Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH:44]([CH3:46])[CH3:45])[NH:5][C:6](=[O:43])[C@H:7]([CH:40]([CH3:42])[CH3:41])[NH:8][C:9](=[O:39])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19])=[CH:14][CH:13]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH:44]([CH3:46])[CH3:45])[NH:5][C:6](=[O:43])[C@H:7]([CH:40]([CH3:41])[CH3:42])[NH:8][C:9](=[O:39])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH3:19])=[CH:14][CH:13]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:12]1[OH:38]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)OCc2ccccc2)=CC(Cc2ccccc2)C1=O)C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)OCc2ccccc2)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the above (38) (0.47 g) in ethanol (15 mL) was added at room temperature NaBH4 (55 mg). After stirring for 30 min the reaction was carefully quenched with acetone then aqueous 1N HCl. The reaction was extracted with ethyl acetate, washed with saturated NaCl, dried over MgSO4 and evaporated. The product (39) was obtained as a mixture of isomers by flash chromatography on silica gel eluted with 50% CHCl3 in ethyl acetate (0.42 g, 89%). TLC Rf 0.36, 0.33 (97:3 CHCl3 :MeOH); MS DCl/NH3 (M+H)+ =650.4.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: CCc1cccc2cc[nH]c12
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.[Na].[CH3:14][CH2:15][OH:16]>>[CH2:15]([O:16][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)[CH3:14]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: [Na]
Product: CCOC(=O)c1ccc(OCC)cn1

Procedure:
To a solution of ethyl 5-bromopyridine-2-carboxylate 2 (1.5 g, 6.5 mmol) in 20 mL of EtOH was added a solution of sodium (0.18 g, 7.8 mmol) in 20 mL of EtOH. The mixture was stirred at reflux for 3 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give ethyl 5-ethoxypyridine-2-carboxylate 3 as an oil. Yield: 0.26 g, 20%. 1HNMR (CDCl3) δ (ppm): 8.38 (d, 1 H), 8.10 (d, 1 H), 8.23 (d, 1 H), 7.22 (dd, 1 H), 4.45 (m, 2 H), 4.25 (m, 1 H), 1.40 (m, 6 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]1=[O:12].[Cl-].[CH3:15][S+](C)C>CS(C)=O>[CH3:13][C:4]1([CH3:3])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]21[O:12][CH2:15]2
Reactant: C[S+](C)C
Reactant: CC1CCC(C)C(C)(C)C1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1CCC(C)C2(CO2)C1(C)C
Reaction time: 6 h

Procedure:
According to a preferred embodiment of the invention, NaOH is added to a mixture consisting of 2,2,3,6-tetramethyl-1-cyclohexanone and trimethylsulfonium chloride in dimethylsulfoxide. The reaction is slightly exothermic, hence the necessity to maintain an external cooling of the reaction mixture so as to keep the temperature at about 25°-30° C. Good stirring is also applied for about 6 hr. 4,4,5,8-Tetramethyl-1-oxaspiro[2.5]octane is then obtained by extraction of the resulting mixture with petrol ether, concentration of the organic extracts and fractional distillation
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.C1(C=CC(O)=CC=1)O>CS(C)=O.O>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:28][CH2:27][C:24]1[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=1)[C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Reactant: C=Cc1ccc(C)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCCC1N2C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A reaction flask with a septum cap was charged with 30% sodium metal dispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (0.48 g, 2.0 mmol; Example 114A) in dimethyl sulfoxide (4 mL). The vessel was sealed, flushed with nitrogen, and stirred for 10 minutes. A solution of 2-methyl-5-vinylpyridine (0.238 g, 2.0 mmol; prepared as described in International Publication No. WO 2001017968) and hydroquinone (0.072 g, 0.66 mmol; Aldrich) in anhydrous dimethyl sulfoxide (1.5 mL) was added and the reaction was heated at 100° C. for 72 hours. After cooling the mixture to room temperature, it was poured into water and extracted with ethyl acetate (4×25 mL). The combined organic extracts were washed with brine, concentrated, and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 0.82-1.00 (m, 1H), 1.17-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.55-1.64 (m, 1H), 1.78-1.99 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H), 2.66 (dd, J=17, 7 Hz, 1H), 3.06-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H), 4.30-4.37 (m, 2H), 6.95 (dd, J=8, 1 Hz, 1H), 7.08-7.14 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH2:17]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([NH:7][CH3:6])[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:10]2[CH:16]=[N:15]1)[CH3:18]
Reactant: CCn1ncc2c(-c3ccc(F)cc3C)c(NC(=O)OC(C)(C)C)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1ncc2c(-c3ccc(F)cc3C)c(NC)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of [1-ethyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-carbamic acid tert-butyl ester (2.6 g, 7.02 mmol) in DMF (50 mL) at 0° C. was added NaH (0.44 g, 50% purity, 9.12 mmol). After 20 minutes, iodomethane (1.49 g, 10.5 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (30 mL) and TFA (8 mL) was added. The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 1.95 g with high purity (no further purification needed) (99%) as a light yellow solid. ES-MS m/e: 285.1 (M+H+).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[N:23]1C=CC=CC=1>>[NH2:23][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccncc1
Agent: O=C(OO)c1cccc(Cl)c1
Product: Nc1nc(Cl)c2[nH]cnc2n1
Yield: 25 %

