Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[F-:14].[Cs+]>CS(C)=O.O>[F:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cnc(F)c2ccccc12
Temperature: 145 °C
Yield: 30.6 %

Procedure:
To a solution of 1-chloro-4-methoxyisoquinolin (2.5 g, 12.91 mmol) in DMSO was added cesium fluoride (4.01 g, 25.82 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (700 mg, 62%) as a white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.10 (m, 1H), 8.08 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.49 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −78.66 (1 F); MS: MS m/z 178.1 (M++1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[C:11]([O:14]C(=O)C)(=O)[CH3:12]>>[F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[C:11]([F:1])(=[O:14])[CH3:12]
Reactant: CC(=O)OC(C)=O
Agent: O=C(C(F)(F)F)C(F)(F)F
Product: CC(=O)F

Procedure:
A difficultly separable hexafluoroacetone-HF complex mixture containing about 1.01 g-moles hexafluoroacetone and 1.54 g-moles HF was contacted with 2.22 g-moles acetic anhydride at 100 psig. The temperature of the mixture rose from 20° to 31° C within a few minutes. A 411.0 g portion of this mixture was then fractionated at atmospheric pressure using a Freon 11/dry ice cooling bath and a 271/2 inch × 7/16 inch column packed with Helipak Monel. A 135.7 g hexafluoroacetone fraction, an 80.4 g intermediate fraction, and an 85.0 g acetic fluoride fraction were obtained leaving a 147.5 g kettle product of acetic hydride and acetic acid. A gas-liquid chromatographic analysis of the samples showed that the purity of the hexafluoroacetone fraction was 90 area percent. However, to demonstrate that a higher purity hexafluoracetone could be obtained, a portion of the overhead and kettle products were recombined, the mixture was redistilled, and a hexafluoroacetone fraction having a purity of 99.9 area percent was obtained.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:52])[CH:23]([O:50][CH3:51])[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:28][C:27]=1[F:49])O>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:52])[CH:23]([O:50][CH3:51])[CH2:24][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:28][C:27]=1[F:49]
Reactant: COC(=O)C(OC)C(O)c1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
Trifluoroacetic anhydride (0.043 mL, 0.37 mmol) and pyridine (0.074 mL, 0.93 mmol) were added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionic acid methyl ester (0.142 g, 0.31 mmol) in methylene chloride (1 mL) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and 10% palladium on carbon (0.064 g) was added to the solution. The mixture was stirred under hydrogen pressure (5 atm) for 16 hours. The mixture was filtered through celite and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid methyl ester as a white solid (30 mg, 22%). 1H NMR (200 MHz, CDCl3): 7.60–7.50 (m, 4H); 7.46–7.27 (m, 3H); 7.18–7.09 (m, 1H); 7.03–6.96 (m, 2H); 6.70–6.61 (m, 2H); 4.17 (dt, 4H, J=9.1, 6.2); 4.00 (dd, 1H, J=7.3, 5.9); 3.74 (s, 3H); 3.37 (s, 3H); 3.13–2.93 (m, 2H); 2.28 (qn, 2H, J=6.2).
Reaction SMILES: [O:1]=[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=O.C(N(CC)CC)C.C(Cl)[Cl:23]>>[O:1]=[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([Cl:23])=[O:14]
Reactant: ClCCl
Reactant: Cc1[nH]cc(OCC(=O)O)c(=O)c1Cl
Solvent: CCN(CC)CC
Product: Cc1[nH]cc(OCC(=O)Cl)c(=O)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid (2.17 g) and triethylamine (5 ml) in methylene chloride (50 ml) was stirred for 15 minutes. After evaporation to dryness, methylene chloride (50 ml) and then thionyl chloride (1.2 g) were added to the residue under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 30 minutes. Precipitated crystals were collected by filtration, washed with methylene chloride and diethyl ether and dried to give powder (2.3 g) of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetyl chloride. A solution of 7-[D-2-(4-hydroxyphenyl)glycinamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (2.1 g) and bis(trimethylsilyl)acetamide (10 ml) in methylene chloride (50 ml) was stirred at 0° C. and the powder (1.2 g) obtained above was added thereto. The reaction mixture was stirred at 0° C. for 2.5 hours and kept in an ice-box over-night. After removal of the solvent, water was added to the residue, and appearing precipitates were collected by filtration, washed with water and dried. The resulting powder (2.5 g) in dry acetone (200 ml) was stirred for 3 hours and collected by filtration, washed with a mixture of acetone and diethyl ether and dried. The resultant powder was dissolved in a mixture of water and an aqueous solution of sodium bicarbonate, whereby the solution was adjusted to pH 7.5, and ethyl acetate (5 ml) was added thereto. To the mixture was added Diaion HP-20 resin (Trade name of the product of Mitsubishi Kasei Co.) (1 ml) and the mixture was stirred for 30 minutes and filtered. The filtrate was adjusted to pH 3 with 10% hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dissolved in hydrous acetone. The solution was treated with active charcoal (0.3 g), and, after removal of the solvent, the resulting crystals were collected by filtration, washed with water and dried to give crystals (0.85 g) of 7-{D-2-[2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy]acetamido-2-(4-hydroxyphenyl)acetamido}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, m.p. 210°-215° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH:10]([CH3:11])[CH3:12])[C:13](=[O:15])[O:14][CH2:16]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OC(C)(C)C

