Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)=O.O>C(#N)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]=2[CH:4]=[CH:3][CH:1]=[O:2])=[CH:8][CH:7]=1
Reactant: C=CC=O
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Use of the crude acrolein coming from Example 4a. To a suspension of 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (130.7 g), phosphorus oxychloride (114.6 g) in acetonitrile (128 ml) cooled at 5° C. a solution of crude acrolein (116.9 g from Example 4a) in acetonitrile (145 ml) is added dropwise in 60 minutes. The reaction mixture is then warmed to 60° C. and kept under stirring at 60° C. for 6 hours; water (1100 ml) is added and after 1 hour at 60° C. the formed solid is filtered on Buchner and washed with water (250 ml×3). The wet solid (131 g) is dissolved in toluene (1050 ml), celite (2.7 g) and charcoal (4 g) are added and the mixture is stirred at room temperature for 30 minutes. After filtration of the solid, the mixture is washed with water (500 ml×2), the phases are separated, the organic solvent is distilled off at reduced pressure and the residue is dissolved at 75° C. with isopropanol (260 ml). The solution is cooled at 10° C. and stirred for 1 hour. The precipitate is filtered on Buchner, washed with isopropanol (60 ml×3) and dried at 60° C. under vacuum. 84.2 g (53% molar yield) of the product are obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Br[C:43]1[CH:48]=[CH:47][C:46]([C:49]2([OH:53])[CH2:52][O:51][CH2:50]2)=[CH:45][CH:44]=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4([OH:53])[CH2:52][O:51][CH2:50]4)=[CH:45][CH:44]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: OC1(c2ccc(Br)cc2)COC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C3(O)COC3)cc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.21 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one (100 mg) and 3-(4-bromo-phenyl)-oxetan-3-ol (53 mg) in N,N-dimethylformamide (2 mL). The resulting mixture was sparged with argon for 10 min prior to the addition of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (17 mg). The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound as a foam-like solid. Yield: 34 mg (32% of theory); Mass spectrum (ESI+): m/z=502 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (s, 3H), 1.19 (s, 3H), 1.47 (d, J=6.9 Hz, 3H), 2.02 (s, 2H), 2.15 (mc, 1H), 2.38-ca. 2.50 (m, 2H) superimposed by D3CSOCHD2 signal, 3.01 (mc, 1H), 4.23 (s, 1H), 4.70 (d, J=6.3 Hz, 2H), 4.79 (d, J=6.3 Hz, 2H), 5.44 (incompletely resolved q, 1H), 6.35 (s, 1H), 6.94 (d, J=7.9 Hz, 2H), 7.26-7.43 (m, 7H), 7.59 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4]CC1.C(=O)CC(C)C.C(N)CCC.C([O:42][C:43](=[O:53])C(SC1SC(N)=NC=1)C)C>>[CH2:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:43]([OH:53])=[O:42])=[CH:13][N:14]=1)[CH2:6][CH2:5][CH3:4]
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CC=O
Solvent: CCCCN
Product: CCCCN(CCC(C)C)C(=O)Nc1ncc(SCCC(=O)O)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, butylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:22]=2[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:30][C:27]1[CH:28]=[CH:29][C:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2CC1
Temperature: 130 °C

