was dissolved in a minimal amount of acetic anhydride and heated to 125° C. for 40 min. The crude mixture was cooled to rt and aqueous NaHCO3 added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was stirred in MeOH (15 mL) and K2CO3 (1 g) for 2 h, concentrated under reduced pressure and partitioned between EtOAc and H2O, Solvent removal and purification by column chromatography (silica gel) using 30-100% EtOAc/hexanes afforded 3.2a as a white solid (920 mg, 38%): 1H-NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.13 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1 H), 5.96 (d, J=8.0 Hz, 1H), 4.84 (s, 2H), 4.15-4.08 (m, 1 H), 1.85-1.04 (m, 14 H)); LC-MS (220 nm), >98%, 263.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCc1cccnc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
In a round-bottom flask a suspension of 4-amino-benzoic acid (2 g, 14.58 mmol), C-pyridin-3-yl-methylamine (1.48 mL, 14.58 mmol), hydroxybenzotriazole (HOBt, 2.17 g, 16.04 mmol) and triethylamine (4.06 mL, 29.16 mmol) in dichloromethane (150 mL) is cooled to 0° C. and EDCI*HCl (3.08 g, 16.04 mmol) is added. The reaction mixture is stirred at room temperature for 20 hours. The solvent is removed in vacuo and ice cooled water is added. The precipitate is collected by filtration, washed once with 1 N NaOH, three times with water, two times with petroleum ether and dried in vacuo to give the title compound (2.56 g) as a solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C>ClCCl>[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:26])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a suspension of 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (750 mg, 2.76 mmol) in dry dichloromethane (10 mL) was added oxalyl chloride (0.481 mL, 5.62 mmol, 2.0 eq.) then a catalytic amount of DMF. After 1 h, the reaction mixture was filtered through a pad of diatomaceous earth, then the solvent was removed under reduced pressure. The residue was treated with excess concentrated ammonium hydroxide in THF (5 mL each). The layers were separated by the addition of brine (10 mL); then the aqueous layer was extracted with THF (2×20 mL). The combined extracts were concentrated to dryness under reduced pressure to give the desired amide as a white solid (602 mg, 93%) after drying under vacuum at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH3:34]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[NH:34]
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(NC(=N)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.059 g) was added to a mixture of 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.105 g), a 2M solution of ammonia in methanol (3 ml) and chloroform (1 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.074 g); NMR Spectrum: (CDCl3) 1.39-1.53 (m, 2H), 1.87-2.02 (q, 5H), 2.29 (s, 3H), 2.36 (s, 6H), 2.9 (d, 2H), 4.01 (m, 5H), 5.79 (br s, 1H), 7.16 (s, 1H), 7.19 (m, 3H), 7.87 (s, 1H), 8.57 (s, 1H); Mass Spectrum: M+H+ 449.
Reaction SMILES: Br.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1.[C:14]([OH:17])(=O)[CH3:15]>>[OH:17][C:14]1[CH:15]=[CH:12][C:8]([N:10]2[C:11](=[O:13])[CH2:12][C:8]([CH2:7][C:3]3[NH:2][CH:6]=[CH:5][N:4]=3)=[N:9]2)=[CH:7][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C1CC(Cc2ncc[nH]2)=NN1
Agent: Br
Product: O=C1CC(Cc2ncc[nH]2)=NN1c1ccc(O)cc1

Procedure:
To a mixture of 1 ml of 47% hydrobromic acid and 1 ml of acetic acid was added 100 mg of 3-(1-imidazolylmethyl)-2-pyrazolin-5-one and stirred under reflux for 4 hours. After removing the solvent by evaporating, the residue was adjusted in pH to 4 by adding water and an aqueous NaHCO3 solution and then extracted with a mixed solvent of chloroform and ethanol (4:1).
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](N(C)C)=[N+:17](C)[CH3:18])C2C=CC=CC=2N=N1.[CH2:23]([O:30][C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([OH:52])=O)=[CH:46][CH:45]=3)=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CNC.CN1CCOCC1>O1CCCC1>[CH2:23]([O:30][C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][C:44]3[CH:49]=[CH:48][C:47]([C:50](=[O:52])[N:17]([CH3:18])[CH3:16])=[CH:46][CH:45]=3)=[CH:38][CH:39]=2)[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(Oc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.44 g) is added to a solution of 7-(4-carboxy-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester, dimethylamine (2 mol/L in tetrahydrofuran, 0.68 mL), and N-methyl-morpholine (0.41 mL) in tetrahydrofuran (20 mL) chilled in an ice bath. The cooling bath is removed and the resulting mixture is stirred at room temperature for 3 h. Then another portion of dimethylamine (2 mol/L in tetrahydrofuran, 0.70 mL) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.20 g) are added and the mixture is further stirred for another 4 h. After adding another portion of dimethylamine (2 mol/L in tetrahydrofuran, 0.30 mL), the mixture ist stirred at room temperature overnight. The mixture is concentrated and the residue is purified by chromatography on silica gel (ethyl acetate) to furnish the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13][CH:14]2[NH:17][C:16](=[O:18])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br.C(OCC)(=O)C>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][N:17]1[CH:14]([S:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:15][C:16]1=[O:18]
Reactant: COc1ccc(SC2CC(=O)N2)cc1OC
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)CC1Sc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Sodium hydride (0.5 g, 12 mmol) in dry DMF (10 ml) was cooled to -5° C. and a solution of 4-(3,4-dimethoxyphenylthio)azetidin-2-one (3 g, 12 mmol) in dry DMF (20 ml) was added dropwise over 15 mins under a nitrogen atmosphere at -5° C. After 15 mins methylbromoacetate (2 g, 12 mmol) was added in one portion, and the mixture stirred for 30 mins at room temperature. The reaction mixture was carefully poured into brine/ice water and ethyl acetate (100 ml) was added. The organic layer was washed with brine (x2), dried (MgSO4) and evaporated to a yellow oil which was purified by flash column chromatography eluted with petroleum ether/ethyl acetate to give the product as a yellow oil (0.96 g, 25% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].CO>C1COCC1>[CH:27]([N:9]1[C:8]2[CH:30]=[CH:31][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:26])[F:25])[CH:19]=[CH:18][C:16]=2[N:17]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89 %

