Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][C:5]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])([N+:8]([O-])=O)[CH2:4][O:3]1.O>C(O)C.C1COCC1.[Ni]>[NH2:8][C:5]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:6][O:7][C:2]([CH3:1])([CH3:21])[O:3][CH2:4]1
Reactant: COC(=O)c1cccc(C2([N+](=O)[O-])COC(C)(C)OC2)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc(C2(N)COC(C)(C)OC2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 106.7 %

Procedure:
Under an argon atmosphere, to a solution of 2.18 g of methyl 3-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)benzoate in 26 ml of ethanol and 7 ml of THF was added a suspension of Raney nickel (manufactured by Aldrich, 1.2 ml of a suspension was washed with water and ethanol) in 5 ml of ethanol, followed by stirring at room temperature for 7 hours under a hydrogen atmosphere of 4 atm. The reaction mixture was filtered over Celite and the liquid was concentrated under reduced pressure. To a solution of the obtained residue in 26 ml of ethanol and 7 ml of THF was added a suspension of Raney nickel (manufactured by Aldrich, 1.2 ml of a suspension was washed with water and ethanol) in 5 ml of ethanol under an argon atmosphere, followed by stirring at room temperature for 16 hours under a hydrogen atmosphere of 4 atm. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain 2.09 g of methyl 3-(5-amino-2,2-dimethyl-1,3-dioxan-5-yl)benzoate.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:36])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:35][CH:33]([F:34])[O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:22]=[C:21]([F:36])[CH2:20][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:24][CH2:25]2)=[CH:27][CH:28]=1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(OC(F)F)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 23.3 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.28 g), tetrahydrofuran (2 ml) and magnesium (24 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-difluoro-methoxyphenyl)cyclopropane (Example 24) (94 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-difluoromethoxyphenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (30 mg, 23%).
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].[CH3:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.C(#N)C>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CCCCCCCC
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 76 °C
Yield: 31 %

Procedure:
A solution of 0.308 g (1.14 g) of ferric chloride hexahydrate and 0.225 g (3.75 mmol) of glacial acetic acid in 5 ml of water is added to a mixture of 10.00 g (19.6 mmol) of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 94 ml of acetonitrile, and 64 ml of n-octane that is heated to 76° C. The reaction mixture is kept at the reflux temperature of 76° as a solution of 11.52 g (169 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 3 hours. A solution of 0.106 g of ferric chloride hexahydrate and 0.102 g of glacial acetic acid in 1.6 g of water is added to the reaction mixture 1.75 hours after the peroxide addition is begun. A solution of 0.106 g of ferric chloride hexahydrate and 0.073 g of glacial acetic acid in 1.6 g of water is added to the reaction mixture 2.75 hours after the peroxide addition is begun. The reaction mixture is maintained at the reflux temperature for 1 hour after the peroxide is added. Excess peroxide is decomposed by stirring the reaction mixture with aqueous sodium sulfite solution. Solids are removed by filtration. The aqueous layer of the filtrate is extracted with ethyl acetate. The combined organic layers are concentrated, and the concentrate is purified twice by flash chromatography with a 100:7.5 mixture of heptane-ethyl acetate to afford 4.43 g (31% yield) of the title compound, a colorless liquid. NMR analysis shows a mixture of octyl regioisomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])/[CH:10]=[CH:11]/[C:12]1[O:19][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[N:14]=1)(=[O:26])[CH3:25]
Reactant: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(/C=C/c2nc3ccccc3c(=O)o2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A solution of (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.6 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at it for 1 h and the precipitate was collected by filtration, providing (E)-2-(3-acetoxy-4-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.50 g, 93%) as a yellow solid; mp 187-190° C.; δH (400 MHz, DMSO-d6) 2.80 (s, 3H, COCH3), 3.83 (s, 3H, OCH3), 6.87 (d, J=16.0 Hz, 1H, CH═CHCO), 7.19 (d, J5′,6=8.0 Hz, 1H, H5′), 7.68 (d, J5′,6=8.0, 1H, H6′), 7.57 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.60 (d, J3,4=8.0 Hz, 1H, H3), 7.66 (s, 1H, H2′), 7.71 (d, J=16.0 Hz, 1H, CH═CHCO), 7.89 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.10 (d, J5,6=8.0 Hz, 1H, H6); δC (100 MHz, DMSO-d6) 20.4, 56.1, 112.9, 116.7, 117.6, 122.1, 127.5, 128.0, 128.1, 128.2, 136.8, 139.6, 140.2, 146.7, 152.7, 157.0, 158.8, 168.4; HRMS (ESI) calculated for C19H15NO5 [M+H]+ 338.1023, found 338.1023; νmax 1197, 1268, 1588, 1631, 1752 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(OCCOC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2cccc(C)c2)cc1
Solvent: CC(=O)OCCOC(C)=O
Product: Cc1ccc2c(c1)oc1ccc(C)cc12

