Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([N:36]([C:44](=[O:46])[CH3:45])[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:28][C@@H:27]3[CH3:47])=[O:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1C=CC(N([C@H]2C3C(=CC=CC=3)N(C(=O)C3C=CC(O)=CC=3)[C@@H](C)C2)C(=O)C)=CC=1.C([O-])([O-])=O.[K+].[K+].C(OC(N1CCN(CCCCl)CC1)=O)(C)(C)C>CN(C=O)C>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([N:36]([C@H:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([C:24](=[O:25])[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:20]=3)[C@@H:27]([CH3:47])[CH2:28]2)[C:44](=[O:46])[CH3:45])=[CH:38][CH:39]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc21
Agent: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCNCC3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 50 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(3-piperazin-1-yl-propoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (2S,4R)-4-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester. (2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.40 g, 0.92 mmol) was dissolved in DMF at room temperature and K2CO3 (0.127 g, 0.921 mmol) was added. 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.242 g, 0.921 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography to afford the product as colorless oil in 50% yield. (2S,4R)-4-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (246 mg) was dissolved in 4M HCl in dioxane (2 mL). The mixture was stirred for 2 h at room temperature. After concentration, the white solid was washed with EtOAc to provide the title compound in 100% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][OH:26])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
1-(4-Benzyloxyphenyl)-2-[2-(tert-butyldimethylsilanyloxy)ethyl]-1H-indole (0.62 mmol, 1.35 mmol) was dissolved in tetrahydrofuran (6 mL) under N2, and tetrabutylammonium fluoride (1.49 mL, 1 M in tetrahydrofuran, 1.49 mmol) was added. The reaction was stirred for 2 hours, then quenched with saturated ammonium acetate. The mixture was extrated with ethyl acetate, dried over MgSO4, and concentrated. The residue was passed through a plug of silica with ethyl acetate. The filtrate was concentrated to give the desired product. The reaction was assumed to be quantitative. LC-MS (C23H21NO2 calc'd 343) m/z 344 (M+H).
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10](NC(CC3SC=CC=3)=O)[C:11](=O)[N:8]2[C:7]=1C([O-])=O)=O.[Na+].C(=O)(O)[O-:29].[Na+].[N-]=[N+]=[N-].[Na+]>O>[N:8]12[CH2:11][CH2:10][CH:9]1[S:22][CH2:23][C:6]([C:5]([OH:4])=[O:29])=[CH:7]2
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C([O-])O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=CN2CCC2SC1
Temperature: 2.7777777777777777 °C

Procedure:
A solution of commercial cephalothin sodium salt (5.0 g), sodium bicarbonate (1.06 g), sodium azide (0.82 g) and water (75 ml) is heated at approximately 50° C. (122° F.) until TLC (thin layer chromatography) shows the starting material is consumed. The reaction is cooled to approximately 3° C. (37° F.), covered with ethyl acetate and acidified with 1N HC1. The ethyl acetate extract is dried over Na2SO4, filtered and the filtrate is concentrated to dryness to give [6R[6a,7B]]-3-(azidomethyl)-8-oxo-7-](2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-carboxylic acid. A mixture of this azido intermediate (1.0 g), 10% Pd/C (1.0 g), NaHCO3 (1.54 g) and 75% methanol/H2O is subjected to hydrogenation at room temperature until TLC shows the disappearance of starting azide. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is dissolved in water, acidified with 1N HCl and the solution is washed with CHCl3. The aqueous phase is concentrated to dryness and the crude product is purified using 50W-X4 cation exchange resin to give product (II).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]([CH2:23][CH3:24])=[CH:17][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>CCO>[CH2:23]([C:16]1[S:15][C:14]([NH:13][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=1)[CH3:24]
Reactant: COc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: CCO
Product: CCc1cc(C(=O)OC)c(Nc2ccc(OC)cc2[N+](=O)[O-])s1