Procedure:
3,4-difluoronitrobenzene (664 mg, 4.18 mmol) was added to a mixture of 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) (1 g, 3.8 mmol) and potassium carbonate (1.3 g, 9.49 mmol) in dimethylformamide (10 ml) and the reaction heated at 130° C. for 3 hours. The reaction was cooled, diluted with ethyl acetate, washed with water and then with a mixture of water:brine (1:1), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 303 [M-COOtBu]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:24]
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.-RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=[CH:23][C:14]=1[CH2:15][O:16]C1CCCCO1.[B:37](OC(C)C)(OC(C)C)[O:38]C(C)C.Cl>C1COCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:26]2[C:13]3[B:37]([OH:38])[O:16][CH2:15][C:14]=3[CH:23]=[CH:24][CH:25]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(COc2cccc(COC3CCCCO3)c2Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc3c2B(O)OC3)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.5 M n-BuLi in hexane (1.53 mL, 3.83 mmol) was added dropwise to a solution of 2-[2-bromo-3-(4-methoxy-benzyloxy)-benzyloxy]-tetrahydro-pyran (1.3 g, 3.2 mmol) in THF (14 mL) under N2 at −78° C. (bath temp). The mixture was stirred at −78° C. (bath temp) for 2 h then triisopropyl borate (0.90 mL, 3.8 mmol) was added slowly and stirred at −78° C. (bath temp) for 4 h. The mixture was allowed to warm up to 0° C. (bath temp) and then acidified with 3 M HCl to pH 5. The mixture was stirred for 3 h and the resulting precipitate was isolated by filtration and washed with 1:9 CH2Cl2/Et2O to give A25 as a yellow solid: yield 0.10 g (12%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:26]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39](Br)[CH:38]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:26]([NH:33][S:34]([C:37]1[CH:38]=[CH:39][C:40]([CH3:43])=[C:41]([NH:1][C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15](=[O:17])(=[O:16])[NH:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:11][CH:10]=3)=[N:4][CH:3]=2)[CH:42]=1)(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)NCCN3CCCC3)cc2)nc1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1Nc1cnc(Nc2ccc(S(=O)(=O)NCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A suspension of intermediate 45 (Example 93) (0.10 g, 0.28 mmol), N-benzyl-3-bromo-4-methyl-benzenesulfonamide (0.10 g, 0.29 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium tert-butoxide (70 mg, 0.63 mmol) in a mixture of dioxane/DNIF (2/1, 3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 25% MeOH and 2% TEA/DCM) to afford the title compound (0.10 g, 58%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10]Cl)[S:7][C:6]=1[CH3:12].[C-:14]#[N:15].[K+].C(Cl)(Cl)Cl.[Na+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10][C:14]#[N:15])[S:7][C:6]=1[CH3:12]
Reactant: [C-]#N
Reactant: COC(=O)Cc1cc(CCl)sc1C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(CC#N)sc1C
Temperature: 50 °C
Yield: 43.4 %

Procedure:
A solution of (5-chloromethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.6 g, 12.1 mmol) and potassium cyanide (1.7 g, 25.4 mmol) in DMF (33 mL) is stirred for 14 h at room temperature then warmed to 50° C. for 0.5 h. After cooling, the mixture is poured into a mixture of CHCl3 and saturated aq NaCl and extracted with CHCl3. The combined extracts are washed with saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography (silica gel, 10-50% ethyl acetate in heptane) to give (5-cyanomethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (1.1 g, 43.4%): 1H NMR (CDCl3, 300 MHz) δ 6.83 (s, 1 H), 3.80 (s, 2 H), 3.70 (s, 3 H), 3.50 (s, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH:14]([S:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:13]([CH:25]([C:39]([CH3:41])=[CH2:40])[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])[C:12]2=[O:42])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(Cl)[Cl:44].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH:14]([S:15][S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[N:13]([CH:25]([C:39]([CH2:41][Cl:44])=[CH2:40])[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[C:12]2=[O:42])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClOCl
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCCOC(C)=O
Product: C=C(CCl)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
A 1.0 g quantity of p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 25 ml of ethoxyethyl acetate. The solution was cooled in an ice bath with stirring. To the mixture was added dropwise over 20 minutes 6.l ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 955 mg of p-nitrobenzyl 2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([CH:10]2[O:11][CH2:12][CH2:13][O:14]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)ccc(C2OCCO2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(Cl)ccc(C2OCCO2)c1Cl
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a suspension of 2,6-dichloro-3-(1,3-dioxolan-2-yl)benzaldehyde (3.9 g) in methanol (19.5 ml) was added sodium borohydride (299 mg) under nitrogen atmosphere, and the mixture was stirred for 1 hour under ice-cooling. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 2,6-dichloro-3-(1,3-dioxolan-2-yl)-1-hydroxymethylbenzene (3.69 g) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=1[O:14][CH2:15][CH3:16])(=O)[CH3:2].Br[C:18]1[CH:23]=CC=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>[Cu].II.C1(C)C=CC=CC=1.C(O)CC(C)C>[C:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=2[O:14][CH2:15][CH3:16])[CH:20]=[CH:19][CH:18]=[CH:23][CH:2]=1
Reactant: CCOc1ccc(NC(C)=O)c(OCC)c1
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: CC(C)CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(Nc2ccccc2)c(OCC)c1
Yield: 70 %