Procedure:
By treating 3,4'-dimethyldiphenyl ether under the same conditions as in Example 6 except that 5 ml of ethylene diacetate was added, 2.7 g (14 m. moles) of 2,7-dimethyldibenzofuran and 0.27 g (0.69 m. mole) of the dimer were obtained. The obtained 2,7-dimethyldibenzofuran melted at 82°-83° C. and was in the form of white needle crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1ccccn1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-2yl-acrylic acid ethyl ester CCXLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13](Br)[CH:14]=[N:15][CH:16]=2)[N:11]=1)=[O:9].OB(O)[C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:23]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=3)[CH:14]=[N:15][CH:16]=2)[N:11]=1)=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: O=C(NCc1ccco1)c1ccc2cncc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: O=C(NCc1ccco1)c1ccc2cncc(-c3ccc(C(=O)O)s3)c2n1
Temperature: 25 °C

Procedure:
Compound 3 (above, 1 equiv.), 5-(dihydroxylboryl)-2-thiophene carboxylic acid (1 equiv.), dichloro(bistriphenylphosphine)palladium (II) (0.02 equiv.), and sodium carbonate (1.5 equiv.) are combined with 7:3:2; DME:water:methanol (4 mL) in a microwavable reaction tube. The reaction mixture is irradiated in the microwave at 140° C. for 300 seconds and then cooled to room temperature. The crude mixture is concentrated in vacuo, affording a green-brown solid. Purification via silica gel chromatography (EtOAc to 4:1; EtOAc:methanol containing 1% acetic acid) affords a bright yellow solid. LC/MS (M+H) 340.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7]>P([O-])([O-])([O-])=O>[CH2:5]1[C:4]2[C:11](=[CH:12][C:13]([C:2]([CH:3]=2)=[O:1])=[O:14])[NH:7][CH:6]1[C:8]([OH:10])=[O:9]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C1C=C2CC(C(=O)O)NC2=CC1=O
Reaction time: 0.5 h