Procedure:
2-Fluoro-5-methoxy-nitrobenzene and methyl 2-amino-5-ethyl-thiophene-3-carboxylate, m.p. 125°-127° C. (EtOH).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=3[C:21](=[O:32])[C:20]=2[CH:33]=1>CC(N(C)C)=O>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:23]2[O:24][CH2:25][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:33][C:20]=3[C:21](=[O:32])[C:22]=2[CH:29]=1
Reactant: COc1ccc2c(c1)C(=O)c1cc(N)ccc1CO2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)C(=O)c1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1CO2
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
In dimethylacetamide (8 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.73 g, 4.63 mmol), and thionyl chloride (0.36 ml, 4.63 mmol) was added thereto at −15° C., followed by stirring at −15 to −5° C. for one hour. To the reaction mixture was added 9-amino-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 11 (0.59 g, 2.32 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained oily residue was dissolved in ethyl acetate (25 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), followed by trituration with isopropyl ether to give Compound 1-48 (yield: 87%).
Reaction SMILES: OCC(CO)O.[O:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15]>O>[O:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCC[C@H](CCCCC(C)=O)C(=O)O
Solvent: O
Solvent: OCC(O)CO
Product: CCC[C@@H](CCCCC(C)=O)C(=O)O

Procedure:
Gelatin (20 kg) and concentrated glycerin (6 kg) were admixed in the presence of purified water (20 kg) at 70° C. to give homogeneous solution. (2R)-7-oxo-2-propyloctanoic acid (0.9 kg) was injected into soft capsule filling machine (rotary-type soft capsule filling machine (TYPE-H1 manufactured by KAMATA CO., LTD.)) to give wet soft capsules each containing (2S)-7-oxo-2-propyloctanoic acid. The obtained wet soft capsules were dried by tumble-dry and rack-dry sequentially, thereby obtaining above captioned soft capsules (2200 capsules) each containing 300 mg of (2S)-7-oxo-2-propyloctanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][CH2:34][CH:35]([OH:37])[CH3:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(O)CN
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+]525.2290, observed 525.2295.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]2[CH2:12][O:11][N:10]3CC2C=CC(OC)=CC=2OC)[CH:5]=[CH:6][C:7]=1[F:8].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]2[CH2:12][O:11][NH:10]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2OCC3CC(O)CC32c2ccc(F)c(Br)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: OC1CC2CONC2(c2ccc(F)c(Br)c2)C1
Temperature: 80 °C

Procedure:
A mixture of racemic (3aRS,5RS,6aSR)-6a-(3-bromo-4-fluorophenyl)-1-(2,4-dimethoxybenzyl)hexahydro-1H-cyclopenta[c]isoxazol-5-ol (0.852 g, 1.79 mmol) and triethylsilane (0.624 g, 5.37 mmol) in TFA (4 mL) is heated to 80° C. for 3 h. The reaction is cooled to room temperature and concentrated under reduced pressure to afford a residue that is purified on a SCX column washing sequentially with dichloromethane, methanol and 7 N NH3 in MeOH to give the title compound as racemic mixture (0.57 g, 100%). ES/MS m/e (79Br/81Br) 302, 304 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O.O.[Sn](Cl)Cl>C1COCC1.C(N(CC)CC)C>[C:11]1([S:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH2:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Sc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccccc1Sc1ccccc1
Reaction time: 4 h

Procedure:
A room temperature solution of 2-fluoronitrobenzene (1.41 g, 10.0 mmol), thiophenol (1.21 g, 11.0 mmol), and triethylamine (2 mL) in THF (20 mL) was stirred for 16 hours, treated with 3M HCl (10 mL) and tin(II) chloride dihydrate (11.4 g, 50 mmol), stirred for 4 hour, and extracted with ethyl acetate (50 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% hexanes/dichloromethane to provide the desired product. MS (DCI) m/e 202 (M+H)+.
Reaction SMILES: O.Cl(O)(=O)(=O)=O.[Cl-].[CH3:8][O:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[Cl:30]>C(O)(C)C>[CH3:8][O:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][NH:27]3)=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[Cl:30]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1Cl
Agent: [Cl-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1Cl
Yield: 30 %