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimid azole-5-carboxylic acid (500.0 mg) was prepared by following General Procedure E starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (580.0 mg) and lithium hydroxide (2.0 N solution, 3.0 mL), MeOH (2.0 mL) and THF (2.0 mL). LCMS: m/z 438; and 1H NMR (DMSO-d6, 400 MHz): δ 8.17 (1H, m), 7.96 (1H, m), 7.84-7.82 (1H, m), 7.72-7.70 (1H, m), 7.64-7.61 (1H, m), 7.40-7.37 (1H, m), 5.16-5.13 (1H, m), 1.59-1.58 (6H, d), —NH proton and —COOH signals were not observed.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[CH:4]1[O:6][CH2:5]1.[CH3:15][Al](C)C>ClCCl.CCCCCC>[F:1][C:2]1[C:3]([CH:4]([CH3:15])[CH2:5][OH:6])=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Reactant: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F

Procedure:
To a solution of 1.05 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 10 ml of dichloromethane, was added a 6 ml of 1.0M solution of trimethylalumimum in hexane, to react for one hour at 40° C. The similar work-up to Example 1 gave 1.10 g of (+)-2-(pentafluorophenyl)-1-propanol. The specific rotation was compared with that of Example 1, and the optical purity was determined to be 69%ee.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH:34]=2)[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC

Procedure:
A mixture of ((3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.9 g, 23.02 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (6.08 g, 25.32 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.45 g, 25.32 mmol) and triethylamine (7.62 mL, 92.07 mmol) in CH2Cl2 (230 mL) is refluxed for 3 h. The reaction is quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/acetone 95:5 to CH2Cl2/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.47. MS (LC-MS): 609.4 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 7.05 min.
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19]C=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=CC=2)C=CC=CC=1.[Li]CCCC.[CH2:27]([C:29]1[CH:30]=[N:31][C:32]([N:35]2CCC([C@H]3C[C@H]3C=O)CC2)=[N:33][CH:34]=1)[CH3:28]>C1COCC1>[CH2:27]([C:29]1[CH:30]=[N:31][C:32]([N:35]2[CH2:17][CH2:16][CH:15]([C@H:8]3[CH2:9][C@H:14]3[CH:13]=[CH2:12])[CH2:20][CH2:19]2)=[N:33][CH:34]=1)[CH3:28]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3C=O)CC2)nc1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@@H]1C1CCN(c2ncc(CC)cn2)CC1
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred suspension of triphenylmethyl phosphonium bromide (10.5 g, 29.4 mmol) in THF (80 mL) was added n-BuLi (11.4 mL of a 2.5M solution in hexanes, 28.4 mmol) dropwise. Upon stirring the resulting orange suspension for 45 min at −78° C., a solution of the product of step B (3.8 g, 14.7 mmol) in THF (25 mL) was added dropwise. The cold bath was removed and the mixture was stirred at RT for 2 h before being quenched with a saturated aqueous solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the desired alkene. MS (ESI) m/z 258 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Solvent: O
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1
Yield: 90.3 %

Procedure:
A mixture of 4.4 g (15 mmol) of 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, 3.9 g (30 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 165°-180° for 2 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching. The solid was collected and washed with ether to give 5.2 g of crude product, mp 258°-260° dec. Recrystallization from pyridine/water gave off-white needles, mp 259°-261°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1)Nc1c(Cl)cccc1Cl

Procedure:
A solution of 4.7 g (0.05 mole) of 4-aminopyridine in 300 ml of anhydrous tetrahydrofuran was treated with 9.4 g (0.05 mole) of 2,6-dichlorophenylisocyanate. The solution was heated at reflux for 24 hours, cooled, and concentrated in vacuo to a solid. Recrystallization from aqueous ethanol afforded the crystalline product, mp 217°-219° C.