Procedure:
(4S)-N-tert-Butyloxycarbonyl4-isopropyl-1,3-oxazolidin-5-one (3) was prepared from N-tert-butyloxycarbonyl-(L)-valine (2.17 g, 10.0 mM) and para-toluenesulfonic acid (30 mg) following general procedure A and obtained as a white solid after crystallisation from chloroform (1.67 g, 73%): [a]D20 +104.9 (c 1, CHCl3); mp 43-45° C.; IR (KBr): 1795, 1705 cm-1 ; 1H NMR (200 MHz, CDCl3): 67 5.55 (br, 1H), 5.10 (d, J=4 Hz, 1H), 4.15 (d, J=4 Hz, 1H), 2.21-2.43 (m, 1H), 1.49 (s, 9H), 1.06 (d, J=7 Hz, 3H), 1.02 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d 171.8, 152.6, 81.6, 78.4, 59.9, 31.1, 27.9, 17.9, 17.5; LRMS (NH3): 230 (MH+). Anal. Calcd for C11H19NO4 : C, 57.63; H, 8.35; N, 6.11; found: C, 57.62; H, 8.54; N, 5.93.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.B(O)O>>[N:8]1[CH:9]=[CH:10][C:5]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc2c(c1)CNCC2
Agent: OBO
Product: c1cc(-c2ccc3c(c2)CNCC3)ccn1

Procedure:
In close analogy to the procedure described above, 7-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH:12]=[O:13])[CH:4]=[CH:5][N:6]=1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH2:12][OH:13])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 5-(2-methylimidazol-1-yl)-2-nitrobenzaldehyde (349 mg) and methanol (5.0 ml) was added slowly sodium borohydride (114 mg) at 0° C. and the mixture was stirred at room temperature for 4 hours. Methanol was distilled at reduced pressure to give a residue. Water was added to the residue and the mixture was stirred at room temperature for 30 minutes, filtered and dried to give 360 mg (100%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[OH:30][C:31]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (87 mg, 0.194 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (40 mg, 0.194 mmol), potassium carbonate (134 mg, 0.971 mmol) and Pd(Ph3P)4 (22.45 mg, 0.019 mmol) was added Dioxane (971 μl) and Water (324 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material was used without further purification. m/z (ESI) 572.3 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(C)C=CC=CC=1.C1COCC1>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC(C)([O-])C.[K+]>[CH3:10][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:17])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:3][CH:4]=1)=[O:18]
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C(=O)c1ccc(N2CCNCC2)cc1)N1CCOCC1
Yield: 96.5 %