Procedure:
Water (1.5 ml), 60% aqueous perchloric acid (0.01 ml) and pentamethylcycloopentadienyliridium(III) chloride dimer) (116 mg, 0.145 mmol, 0.05 equiv.) were added to 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester (1.42 g, 4.17 mmol) in degassed isopropanol (100 ml) under a nitrogen atmosphere and the mixture was refluxed for 48 hours. The mixture was evaporated to give a tan solid. The solid was purified by flash chromatography (SiO2, 1:9 tert-butyl-methyl ether:dichloromethane to 1:1:8 tert-butyl-methyl ether:methanol:dichloromethane). The fractions were combined to afford 2-chloro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 0.434 g (30% yield) as a tan solid. LC @215 nm; Rt 1.15: 98%, m/z (ES+): 345 (M+H+.); δH (250 MHz; d6-DMSO) 10.39 (1H, br.s), 8.07 (1H, m), 7.91-7.80 (2H, m), 7.05-6.90 (3H, m), 5.95 (1H, br.s), 3.82 (3H, s), 3.19 (2H, m), 2.70 (2H, m), 1.79 (2H, m).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3].C(OC(=O)[NH:25][C@H:26]([CH:34]1[CH2:36][O:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C)(C)C>>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH:18][CH2:36][C@@H:34]([OH:35])[C@@H:26]([NH2:25])[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C1CO1
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(OCCC)ccc21

Procedure:
Step AZ (1): (2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-phenylbutan-2-ol (590 mg) was prepared from (1S,3R)-3-(allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-amine (1.2 g, 4.9 mmol, from Step AY (1)) and (S)-(1-oxiranyl-2-phenylethyl)-carbamic acid tert-butyl ester in three steps and 30% overall yield using procedures analogous to the Steps AW (1-3). LC-MS (M+H)+=411.19. 1H NMR (300 MHz, CDCl3) δ 0.9-1.0 (t, 3H) 1.7-1.9 (m, 2H) 2.0-2.2 (m, 1H) 2.4-2.6 (m, 2H) 2.7-3.0 (m, 3H) 3.1-3.2 (m, 1H) 3.8-4.1 (m, 5H) 4.2-4.4 (m, 1H) 4.6-4.8 (m, 1H) 5.1-5.3 (m, 2H) 5.7-5.9 (m, 1H) 6.9-7.0 (m, 1H) 7.0-7.3 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([CH:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)=[O:8])C.Cl>CO>[CH3:1][O:3][C:4]([C:5]1[O:20][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[C:7](=[O:8])[CH:6]=1)=[O:21]
Reactant: CCOC(=O)C(=O)CC(=O)C1COc2ccccc2C1=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(=O)c2c(o1)-c1ccccc1OC2

