Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C([C:7]([C:10]([CH2:13][OH:14])([F:12])[F:11])([F:9])[F:8])(F)F)(F)F.N#N.C(C(CF)(F)F)(F)(F)[F:18]>>[C:7]([C:10]([CH2:13][OH:14])([F:12])[F:11])([F:18])([F:9])[F:8]
Reactant: FCC(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: N#N
Product: OCC(F)(F)C(F)(F)F
Temperature: 277 °C

Procedure:
The same catalyst was used from Example 4 above. The reactor was cooled to 277° C. The alcohol (CF3CF2CH2OH) flow of 0.49 mL/hr (2.0 sccm, 3.3×10-8 m3 /s), the COCl2 flow of 3.0 sccm (5.0×10-8 m3 /s), the HF flow of 7.0 sccm (1.2×10-7 m3 /s), and an N2 flow of 2 sccm (3.3×10-8 m3 /s) were begun. The gaseous effluent was analyzed by GCMS and found to be 89.3-90.5% CF3CF2CH2F over a 2 hour period with no evidence for catalyst deactivation.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O>C1COCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12]2=[O:16])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCN(C(=O)CCC1CCNC1=O)c1cn(-c2cccnc2)nc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)CCC1CCN(CC(F)(F)F)C1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Yield: 24.8 %

Procedure:
N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(2-oxopyrrolidin-3-yl)propanamide (0.037 g, 0.10 mmol) was added to a vial with stir bar, followed sodium hydride (60% in mineral oil, 0.010 g, 0.26 mmol). The vial was placed under N2 and chilled to 0° C. THF (1 mL) was then added and the reaction was allowed to stir for 30 minutes 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.037 mL, 0.26 mmol) was added neat, dropwise. The reaction stirred overnight. The reaction was adsorbed onto CELITE®. Purification by flash column chromatography using MeOH/CH2Cl2 as eluent provided the title compound as a colorless oil (0.011 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[CH2:18]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[OH:11])[CH:17]=[CH2:16]
Reactant: Oc1ccc(Oc2ccccc2Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cc(Oc2ccccc2Cl)ccc1O
Temperature: 230 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 4-(2-chlorophenoxy)phenol (15 g), allyl bromide (12.5 g) and potassium carbonate (14 g) in methyl isobutyl ketone (100 ml) was refluxed under heating for 3 hours. After cooling, the reaction mixture was filtered, and the filtrate was evaporated. The residue was dissolved in diethyl ether, washed with dil. aqueous sodium hydroxide and water, dried and evaporated. The oily residue was stirred in a oil bath at 230° C. for 2 hours and distilled to give 2-allyl-4-(2-chlorophenoxy)phenol (14.7 g). bp 189°-192° C./3 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:26])[CH3:22]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (135.0 g, 700 mmol) and K2CO3 (289.8 g, 2100 mmol) in DMF (1.5 L) was stirred at 70° C. for 0.5 h and then 2-bromo-propionic acid ethyl ester (136.3 mL, 1050 mmol) was added to the mixture. The reaction mixture was heated at 80° C. for 2 h then cooled to ambient temperature. The solvent was removed in vacuo and the residue was dissolved in water (600 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was concentrated, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a brown liquid (185.0 g, 90%). 1H NMR (CDCl3, 400 MHz): δ 7.90 (dd, J=2.4 Hz, J=9.2 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 5.27 (q, J=7.2 Hz, 1H), 4.67 (d, J=15.2 Hz, 2H), 4.18 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O-:13].[Na+]>CN(C=O)C>[CH3:12][O:13][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc2ccccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.2 %

Procedure:
A solution of 3-bromoquinoline (22.54 g, 108 mmol) in anhydrous DMF (110 mL) was treated with sodium methoxide (11.70 g, 217 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was then concentrated and the residue taken up in ethyl acetate (300 mL) and water (60 mL). The organic phase was separated, washed with brine (2×60 mL), dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:3) to give 3-methoxyquinoline (1.06 g, 6%). 1H NMR (CDCl3) δ3.95 (s, 3H), 7.38 (d, 1H, J=1.5 Hz), 7.54 (m, 2H), 7.72 (d, 1H, J=7.5 Hz), 8.04 (d, 1H, J=7.5 Hz), 8.67 (d, 1H, J=1.5 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C([Li:22])CCC>C1(C)C=CC=CC=1>[C:13]([C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:17][Li:22])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: [Li]Oc1c(C(C)(C)C)cc(OC)cc1C(C)(C)C
Yield: 95 %