Procedure:
To a mixture of 66.9 g of N-acetyl-2,4-diethoxyaniline and 70.7 g of bromobenzene, 29 g of anhydrous potassium carbonate, 2.1 g of copper powder and 0.8 g of iodine were added, and the mixture was reacted at a temperature of from 170° to 180° C. for 20 hours. Then, to this reaction mixture, 30 g of potassium hydroxide and 100 ml of isoamylalcohol were added, and the mixture was reacted at a temperature from 120° to 130° C. for 3 hours. Then, 300 ml of toluene was added thereto. The toluene layer was washed with water, separated by liquid separation, concentrated and then purified by distillation under reduced pressure, whereby 54 g of oily N-phenyl-2,4-di-ethoxyaniline was obtained. The boiling point of this product was from 180° to 185° C./3 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:14]=[CH:15][CH:16]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(NC1CCCCC1)c1cccc(Br)c1
Reactant: C=CCNC(=O)C(F)(F)F
Product: O=C(NC1CCCCC1)c1cccc(/C=C/CNC(=O)C(F)(F)F)c1

Procedure:
Heck coupling of 3-bromo-N-cyclohexylbenzamide and N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gave (E)-N-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamide as a light yellow solid. Yield (0.50 g, 71%): 1H NMR (400 MHz, CD3OD) δ 8.18-8.26 (m, 1H), 7.83 (t, J=1.6 Hz, 1H), 7.65-7.68 (m, 1H), 7.54-7.56 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 6.62 (d, J=16.0 Hz, 1H), 6.32 (dt, J=16.0, 6.4 Hz, 1H), 4.06 (d, J=5.6 Hz, 2H), 3.80-3.90 (m, 1H), 1.93-1.95 (m, 2H), 1.79-1.82 (m, 2H), 1.66-1.70 (m, 1H), 1.18-1.48 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[C:9]2=[CH:10][C:11]3[C:12](=[N+:14]([O-])[O:15][N:16]=3)[CH:13]=[C:8]2[O:7][C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].P(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:9]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:8]2[O:7][C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2cc3c(cc21)no[n+]3[O-]
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(C)(C)Oc2cc3nonc3cc21
Yield: 68.6 %

Procedure:
A mixture of 211 mg 8-acetyl-7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine 3-oxide, 15 ml toluene and 0.18 ml triethyl phosphite was heated under reflux for 16 hours, the solvent was distilled off from the reaction mixture, diethyl ether was added to the residue, and the precipitate was collected by filtration and recrystallized from 2 ml ethanol, giving 136 mg of 8-acetyl-7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[Si:33]([O:40][CH2:41][C@H:42](O)[CH3:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][C@@H:42]([CH3:43])[CH2:41][O:40][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
[2-(2-Fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d), 275 mg), (R)-1-(t-butyldimethylsilanyloxy)propan-2-ol [CAS No. 136918-07-5] (171 mg), and triphenylphosphine (236 mg) were dissolved in 3 ml of THF under a nitrogen atmosphere, and the resulting mixture was cooled to −78° C. After the addition of 0.177 ml of N,N′-diisopropylazodicarboxylate, the mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (343 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([C@@H:27]([N:29]3[CH2:34][CH2:33][C@:32]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:31][C:30]3=[O:46])[CH3:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[OH:45][C:42]([CH3:43])([CH3:44])[CH2:41][C@@:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C:30](=[O:46])[N:29]([C@H:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:22][CH:23]=2)[CH3:28])[CH2:34][CH2:33]1
Reactant: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.40 mL) was added to a solution of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.29 g) in dichloromethane (10 mL). The resulting solution was stirred at room temperature overnight. Then, more dichloromethane was added and the solution was neutralized using aqueous saturated NaHCO3 solution. The organic phase was separated, washed with water, and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C(O)(=O)C.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:1]([O:4][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
78.5 g (0.80 mol) of potassium acetate, 5.0 g (0.08 mol) of acetic acid and 123.7 g (0.80 mol) of 2-chloroacetophenone was heated under reflux in 500 ml of ethanol for 6 hours. After the completion of heating, the reaction solution was cooled to room temperature, precipitated potassium chloride was filtered off, and ethanol was evaporated off under reduced pressure, giving an oily and caramel-like substance. The obtained oily substance was poured into 1 liter of water and the precipitated yellowish-brown crystalline solid was filtered off, followed by recrystallization from methanol, giving 113.1 g (0.635 mol, 79.3% yield) 2-acetoxyacetophenone.