Procedure:
To a 96-well plate, 40 μl of mushroom-derived tyrosinase (125 unit/ml; dissolved in a 67 mmol/l phosphate buffer solution; Sigma), 120 μl of 3,4-dihydroxyphenylalanine that serves as a substrate (L-dopa; 5 mmol/l; dissolved in a 67 mmol/l phosphate buffer solution; Sigma), and 40 μl of an inhibitor solution were added. The plate was allowed to stand for 37° C. for 30 minutes. Then, the amount of dopachrome produced was determined by absorbance at 490 nm. Tyrosinase inhibitory activity was expressed as an inhibitory rate obtained by the following equation: Inhibitory Rate (%)=[(A−B)−(C−D)]/(A−B)×100
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#Cc1cc(Br)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Propyne (28 g, 700 mmol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (150 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-bromo-3-iodo-pyridin-2-ylamine (139 g, 465 mmol), bis(triphenylphosphine)dichloropalladium(0) (16.3 g, 23.2 mmol), copper (I) iodide (5.3 g, 27.9 mmol) and triethylamine (141 g, 194 mL, 1.4 mol) in THF (1.25 L). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a buff solid (91 g, 93%). 1H NMR (400 MHz, CDCl3): 8.01 (d, J=2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 4.96 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [N+](C1C=CC([CH2:8][C@:9]2(C)[C@@H:13]3[C@@H:14]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:16])[N:12]3[C:11]([C:20]([O-:22])=[O:21])=[C:10]2[S:23][CH:24]2[CH2:27][N:26]([C:28]3[S:29][CH:30]=[C:31]([CH2:33][NH:34][C:35]([C:37]4[O:38][CH:39]=[CH:40][CH:41]=4)=[O:36])[N:32]=3)[CH2:25]2)=CC=1)([O-])=O.[Na+:45].O1C=CC=C1C(NCC1N=C(N2CC(SC3[C@H](C)[C@@H]4[C@@H]([C@H](O)C)C(=O)N4C=3C(O)=O)C2)SC=1)=O>O1CCCC1>[Na+:45].[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[C:35]([NH:34][CH2:33][C:31]1[N:32]=[C:28]([N:26]2[CH2:27][CH:24]([S:23][C:10]3[C@H:9]([CH3:8])[C@@H:13]4[C@@H:14]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:16])[N:12]4[C:11]=3[C:20]([O-:22])=[O:21])[CH2:25]2)[S:29][CH:30]=1)=[O:36]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(CNC(=O)c5ccco5)cs4)C3)[C@](C)(Cc3ccc([N+](=O)[O-])cc3)[C@H]12
Agent: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(CNC(=O)c5ccco5)cs4)C3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(CNC(=O)c5ccco5)cs4)C3)[C@H](C)[C@H]12
Reaction time: 2 h
Yield: 41.4 %

Procedure:
(1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (640 mg,1.00 mmol) (obtained as described in Example 72(1)) in a mixture of tetrahydrofuran (32 ml) and distilled water (32 ml) was subjected to catalytic hydrogenation in the presence of 7.5% palladium on charcoal (640 mg) in a water bath (35° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added sodium hydrogencarbonate (84 mg), ethyl acetate and distilled water. The resulting mixture was shaken in a separatory funnel and the aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→2% acetonitrile in distilled water→4% acetonitrile in distilled water→6% acetonitrile in distilled water→8% acetonitrile in distilled water→10% acetonitrile in distilled water→15% acetonitrile in distilled water) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (218 mg, yield 41%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][OH:15])[CH3:2].CCOC(C)=O.CCCCCC>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH:14]=[O:15])[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nn2c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 0.886 g (4.32 mmol) of the product of Step B dissolved in 15 mL of CH2Cl2 was added 1.772 g of powdered 4A molecular sieves and 4.430 g (51 mmol) of manganese dioxide and the reaction mixture was magnetically stirred at room temperature. After 16 h, TLC analysis (50% EtOAc-hexane) indicated complete reaction and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was redissolved in 50% EtOAc-hexane and purified by filtration through a short plug of silica gel. Evaporation of the filtrate and drying in vacuo afforded 0.781 g (89%) of the title compound as a tan solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]Br>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:14][CH:13]=[C:12]([CH3:16])[CH3:11]
Reactant: Oc1ccccc1I
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOc1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 2-iodophenol (3.69 g, 16.8 mmol) in THF (50 mL) is added NaH (804 mg, 33.5 mmol) portion wise and stirred for 30 min at room temperature. 3,3-Dimethylallylbromide (3.9 mL, 33.5 mmol) was added and the reaction was stirred over night at room temperature. The reaction is quenched with water (20 mL) and extracted with diethyl ether (3×25 mL), the organic layers are dried over magnesium sulfate, filtered and concentrated. The compound was purified on silica gel using 100% hexanes as the eluent to yield 4.78 g (98%) of the title compound as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=6.0 Hz, 1H), 7.35 (t, J=9.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.74 (t, J=9.0 Hz, 1H), 5.45 (m, 1H), 4.60 (d, J=6.0 Hz, 2H), 1.75 (2s, 6H)
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C@H:24]([CH2:29][CH3:30])[CH2:25][C:26]([OH:28])=O)=[CH:19][CH:18]=1.O>CS(O)(=O)=O>[CH2:29]([C@@H:24]1[CH2:25][C:26](=[O:28])[C:19]2[C:20](=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:32])[F:31])[CH:18]=2)[NH:23]1)[CH3:30]
Reactant: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CC[C@@H]1CC(=O)c2cc(C(F)(F)F)ccc2N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
Phosphorus pentoxide (13.1 kg) was dissolved in methanesulfonic acid (131 liter) warmed, the solution was added to the compound (26.27 kg) obtained in Example 2 (1) above and the mixture was stirred at 65-75° C. for about 3 hours. To the reaction mixture, was added water (342 liter) dropwise while keeping the temperature at 10-50° C., and then the solution was cooled at below 10° C. The precipitated crystalline was collected by filtration and washed with water (393 liter). When the pH of the washing was acidic, the precipitate was washed again. The wet crystalline was dissolved in ethyl acetate (26.3 liter) and n-heptane (105 liter) at 60-70° C., and n-heptane (158 liter) was further added at the same temperature. The solution was stirred at 45-50 for about 3 hours, cooled to below 10° C., and the precipitated crystalline was filtered and washed with ethyl acetate/n-heptane=1/10 (26.3 liter). The wet product was dried under reduced pressure at below 50° C. to give the titled compound (11.5 kg, yield 47%). MS (APCI) m/z: 244 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:33])([F:1])[F:32])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Yield: 98.7 %