Procedure:
Both 10 mmol (2.2 g) of monocyclopentadienyl titanium chloride(CpTiCl3) and 100 ml of toluene were added to a 200 ml Schlenk reactor in the atmosphere of inert gas. Then, 10 mmol of 2,6-di-t-butyl 4-methoxy phenoxy lithium, so obtained from the reaction between 2,6-di-t-butyl 4-methoxy phenol and n-butyl lithium, was slowly added to the mixture. The reactional solution was stirred at room temperature and stood for 1 hour. After 1 hour, some mixture was collected and was analyzed by 1H-NMR spectroscopy to ascertain the reaction results.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:24]2[CH:25]=[C:26]([CH3:34])[C:27]([O:32][CH3:33])=[C:28]([CH2:30]O)[CH:29]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:13]=2)[N:3]=1.[BrH:35].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][CH2:30][C:28]1[CH:29]=[C:24]([C:4]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)[CH:13]=3)[C:5]3[C:10](=[C:9]([F:11])[CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH:25]=[C:26]([CH3:34])[C:27]=1[O:32][CH3:33]
Reactant: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CO
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CBr
Temperature: 25 °C
Yield: 65 %

Procedure:
To (5-(3-amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxy-3-methylphenyl)methanol (250 mg, 0.55 mmol) in DCM (5 mL) was added HBr (33% in acetic acid) (5 mL, 92.08 mmol) and the mixture was stirred at rt over night. Aqueous Na2CO3 was added to the mixture to reach pH ˜9. The water layer was extracted with DCM and the combined extracts were dried (MgSO4) and concentrated under reduced pressure to afford 185 mg (65%) of the title compound. MS (ES+) m/z 517, 519 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[S:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[S:33][CH:34]=3)[CH:21]=[CH:20][CH:19]=2)=[O:6])=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cs1

Procedure:
A mixture of 3-bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol in 2.4 mL DME), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL), and (Ph3P)4Pd (8 mg, 6.94 μmol) in a sealed vial were subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated to dryness under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=2.37 min, m/z=422.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:19][N:18]=2)=[O:16])=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:26]1([CH2:25][O:24][C:20]2[C:21]([F:23])=[CH:22][C:17]([C:15]3[O:16][C:10]4[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=4[N:14]=3)=[N:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)cn2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4)cn3)nc2cn1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5.9 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-5-(cyclopropylmethoxy)-4-fluoropyridine-2-carboxamide (1.05 g), potassium carbonate (664 mg) and copper(I) iodide (46.0 mg) in DMF (10 mL) was stirred at 160° C. for 1.5 hr. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[C:67](Cl)(=[O:70])[CH2:68][CH3:69]>C1COCC1>[CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)[NH:55][C:67](=[O:70])[CH2:68][CH3:69])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.05 g, 0.057 mmol) was suspended in THF (0.572 mL). Upon addition of DIPEA (0.050 mL, 0.286 mmol), the slurry partially clarified. Propionyl chloride (0.005 mL, 0.057 mmol) was added at room temperature and the reaction was allowed to stir at room temperature overnight. Upon completion, the reaction was quenched with a small amount of formic acid and purified by reverse phase HPLC (10-45% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.008 g, 17%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O5: 820.41 (M+); Found: 821.51 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](/[CH:11]=[C:12](/[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)\[C:13]#[N:14])=[CH:4][C:3]=1[O:25]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:25][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](/[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)\[C:13]#[N:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: N#C/C(=C\c1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (Z)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile (0.526 g, 1.44 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath was added aluminium chloride (0.24 g, 1.80 mmol) in one portion followed by pyridine (0.46 g, 5.77 mmol) dropwise. The resulting red suspension was stirred at 80° C. for two hours, then cooled to room temperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL). The precipitate was filtered off, washed with water and dried to give (Z)-3-(3,4-dihydroxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile, 0.308 g (61%)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Concentrated nitric acid (20 ml) was added cautiously with cooling to concentrated sulphuric acid (50 ml) maintaining a temperature of −5° C. Another solution of 2-methyl-1-phenyl-1-propanone (29.6 g, 0.2 mol) in concentrated sulphuric acid (70 ml) was made up with shaking, keeping the temperature at −5° C. The former nitric acid/sulphuric acid solution was added portionwise over 30 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1 l) and then extracted with diethyl ether (3×100 ml). The organic extracts were washed with water (300 ml) and then brine (300 ml), dried (Na2SO4) and then concentrated in vacuo. The crude product was obtained as an orange oil (40 g) which was purified by chromatography on silica gel (450 g) eluting with hexane :diethyl ether (9:1) to give the title compound as a pale yellow solid (16.3 g, 42%), m.p.33-35° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[C:14]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[C:32]([F:43])[CH:31]=3)=[CH:26][CH:25]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].C(O[CH:49](OC(C)(C)C)[N:50]([CH3:52])[CH3:51])(C)(C)C.O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:15]=[C:14]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])=[CH:49][N:50]([CH3:52])[CH3:51])=[C:32]([F:43])[CH:31]=3)=[CH:26][CH:25]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Yield: 65.2 %