Procedure:
A solution of 3-acetyl-4-chromanone (1.8 g, 9.5 mmoles, described in Example 5) in dry tetrahydrofuran (20 ml) is added dropwise to a suspension of 57% sodium hydride (1.17 g, 28.5 mmoles) in tetrahydrofuran (30 ml) and the mixture is heated at reflux temperature for 15 min. A solution of diethyl oxalate (1.39 g, 9.5 mmoles) is added dropwise under an atmosphere of nitrogen. The reaction mixture is heated at reflux temperature overnight and cooled to -40° C. A solution of 50% aqueous acetic acid (4 ml) is added and the reaction mixture evaporated. The residue is partitioned between chloroform and water, the organic phase is separated and the aqeuous phase is re-extracted with chloroform. The combined chloroform extracts are dried and evaporated. The residue is subjected to chromatography on silica gel. Elution with chloroform affords 4-(4-chromanon-3-yl)-2,4-dioxobutyric acid ethyl ester (VII; R1, R2, R3R4 and R17 = H, R19 = C2H5 and X = 0), which is crystallized from ether, m.p. 117°-119° C. b. Solid 3-acetyl-4-chromanone (0.570 g, 3 mmoles, described in Example 5) is added in portions at room temperature to a suspension of 57% sodium hydride (0.379 g, 9 mmoles) in dry tetrahydrofuran (10 ml). The mixture is heated within 15 min to 60° C and diethyl oxalate (0.438 g, 3 mmoles) in tetrahydrofuran (10 ml) is added. After heating at reflux temperature under an atmosphere of nitrogen for 17 hr., the solvent is removed under reduced pressure, the residue is dissolved in ice-water and extracted with ether. The aqeuous phase is acidified with 6N hydrochloric acid and extracted with chloroform. The organic phase is dried, evaporated, and the residue crystallized from methanol-chloroform to give 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid (VI; R1, R2, R3, R4 and R5 = H, and X = 0), νmaxnujol 1705, 1615 and 1560 cm-1. c. A solution of 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester [0.70 g, 2.4 mmoles, described above in (a)] in methanol is saturated with hydrogen chloride gas. The solution is heated at reflux temperature overnight and evaporated to dryness. The residue is chromatographed on silica gel using benzene-ethyl acetate (4:1). The eluate is evaporated and the residue is crystallized from chloroform-ether to give the title compound, m.p. 173°-174° C. d. In the same manner as described above in (c) but replacing 4(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester with an equivalent amount of the corresponding acid, 4-(4-chromanone-3-yl)-2,4-dioxobutric acid [described above in (b)], the title compound is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:20]([OH:23])(=[O:22])=[O:21].Cl.C[O-].[Na+:27]>C(Cl)(Cl)Cl>[S:20]([O-:23])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21].[Na+:27]
Reactant: CCCCCCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methylhexadecanol (124 g, 0.484 mol), prepared as an intermediate in Example I. Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2 L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2 L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50° C. for 3 hrs. to obtain a white solid (136 g, 92% active by cat SO3 titration).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].Br[CH2:11][C:12]1[CH:13]=[C:14]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:15]=[CH:16][CH:17]=1.O>CN(C)C=O>[CH3:23][C:21]1([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19][B:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:5][C@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:13]=2)[O:22]1
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
Under argon stream, to a solution of (R)-1,1,1-trifluoropropan-2-ol (3.32 g) in N,N-dimethylformamide (43 ml) was added portionwise sodium hydride (1.16 g, 60 wt % oil dispersion) at 0° C., and the mixture was stirred for 20 minutes. Then, 2-(3-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.32 g) was added thereto, and then the mixture was stirred at room temperature overnight. To this reaction mixture were sequentially added water and a 2M aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (3.43 g).
Reaction SMILES: O.C(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=O)C.C(OC(=O)C)(=O)C.P(=O)(O)(O)O>C(O)(=O)C>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]=[CH2:6])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCc1ccc(OC(C)=O)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
A flask heated by hot oil was fitted with a chilled water overhead condenser, a thermowell with a thermocouple, an overhead stirrer and a vacuum pump. Crude APMC-Ether (20 grams) containing 78.2 weight percent APMC-Ether, 7.2 weight percent APMC and 3.9 weight percent 4-acetoxyphenylmethylcarbinol acetate (sometimes referred to herein as "APMC-Acetate") was mixed in another flask with six (6.0) grams of acetic anhydride. Phosphoric acid (0.022 grams) having a concentration of 85 weight percent that corresponds to 0.32 moles of pure phosphoric acid per 100 moles of APMC-Ether was added to said mixture. The resultant mixture was fed to the hot flask at a rate of 1.2 grams per minute. The hot oil temperature was maintained at about 220° C. to about 230° C. and the reaction mass temperature in the hot flask was maintained at about 180° C. to about 200° C. The vacuum pump maintained a vacuum in the flask at about 80 mm Hg. 4-acetoxystyrene and acetic acid were produced in the hot flask.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:42])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:42][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4ccccc4)c3)ccc2O1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccccc1)Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 25 °C
Yield: 216.7 %

Procedure:
A solution of N-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]-N′-phenylurea (0.025 g) in acetic acid (1 ml) and water (0.5 ml) were stirred under nitrogen at 70° C. for 75 min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (2×10 ml) to give the title compound (0.028 g). LCMS RT=2.50 min, ES+ve 552 (MH)+.