Procedure:
A mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(3-nitrophenoxy)piperidin-1-yl)methyl)-phenyl)propan-2-ol (8.36 mmol, 4 g) and palladium on carbon (10%) (0.251 mmol, 0.267 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The reaction was filtered through celite and concentrated under reduced pressure. Chromatography on silica, eluting with ethyl acetate, gave the title compound (3.7 g). MS (ESI) m/z 449.2 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.C(Cl)Cl.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:30](=[O:31])([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A stirred solution of 2.54 g (0.01 mol) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol of Example 1, 20 ml of sieve dried CH2Cl2 and 1.55 g (0.013 mol) of phenylisocyanate was heated 20 hours under reflux with exclusion of moisture. The cooled solution was concentrated on a rotary evaporator to afford an oil which was dissolved in 10 ml of hot toluene. The solution was seeded with product (previously obtained by the method described herein), stirred until a thick suspension formed and allowed to stand overnight (about 16 hours) at ambient temperature. Filtration and drying in vacuo afforded 2.53 g (67.8%) of a colorless solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl carbanilate m.p. 98°-99° C.
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[C:9]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])(=[S:11])[NH2:10].C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:2]1[S:11][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:10][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(=S)NC(=O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)c1sc(NC(=O)c2c(F)cccc2F)nc1C
Temperature: 25 °C
Yield: 69.2 %

Procedure:
The solution of 3-chloro-2,4-pentanedione (670 mg, 4.88 mmol), N-carbamothioyl-2,6-difluorobenzamide (1.08 g, 5.0 mmol) and K2CO3 (0.8 g) in 20 mL of MeOH was stirred at reflux for 5 hours. The reaction was cooled to room temperature, and concentrated under reduced pressure. The residue was taken up with EtOAc. The solution was washed with water, dried (Na2SO4), filtered and concentrated. Purification on silica gel gave N-(5-Acetyl-4-methylthiazol-2-yl)-2,6-difluorobenzamide (1.0 g, 71%) as a white solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C1C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:36](=[O:37])[C:35]1[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=1)[CH3:15]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cccc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Yield: 84.4 %

Procedure:
Analogously to Example 47b, 11.8 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 5.4 g of ethyldiisopropylamine are reacted in 70 ml of benzene with 8.7 g of m-trifluoromethylbenzoyl chloride. The reaction product is recrystallized from a mixture of isopropyl alcohol and water (1:1) to obtain 16.0 g (84.4% of theory) of ethyl-4-[m-trifluoromethyl-N-(biphenyl-2-yl)benzamido]-butyrate, MP 65° to 67°.