Procedure:
tert-Butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (200 mg, 0.33 mmol) obtained in Example (11-6) was dissolved in toluene (3 ml) and N,N-dimethylformamide di-tert-butyl acetal (0.4 ml, 1.7 mmol) was added thereto, and the mixture was heated under reflux for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-1/1) to give tert-butyl 2-(allyloxy)-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (141 mg, yield: 65%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].CC(C)=O.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>O.[OH-].[Na+]>[C:22]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 20 g (0.081 mols) of α-aspartylaspartic acid in 80 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 40 ml of acetone were added thereto. To the solution were added dropwise 17.7 g (0.081 mols) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 31.7 g of N-(N'-lauroyl-α-aspartyl)aspartic acid in a yield of 91%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]#[N:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]#[N:19])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#CC=Cc1ccc(OCc2ccccc2)cc1
Agent: [Mg]
Solvent: CO
Product: N#CCCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Magnesium turnings (28 g) are added to a solution of 3-(4-benzyloxyphenyl)-acrylonitrile (17.0 g, 72.3 mmol) in dry MeOH (800 mL). As soon as moderate H2 evolution is observed, the flask is immersed in an efficient ice/water cooling bath until the initially vigorous reaction subsides after about 45 minutes. Additional Mg (10 g) is added, and the reaction mixture is stirred for 4 hours with intermittent cooling during which time most of the Mg metal is consumed. The mixture is evaporated to a thick paste, which is then cooled to 0° C. and treated slowly with enough cold 6 N HCl to dissolve the magnesium salts. The turbid solution is extracted with CHCl3, and the organic layer is washed with 0.1 N NaOH and H2O, dried over Na2SO4, and evaporated to give white waxy solid residue that is recrystallized from EtOH/H2O (2:1) to give 3-(4-benzyloxyphenyl)-propionitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=[O:28]>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:27]([OH:28])[C:26]4[S:25][CH:24]=[N:23][C:22]=4[CH3:21])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: Cc1ncsc1C=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: COC(=O)c1nc2n(c1C(O)c1scnc1C)CCOc1cc(F)c(Br)cc1-2

Procedure:
methyl 10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with 4-methylthiazole-5-carboxaldehyde to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])=[O:28]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 71 %

Procedure:
A solution of 21.5 g (0.067 mol) of 2-(4-bromophenyl)-hexafluoro-2-propanol and 6.8 g (0.067 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 8.7 g (0.08 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 18.8 g (71 percent of theory) of 2-(4-bromophenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 66° to 69° C. (under 0.13 mbar) were obtained.