Procedure:
The synthesis of purine analogues needed more careful treatments. The key intermediate D-8 was condensed with 6-chloropurine and 2-fluoro-6-chloropurine to give the corresponding nucleosides D-21 and D-22 in 65% and 66% yield, respectively. To achieve a clean and high-yield conversion, the temperature of the reaction mixture had to be carefully controlled in such a manner that, after addition of TMSOTf at 0° C., the reaction mixture was stirred for 6 hours at room temperature and then for 2 hours at 60° C. The 6-chloropurine derivative D-21 was syn-eliminated by successive treatment with mCPBA and pyridine to give an inseparable mixture of 2′,3′-unsaturated nucleoside D-23 and its Δ1,2-isomer D-24 in 81% yield (3:1 determined by 1H NMR). Amination of the mixture of D-23 and D-24 by treatment with methanolic ammonia at 100° C. in a steel bomb gave the adenosine analogue, which was deprotected by TBAF in THF to give 2′-fluoro4′-thio-2′,3′-unsaturated adenosine 24 in 61% yield. The Δ1,2-isomer D-24, however, did not survive under reaction conditions and silica gel column chromatography due to its instability. The 2-fluoro-6-chloropurine derivative D-22 was also treated with mCPBA followed by pyridine to give an inseparable mixture of the syn-eliminated product D-25 and its Δ1,2-isomer D-26 in 71% yield. Dry ammonia gas was bubbled into a solution of D-25 and D-26 in ethylene glycol dimethyl ether (DME) at room temperature for 16 hours to give the 2-amino-6-chloropurine derivative D-29 and 2-fluoro-6-aminopurine derivative D-30 in 45% and 25% yield, respectively, which were readily separated by silica gel column chromatography. The Δ1,2-isomer D-26 was not stable enough to survive the reaction and purification conditions.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-]>CO>[CH2:1]([O:8][C:9]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1)(=[O:13])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Agent: [OH-]
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(C(=O)O)cc1)OCc1ccccc1
Reaction time: 0.58 h

Procedure:
A suspension of methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate (3.38 g) and 85% pottasium hydroxide (1.28 g) in methanol (40 mL) was stirred for 35 minutes. Methanol was evaporated off, and to the mixture was added 1N hydrochloric acid (20 mL). A white crystal was formed, which was collected by filtration and washed with water and diisopropyl ether, and dried under vacuum. 4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid was obtained as a white crystal (2.92 g).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)=O)=[CH:13][CH:12]=1)([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].Cl>CO>[C:1]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([C:4]([C:7]([F:8])([F:9])[F:10])([F:6])[F:5])([F:3])[F:2]
Reactant: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(C(F)(F)C(F)(F)C(F)(F)F)cc1
Yield: 71.4 %

Procedure:
A solution of p-C3F7C6H4OC(O)CH3 (33.2 g; 0.14 mole) in CH3OH (200 ml) containing concentrated HCl (20 ml) was heated to reflux for 24 hours. After cooling and aspiration of the solvent, a brown liquid resulted (28.4 g; 99% crude yield). A gas chromatographic analysis indicated primarily one major component. Distillation provided the product p-C3F7C6H4OH (26.2 g; 92% yield).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]=3)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:2][CH2:1][NH2:3])=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]=3)[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Oc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Reactant: CCN
Product: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine was prepared analogously to 2-{1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine using 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-ol in place of 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 65).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCCC1