Procedure:
Further, in a 300 mL four-neck flask provided with a stirrer, a condenser, a thermocouple, and a nitrogen inlet tube, 16 g of 1-(4-chlorophenyl)-2-methyl-2-morpholino-propan-1-one, 20.7 g of piperazine, 140 mg of palladium acetate, 360 mg of (2-biphenyl)di-tert-butylphosphine, 100 mL of toluene, 40 mL of THF, and 9.4 mg of potassium-tert-butoxide were added, followed by reaction at room temperature for 46 hours under a nitrogen stream. The reaction product was diluted with 100 mL of diethyl ether and washed with 100 mL of water, and then an organic layer was dried with anhydrous sodium sulfate. The organic layer was concentrated and then recrystallized with dichloromethane/hexane to produce 18.3 g of 2-methyl-2-morpholin-4-yl-1-(4-piperazinylphenyl)propan-1-one (10). 1H-NMR (CDCl3): 1.34 ppm (s, 6H, —CH3), 2.60 ppm (m, 4H, —CH2—), 3.05 ppm (m, 4H, —CH2—), 3.34 ppm (m, 4H, —CH2—), 3.72 ppm (m, 4H, —CH2), 6.86 ppm (m, 2H, aromatic), 8.58 ppm (m, 2H, aromatic)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:22][C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([C:34]#[N:35])[CH:25]=4)[CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:37][C:38]1[C:42](B(O)O)=[C:41]([CH3:46])[O:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:32])[CH3:33])[C:23]([NH:22][C@@H:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:46])=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][OH:21])=[O:36])#[N:35]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1C#N
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(C#N)c4)cc3)nc12
Temperature: 100 °C
Reaction time: 22 h
Yield: 21.8 %

Procedure:
To a solution of N-((1S)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (200 mg, 0.366 mmol) in dry DMF (2 mL) were added 3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol), tetrakistriphenylphosphine palladium(0) (21 mg, 0.018 mmol) and 2.0 M aqueous K2CO3 (0.46 mL) successively at rt. The reaction mixture was purged with argon and heated to 100° C., stirred for 22 h, cooled to rt, filtered and purified directly by reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were adjusted to pH ˜8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m/e 564.2 (M+H)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)=[O:15])=[C:8]([CH3:40])[CH:7]=1.C(#N)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH:2]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:23]2)=[O:15])=[C:8]([CH3:40])[CH:7]=1)=[O:1]
Reactant: Cc1cc(C2OCCO2)c(C)cc1NC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a 500 mL round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (15 g, 27.6 mmol) and acetonitrile (150 mL) to form a slurry. Aqueous 2 M hydrochloric acid (75 mL) was added and the resulting mixture was stirred at 30° C. for 1 hour. The mixture was then cooled to room temperature and ethyl acetate (150 mL) was added. Aqueous 2 M sodium hydroxide (75 mL) was added, the pH was checked and then additional 2 M sodium hydroxide was added until the pH of the solution was in the range of 9 to 10. The layers were separated and the organic layer was washed with diluted brine (75 mL; 1:1 brine/water), dried over anhydrous sodium sulfate and the solvent removed on a rotary evaporator to give biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenyl-carbamoyl)ethyl]piperidin-4-yl ester (12.5 g, about 98% purity). If desired, the purity of this intermediate can be increased by forming a slurry with ethanol (3 volumes of ethanol), heating the slurry to 80° C., and then cooling slowly to room temperature and isolating by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[CH:28][CH:29]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 18 %

