Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
2-Pyridylcarbinol(0.19 ml, 1.71 mmol) was dissolved in methylene chloride(2 ml), triethylamine(0.59 ml, 4.27 mmol) was added thereto, and the mixture was stirred for 10 minutes at 0° C. Then, methanesulfonyl-chloride(0.26 ml, 3.41 mmol) was added and the resulting mixture was stirred for 10 minutes at the same temperature. The reaction solution was sequentially washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give 2-(methanesulfonyloxymethyl)pyridine(315 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:4]=1[F:21])=[O:29]
Reactant: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
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: C1CCOC1
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 49.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (0.059 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.041 g, 0.090 mmol, 49.6% yield) as a white solid. The mother liquor was concentrated to small volume, diluted with IPA, stirred for 30 minutes, and filtered to give a second batch of 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.011 g, 0.024 mmol, 13.31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (t, J=5.56 Hz, 1H), 7.88-7.99 (m, 1H), 7.78 (s, 1H), 7.37-7.57 (m, 2H), 7.30 (s, 1H), 4.55 (d, J=5.49 Hz, 2H). LC-MS (ES−) m/z 455.10, 457.03 [M−1]. LC-MS (ES+) m/z 456.99, 459.87 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>FC1C=CC=CC=1CN.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:3]4[CH:4]=[CH:5][CH:20]=[CH:21][C:2]=4[F:1])=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: NCc1ccccc1F
Solvent: CCO
Product: O[C@H](CNCc1ccccc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-fluorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[K+].O>C(O)C>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:20])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 4-cyclohexyl-3-(trifluoromethyl)benzamide (D33) (822 mg, 3.03 mmol) in ethanol (40 ml) was added potassium hydroxide (1.700 g, 30.3 mmol) and water (5 ml) and the reaction heated to 90° C. block temperature for 3 h and stirred at room temperature for 16 h. Further potassium hydroxide (1.700 g, 30.3 mmol) was added and the reaction heated at reflux for 27 h. A further 5 mL of water was added and the reaction heated for 66 hours (weekend). The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (25 mL) and aqueous hydrochloric acid (2M, 25 mL). The aqueous layer was further extracted with ethyl acetate (25 mL) and the combined organic phases dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a white solid (737 mg). MS (ES): C14H15F3O2 requires 272; found 271 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)C1CCCCC1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)cyclohexanecarboxamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and cyclohexane carbonyl chloride to give a tan solid (62% yield). 1H-NMR (CDCl3): δ 8.86 (s, 1H), 7.58 (m, 1H), 7.21 (dd, 1H), 7.16 (d, 1H), 5.74 (m, 1H), 5.07 (m, 1H), 2.66 (m, 2H), 2.26-2.05 (m, 2H), 1.96-1.72 (m, 7H), 1.70-1.63 (m, 1H), 1.52-1.35 (m, 2H), 1.31-1.16 (m, 3H); MS m/z 375 (M−1):
Reaction SMILES: [PH4+].[C:2]([OH:5])(=O)[CH3:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(=O)O
Agent: [PH4+]
Product: CC(=O)Nc1ccccc1
Yield: 90 %

Procedure:
To the same reaction mixture containing the phosphonium salt as in Example 1 was added a mixture of 3.0 g. (0.05 mole) of acetic acid and 5.2 g. (0.056 mole) of aniline, and the resulting mixture was reacted under reflux for 2 hours. Thereafter, the same after-treatment as in Example 1 was effected to obtain acetanilide, yield 90% based on acetic acid.
Reaction SMILES: [CH:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].CN(P(N(C)C)N(C)C)C.[H-].[Na+].[CH2:27](Cl)[C:28](=[CH2:30])[CH3:29]>C1(C)C=CC=CC=1.CN(P(N(C)C)N(C)C)C.C1(C)C=CC=CC=1>[CH:1]([C:4]([CH2:29][C:28]([CH3:30])=[CH2:27])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:2])[CH3:3]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C(C)CC(C(=O)OCC)(C(=O)OCC)C(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl isopropylmalonate (8.1g) in 25 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (50mM) in 25% HMPT/toluene (50ml) at room temperature. The mixture was then stirred at 60° C for 1/2 hour, cooled to 25° C and methallyl chloride (4.0g) in 25% HMPT/toluene was added over 10 minutes. The mixture was stirred at 80°-85° C overnight, cooled to room temperature and poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with water, followed by 2N sodium hydroxide and then water, and dried over magnesium sulphate. Removal of solvent gave diethyl isopropyl-2-methylprop-2-enylmalonate as a pale yellow liquid. R.I. nD21 1.4467.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=O.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42]([NH:1][CH:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]2)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of 1.75 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 1.1 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 24 hours. After cooling, the reaction solution is diluted with 200 ml of ethyl acetate, and the resulting solution is washed with 30 ml of 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is separated and purified by silica gel colum chromatography (hexane:ethyl acetate=2:1), whereby the first fraction yields 0.8 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30]>CCN(CC)CC>[NH2:31][C:29](=[O:30])[CH2:28][N:25]([CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=1)[CH3:26]
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Product: CN(CC(N)=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 104.6 %

Procedure:
Method as for preparation 106 using tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (244 mg, 0.67 mmol) and 2-bromoacetamide (95 mg, 0.69 mmol) as starting materials and Et3N as the base to afford the title compound as a colourless oil (296 mg).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[OH:16])[C:9]([O:11][CH3:12])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1/[C:1](=[N:24]/[OH:25])/[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCC(=O)c1cc(C(=O)OC)ccc1O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O

Procedure:
A stirred solution of methyl 3-butyryl-4-hydroxybenzoate, pyridine (3.7 mL, 46 mmol), and hydroxylamine hydrochloride (3.55 g, 51 mmol) in ethanol (30 mL) was heated reflux for 2 h. The mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg): 1H NMR (500 MHz, CD3OD): δ 8.30–8.28 (m, 1H), 7.85–7.82 (m, 1H), 6.92–6.89 (m, 1H), 3.88 (s, 3H), 2.87–2.84 (m, 2H), 1.67–1.60 (m, 2H), 1.05–1.00 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 10 ml of methylene chloride is added 0.46 g of triethylamine and 36 mg of dimethylamino-pyridine followed by the slow addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room temperature for 3 hours then partitioned with 10 ml of 50% NaHCO3 and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, washed with 50% NaHCO3, H2O, EtOAc (2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][C@H:13]([OH:15])[CH:12]=[CH:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1CC(=O)C=C1)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[CH2:14][C:13](=[O:15])[CH:12]=[CH:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@@H]1C=C[C@@H](O)C1)c1ccccc1
Agent: CC(=O)OC1C=CC(=O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1C=C[C@@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
38 milligrams of the (S)-trans-3-benzoyloxy-5-hydroxycyclopent-1-ene obtained by the method of (1), above, was added in 15 milliliters of methylene chloride to a chromic acid-pyridine complex prepared from 100 milligrams of chromic anhydride and 159 milligrams of pyridine, following which the mixture was stirred for 20 minutes at room temperature. The organic layer was then separated, successively washed in a 5% aqueous NaOH solution, 5% aqueous HCl solution and water and dried, after which the solvent was distilled off to obtain 22 milligrams of 4(S)-benzoyloxycyclopent-2-en-1-one having a Δε226 = -14° and exhibiting the same IR, NMR and mass as those of the product obtained in Example 9. The yield was 58%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:67]1([NH2:77])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31](=[O:32])[NH:77][C@H:67]1[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:70][CH2:69][CH2:68]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
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: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
To a solution of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (7.5 g, 16.593 mmol) in DMF (100 mL) were added HATU (6.93 g, 18.252 mmol) and DIPEA (14.36 mL, 82.965 mmol) and the mixture was cooled to 0° C. (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (2.44 g, 16.593 mmol) was added dropwise and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to afford the title compound as an off white solid (9.6 g) which was used without purification. LC-MS: 582 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17].Cl>C(OCC)(=O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])=[CH:7][CH:8]=1)=[O:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(CNC(=O)c2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 20 ml of ethyl acetate was added 1.04 g of isatoic anhydride. The mixture was stirred at room temperature for 15 minutes. Hydrochloric acid (10%) was added to the mixture. The aqueous layer was separated, made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.ClCCl>[N:14]1([CH2:9][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH2:3][CH2:2][OH:1])[CH:13]=[CH:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C#CCCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a mechanical stirrer, a rubber septum with a nitrogen inlet and a stopper. The flask was charged with the product of Example 5 (14.6 g) and dichloromethane (250 mL). Morpholine (8.85 mL) was added, and then to this well-stirred reaction mixture was added sodium triacetoxyborohydride (32 g) in 4 equal portions. After the addition, the reaction mixture was stirred at room temperature overnight. Aqueous NaOH (10% w/v, 75 mL) was added, and the reaction mixture was transferred to a 1-L separatory funnel, to which water(100 mL) was then added. After separation of the layers, the aqueous phase was extracted once with dichloromethane (100 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to yield the product as yellow oil. The crude product was purified by filtration through a pad of silica gel (ethyl acetate/hexanes; 7:3) to obtain the title compound as a pale yellow oil (13.7 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1
Yield: 68.7 %

Procedure:
Hydroxylamine hydrochloride (41.7 g) in 70 ml of water was added to a solution of 36.1 g of 4-methylbenzaldehyde in 180 ml of absolute ethanol. A solution of 18 g of sodium hydroxide in 36 ml of water was added in portions during 5 to 10 minutes. The reaction mixture was then heated to boiling and filtered hot, and the filtrate was cooled in a dry ice-acetone bath. Water was added to the cooled filtrate until solid product precipitated. The solid was separated by filtration, air-dried overnight, and recrystallized from hexane to give 27.9 g of 4-methylbenzaldoxime, m.p. 73°-77°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:22](O)=[O:23])[O:13][C:12]1([CH3:35])[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:22](=[O:23])[C:21]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:20][C@@H:14]2[O:13][C:12]([CH3:35])([CH3:34])[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C@H:15]2[CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:38][CH:37]=1
Reactant: NCc1ccncc1
Reactant: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)NCc2ccncc2)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
98 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid was dissolved in 0.4 ml of dry dichloromethane, and 21 μl of 4-picolylamine, 30 mg of 1-hydroxybenzotriazole and 45 mg of N,N'-dicyclohexylcarbodiimide were added thereto at 0° C. under stirring. The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. Insolubles were filtered off, and 20 ml of ethyl acetate was added. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (2 g of Kieselgel 60) by using chloroform/methanol (20/1) to obtain 121 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid 4-picolylamide as a colorless oily substance.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O.O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O=CO
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide (0.316 g, 1.04 mmol) in 88% formic acid (5.2 mL). Stir at room temperature for 1.25 hours before diluting with water. Extract with dichloroethane (2× 50 mL). Wash the organic layer with brine (1× 25 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.269 g, 99.6%): TOF MS ES+ 261.1 (M+H)+, HRMS calcd for C13H10N2O3F 261.0675 (M+H)+, found 261.0682, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 9.0 min, 100% purity.