Procedure:
Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) and 4-methylsulfonylphenylboronic acid, follow a procedure significantly analogous to that found in Example 22 to give the titled compound. MS (m/e): 411.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[CH:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH:12][OH:13])[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC=O
Product: N#CC(=CO)c1ccc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
0.6 g of metal sodium was added to dry ethanol to obtain an ethanol solution of sodium ethoxide. Then, a mixed liquid comprising 37.2 g of 2,4-dichlorophenyl acetonitrile and 22.2 g of ethyl formate, was added thereto under heating to 70° C. After the addition, the mixture was further heated and refluxed for 2 hours and then, left to stand for 1 day. The reaction solution was cooled to 0° C. and then subjected to filtration. After washing with diethyl ether, the sodium salt collected by filtration was added to 130 ml of distilled water, and 9 ml of acetic acid was dropwise added thereto under cooling at 0° C. After the dropwise addition, the mixture was stirred at room temperature for about 30 minutes. Then, the formed precipitate was collected by filtration and washed with water. It was dried to obtain 31.7 g (yield: 74%) of the desired product. Melting point: 162-163° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([NH2:38])(=[O:37])[CH2:35]O>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:35][C:34](=[O:37])[NH2:38])=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: NC(=O)CO
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 15.5 g (0.05 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 8.50 g (0.052 mol) of 1,1'-carbonyldiimidazole in 350 ml of tetrahydrofuran is stirred at room temperature for 2 hours and 4.00 g (0.052 mol) of glycolamide are added thereto. After stirring at room temperature overnight, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with methylene chloride-methanol (20:1) and crystallization from ethyl acetate/ether gives carbamoylmethyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate as white crystals with melting point 114°-116°.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1([NH2:22])[CH2:13][CH2:12][CH2:11][C:10]2[N:9]=[C:8]([O:14]CC3C=CC=CC=3)[CH:7]=[CH:6][C:5]1=2.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:22][C:4]1([CH3:3])[CH2:13][CH2:12][CH2:11][C:10]2[NH:9][C:8](=[O:14])[CH:7]=[CH:6][C:5]1=2
Reactant: [H][H]
Reactant: CC1(N)CCCc2nc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(N)CCCc2[nH]c(=O)ccc21
Yield: 56.2 %

Procedure:
5,6,7,8-Tetrahydro-5-methyl-2-(phenylmethoxy)-5-quinolinamine dihydrochloride (9.5 g) and 10% palladium-on-carbon (730 mg) in absolute ethanol (500 ml) were shaken on a Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen unptake ceased. The catalyst was removed by filtration, and the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was suspended in hot methanol and the solid was collected. The solid was combined with the material that crystallized from the methanol to afford 3.36 g (56%) of product, mp 214°-216° C. (dec).
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:1]([NH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:38](=[O:39])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[CH:32]([O:31][C:28](=[O:30])[CH3:29])[C:41]([CH3:47])([CH3:48])[CH2:42][O:43][C:44](=[O:46])[CH3:45])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1NC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O
Yield: 61.7 %

Procedure:
2-Oleoylaminoaniline (744 mg) and 606 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 810 mg of the title compound (yield: 65%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)CC)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(I)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: COc1ccc(Cc2ccc(NC(=O)OC(C)(C)C)cc2)cc1-c1cccc(Cl)c1
Reaction time: 0.17 h

Procedure:
Synthesis of [4-(3′-Chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-ethyl-carbamic acid tert-butyl ester (I-302) I-301 (140 mg, 0.33 mmol) was dissolved in 2 mL of DMF and stirred for 10 minutes under N2; then NaH was added. Once effervescence had ceased. ethyl iodide was added and the reaction mixture was stirred at room temperature for 2 hours and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3×5 mL), and the combined organic extracts were washed with brine and dried over Na2SO4. After filtration and removal of solvent, 120 mg (81%) of I-302 was collected.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH:20]=[CH2:21])[C:11]=3[C:12]=2[CH3:13])=O)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: C=CCc1c(O)ccc2oc(C(=O)c3ccc(F)cc3)c(C)c12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2oc(Cc3ccc(F)cc3)c(C)c12
Yield: 41.9 %

Procedure:
A solution of 2-(p-fluorobenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran (1.5 gm; 4.8 mmoles) in ethanol (50 mL) was hydrogenated in a Parr apparatus in presence of 10% palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 600 mg (42%) of 2-(p-fluorobenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp 121°-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH:20]=[C:21]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:12]=2)=[CH:4][CH:3]=1.[NH2:32][O:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:35][C:34]([O:37][CH3:38])([O:33][NH:32][C:28](=[O:29])[CH2:27][CH2:26][C:21]1[C:22]2[C:17](=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH3:31])[CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH:20]=1)[CH3:36]
Reactant: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC(=O)O)c(C)o2)cc1
Reactant: COC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(C)(C)ONC(=O)CCC1=CCCc2c(OCCc3nc(-c4ccc(C)cc4)oc3C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a dimethylformamide (5 ml) solution of the compound (208 mg) prepared in Example 2 and 2-aminooxy-2-methoxypropane (57.7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), 1-hydroxybenzotriazole (81 mg) and triethylamine (83 μl ) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with methylene chloride. The diluted solution was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to thereby obtain the title compound (239 mg) having the following physical data.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])(=[O:34])=[O:33])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:40])([F:41])[F:42])(=[O:34])=[O:33])[C:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCNS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCNS(=O)(=O)CCCC(F)(F)C(F)(F)F
Yield: 71.7 %

Procedure:
To a solution of 7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]thiochroman (124 mg, 0.186 mmol) in methylene chloride (1 ml) was added at −78° C. BBr3 (1.0 mol/l, 1.12 ml), which was then slowly warmed over 3 hours. After the reaction was completed, saturated aqueous NaHCO3 solution was added at 0° C. The resulting mixture was then extracted with methylene chloride and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]thiochroman (85.0 mg, yield 72%) and trans form thereof (12.0 mg, yield 10%).