Procedure:
The titled compound (40 mg) was prepared in 18% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 1-(4-bromomethyl-phenyl)-1H-pyrazole according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 8.46 (s, 1 H), 7.79 (d, 2 H, J=12.0 Hz), 7.71 (m, 3 H), 7.62 (d, 2 H, J=8.0 Hz), 7.40 (d, 2 H), J=8.0 Hz), 7.33 (s br, 1 H), 6.70 (s br, 1 H), 6.54 (s, 1 H), 4.56 (AB2,2 H,Δv=16,Jab=96 Hz), 4.00 (m, 1 H), 2.78 (m, 1 H), 2.30 (m, 1 H), 1.73 (m, 2 H), 1.37 (m, 7 H); MS m/e 509.12 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=O)(=O)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([CH3:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC.[Cl-].[NH4+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: Cc1cc(Br)ccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To 16B (11 g, 48.0 mmol) in CH2Cl2 (200 ml) was added oxalyl chloride (7.36 ml, 84 mmol) and DMF (0.112 ml, 1.441 mmol). The reaction was stirred at rt for 2 h. The solvent was removed and chased with ethyl acetate (2×). The residue was dried under high vac for 1.5 h. To (S)-4-benzyloxazolidin-2-one (10.21 g, 57.6 mmol) in THF (200 ml) at −78° C. was added n-butyllithium (1.6 M in hexanes, 36.0 ml, 57.6 mmol). The reaction was stirred for 25 min at −78° C. Then the above acylchloride dissolved in THF (100 mL) was added. The reaction was stirred at −78° C. for 1 h and then at rt for 15 min. Sat ammonium chloride was added to quench the reaction and ethyl acetate to dilute the reaction. The organic layer was then washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give 16C (14.1 g, 36.3 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.38 (d, J=1.77 Hz, 1H) 7.27-7.38 (m, 4H) 7.16-7.23 (m, 2H) 7.06 (d, J=8.08 Hz, 1H) 4.64-4.76 (m, 1H) 4.14-4.36 (m, 4H) 3.32 (dd, J=13.26, 3.16 Hz, 1H) 2.79 (dd, J=13.39, 9.60 Hz, 1H) 2.26-2.32 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:24][CH2:25][CH2:26][CH:27]([CH3:39])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:17])[C:13]=2[CH3:16])[O:10]C(CCC)O[CH:7]3[CH2:21][CH2:22][CH3:23])[CH2:4][CH2:3]1>CC(O)=O.OS(O)(=O)=O.C(Cl)Cl.[Pd]>[CH2:7]([C:6]1[C:11]([OH:10])=[C:12]([CH3:17])[C:13]([CH3:16])=[C:14]2[C:5]=1[CH2:4][CH2:3][C@@:2]([CH3:1])([CH2:24][CH2:25][CH2:26][C@H:27]([CH3:39])[CH2:28][CH2:29][CH2:30][C@H:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[O:15]2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC1Oc2c(C)c(C)c3c(c2C(CCC)O1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O3
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1c(O)c(C)c(C)c2c1CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 105.3 %

Procedure:
A solution of 7,9,10-trimethyl-2,4-dipropyl-7-(4,8,12-trimethyl-tridecyl)-4,5,6,7-tetrahydro-1,3,8-trioxa-phenanthrene (Ex-1C-2) (180 mg of crude material form above) in AcOH (10 mL) and conc. H2SO4 (10 drops) was hydrogenated (H2, 50 psi, RT) with 5% Pd/C (20 mg of 50% w/w wet) at RT for 16 h. The reaction mixture was then filtered through celite. The celite was rinsed with DCM (2×2 mL). The DCM layer was concentrated by rotary evaporation to yield a light brown oil. The oil was dissolved in DCM (15 mL) and passed through a silica plug. The DCM was concentrated by rotary evaporation to yield (R,R,R)-5-butyl-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol (Ex-1C-3) as a cloudy yellow oil (165 mg, >100%), which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14]O>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: Cc1cc(O)c(CC(=O)O)cc1O
Product: COC(=O)Cc1cc(O)c(C)cc1O

Procedure:
A mixture of 145.6 g of 2,5-dihydroxy-4-methylphenylacetic acid and 45 g of dry sulfonic acid resin (IRN-77R) is heated under reflux in 4.38 liters of absolute methanol. The mixture is filtered and the filtrate evaporated. The white solid is recrystallized from a mixture of ethyl acetate and heptane (50:50), yielding white crystals with the following characteristics: