Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([S:14][CH3:15])[N:6]=1)(=[O:3])[CH3:2].[CH2:16]([O:23][C@H:24]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:27]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:26][C@@H:25]1Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:25]2[O:26][C@H:27]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:24]2[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([S:14][CH3:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CSc1nc(NC(C)=O)nc2nc[nH]c12
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1nc(NC(C)=O)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A mixture of 4.46 g. of 2-acetamido-6-methylthiopurine, 4.87 g. of 2,3,5-tri-O-benzyl-α-D-arabinofuranosylchloride, 2 g. of triethylamine and 200 ml. of acetonitrile was stirred with 4-A molecular sieves at room termperature for one week. The mixture was filtered, and the filtrate, which contained the product, was evaporated to a syrup in vacuo. The syrup was dissolved in methanol treated with Dowex-1 (bicarbonate) and the product was purified by chromatography on a Silica gel column, eluted with benzene-ethyl acetate. Evaporation of the solvent gave the syrup 2-acetamido-6-methylthio-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl) purine. To a solution of 1.13 g. of the compound isolated from the previous step in 20 ml. of ethanol, 0.25 ml. of 10N NaOH plus 0.5 ml. of water were added. The stirred solution was kept at 70° for 30 min. and then evaporated to dryness in vacuo. The product was extracted into ether. After evaporation of the ether, 0.92 g. of 2-amino-6-methylthio-9-( 2,3,5-tri-O-benzyl-β-D-arabinofuranosyl) purine was obtained. The identity was established by its NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32]Br)(=[O:23])[CH3:22].C(O)(=O)C>CN(C=O)C>[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1CBr
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1Cn1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-6-benzyloxypurine (1 mmol) in DMF (2 mL) was added sodium hydride (1.15 eq) and the mixture stirred at room temperature for 30 minutes. A solution of 1(R)-acetoxymethyl-2(S)-bromomethylcyclohex-4-ene (1.1 eq) in DMF (0.75 mL) and the reaction stirred at 60° C. for 16 hours. The reaction was neutralized with acetic acid and concentrated. The desired compound was purified by silica gel chromatography (chloroform:methanol 95:5) as a colorless foam. 1HNMR (500 mHz, CDCl3): 8.02 ppm (s, 1H); 7.65 (s, 1H); 7.49 (d, 2H); 7.38-7.26 (m, 3H); 5.65 (dd, 2H); 5.56 (s, 2H); 4.33 (dd, 1H); 4.12 (dd, 1H); 4.06-3.97 (m, 2H); 2.40 (bs, 1H); 2.23-1.75 (m, 6H); 2.20 (s, 3H).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:17]=[CH:16][C:7]2[S:8][C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][C:6]=2[CH:5]=1>O.C(O)C>[I:3][C:4]1[CH:17]=[CH:16][C:7]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cc2cc(I)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc(I)ccc2s1
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Sodium hydroxide (5 g) in water (150 ml) was added to ethyl 5-iodobenzo[b]thiophene-2-carboxylate (14 g) in ethanol (200 ml) and the mixture was stirred for 16 hours. The mixture was concentrated to about 150 ml by evaporation and the mixture was adjusted to ~pH 3 by addition of dilute hydrochloric acid. The mixture was then extracted with diethyl ether (2×100 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 5-iodobenzo[b]thiophene-2-carboxylic acid (11.7 g) as a solid; NMR (d6 -DMSO): 7.8 (dd, 1H), 7.9 (d, 1H), 8.05 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5](Cl)=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([OH:24])[C:22]#[CH:23]>C(N(CC)CC)C>[F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5]([C:23]#[C:22][CH2:21][OH:24])=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2nc(Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: C#CCO
Solvent: CCN(CC)CC
Product: Cn1nc(-c2nc(C#CCO)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 67 °C
Reaction time: 8 h

Procedure:
2.0 of 3-(3-fluoro-5,6-dichloro-2-pyridyl)-4-chloro-5difluoromethoxy-1-methyl-[1H]-pyrazole (Example H21) are initially introduced into 15 ml of triethylamine, and 0.37 ml of propargyl alcohol is added. The mixture is then evacuated and gassed with argon 3 times under a partial water pump vacuum. Thereafter, 0.03 g of copper(I) iodide and 0.12 g of bis-triphenylphosphine-palladium dichloride (PdCl2(PPH3)2) are added and the mixture is stirred overnight at 67° C. under argon. The following day, after cooling to 22° C., 0.20 ml of propargyl alcohol, 0.03 g of copper(l) iodide and 0.12 g of PdCl2(PPH3)2 are added. The mixture is then stirred at 67° C. for 6 hours. After cooling to 22° C., ethyl acetate is added and the mixture is washed successively with dilute hydrochloric acid, water and brine. After drying over sodium sulfate, filtration and concentration in vacuo, the residue is purified over a silica gel flash column (eluting agent: n-hexane/ethyl acetate 1/1). 0.97 g of the desired title compound is obtained as a yellow oil which gradually crystallizes; melting point 92-94° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) (1.20 g, 5.43 mmol) and cesium carbonate (1.77 g, 5.43 mmol) in DMF (10 ml) was sonicated for 15 minutes. Iodomethane (0.372 ml, 5.97 mmol) was added and the mixture was stirred at room temperature. After 1 hr more iodomethane (0.05 ml) was added and stirring was continued for a further 30 minutes. The solvent was evaporated, ethyl acetate and 2N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by trituration with ethyl acetate and/or chromatography on silica gel (elution with ethyl acetate) gave the title compound (D41). (1.042 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:36])[N:4](C(C2C=CC=CC=2)=O)[C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[N:7]=1.CO>N>[CH3:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[N:7]=1
Reactant: Cc1nn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: N
Solvent: CO
Product: Cc1nn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
6-methyl-4-(phenylcarbonyl)-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P4, 102 mg, 0.205 mmol) was dissolved in a 2.0 M solution of ammonia in MeOH (2.046 ml, 4.09 mmol) and the mixture was stirred for 2 hours at rt. Solvent was eliminated under reduced pressure and crude was purified by flash chromatography (eluent DCM to DCM/MeOH/NH3 9:1:0.1) affording the title compound 6-methyl-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (E1, 67.7 mg, 0.172 mmol).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[N+:21]([O-])(OCC(C)C)=O.C(O)(=O)C>CCOCC.CCCCCC.O>[NH2:21][C:4]1[C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: CC(C)CO[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1cccc2c1Nc1ccccc1C=C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
1 g (5.2 mmol) of 5H-dibenz(b,f)azepine was suspended in 40 ml of dry ether and 9.7 ml (15.5 mmol) of a 1.6M solution of n-butyllithium in hexane was dropped thereinto under stirring at room temperature. After 24 hours, the reaction mixture was cooled in a dry ice-acetone bath and 2 ml of a solution of 0.93 g (7.8 mmol) of isobutyl nitrate in dry ether was dropped thereinto. After stirring at room temperature for 30 minutes, 2 ml of acetic acid was added thereto. Then the reaction mixture was poured into 50 ml of water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. Then the residue was purified by silica gel column chromatography to thereby give 4-nitro-5H-dibenz(b,f)azepine. This product was dissolved in 50 ml of tetrahydrofuran and 1 g of zinc dust was added. Under stirring, conc. hydrochloric acid was dropped thereinto. When the reaction mixture turned from reddish brown into pale yellow, the addition was ceased and the formed insoluble matters were filtered off. The filtrate was made basic by adding diluted aqueous ammonia and then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated and the residue was purified by silica gel column chromatography. Thus 45 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=C)=[N:9]2)[CH:5]=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=[O:22])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C=Cc1nn(-c2cncc(F)c2)cc1NC(=O)C(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)isobutyramide (0.706 g, 2.57 mmol) in tetrahydrofuran (12.87 ml) and water (12.87 ml) was added osmium tetroxide (0.164 ml, 0.026 mmol). After 10 minutes at room temperature, sodium periodate (1.101 g, 5.15 mmol) was added in portions over 3 minutes and the resulting solution was stirred at room temperature. After 18 hours, the solution was poured into 10 mL water and was extracted with 3×10 mL dichloromethane. The combined organic layers were dried, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide (626 mg, 2.266 mmol, 88% yield) as a yellow solid: mp 140.0-142.0° C.; 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.92 (dt, J=9.2, 2.4 Hz, 1H), 2.65 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H); ESIMS m/z 277 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1.O.C(OCC)(=O)C>[C:10]([N:9]1[C:6]2[C:5](=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[C:14]([CH3:16])([CH3:15])[CH2:13]1)(=[O:12])[CH3:11]
Reactant: C=C(C)CN(C(C)=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Yield: 33.1 %

Procedure:
A solution of N-(4-methoxyphenyl)-N-(2-methylallyl)acetamide (1.00 g, 4.56 mmol) and aluminium chloride (2.0 g, 15.0 mmol) in 1.0 mL of chlorobenzene was stirred at 110° C. for 3 h. After the reaction mixture was cooled to 0° C., the reaction mixture was diluted with water and ethyl acetate. The separated organic layer was washed with 1 M HCl, saturated NaHCO3 aqueous solution and brine, successively, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 20/80) to obtain the title compound (0.31 g, 33%), and followed by recrystallization (hexane/ethyl acetate) to obtain the title compound (0.17 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-piperidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 98-100° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (bs, 6 H), 2.06 (s, 2 H), 2.33 (s, 4 H), 2.55-2.94 (m, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.20-6.35 (bd, 1H), 6.95 (s, 1H), 7.04 (d, J=12.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.55-7.61 (m, 3H), 7.81-7.83 (m, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 10.45 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH:2]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1)=[O:1]
Reactant: CCOC(=O)CCCOc1ccc(CO)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCOC(=O)CCCOc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 63.1 %

Procedure:
4-[4-(Hydroxymethyl)2-nitrophenoxy]butanoic acid, ethyl ester (300 mg, 1.06 mmol) is treated with 799 mg (3.71 mmol) of pyridinium chlorochromate by the procedure described in Example 5 to give 188 mg (63%) of 4-(4-formyl-2-nitrophenoxy)butanoic acid, ethyl ester as a colorless oil. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1700, 1610, 1570 cm-1 ; MS (CI) m/e 282 (M+H).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:10][C:4]=2[N:3]=1.[Cl-].Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][NH+:22]=1.[OH-].[Na+]>C(O)C>[CH3:28][O:27][C:25]1[C:24]([O:29][CH3:30])=[CH:23][N:22]=[C:21]([CH2:20][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:10][C:4]=3[N:3]=2)[CH:26]=1
Reactant: FC(F)C(F)(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1c[nH+]c(CCl)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)cc1OC

Procedure:
1.40 g of the title compound are obtained as a yellow oil by the procedure described in Example 1, by reacting 1.07 g of 2-mercapto-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with 0.90 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 15 ml of ethanol with the addition of 17 ml of 0.5N sodium hydroxide solution. Recrystallization from petroleum ether yields 1.20 g (72% of theoretical) of the desired compound as colorless crystals of m.p. 125°-127° C.
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH2:8][CH2:7]2.[OH-:20].[Na+].OO>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:20])[CH2:8][CH2:7]2
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CCC=C2c1ccccc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Yield: 37 %

Procedure:
Borane in tetrahydrofuran (34 mL of a 1M solution, 34 mmol) was added to tetrahydrofuran (50 mL) and the resultant solution was cooled to 0° C. A solution of 6-methoxy-1-phenyl-3,4-dihydronaphthalene 28 (5.0 g, 21.2 mmol) in tetrahydrofuran (10 mL) was added. The resultant mixture was stirred at ambient temperature for 18 h. A solution of water (5 mL) in tetrahydrofuran (20 mL) was slowly added to the cooled solution which resulted in considerable foaming. Additional water (10 mL) was added followed by 10% aqueous sodium hydroxide (15 mL) and 30% hydrogen peroxide (30 mL). The resultant mixture was stirred at room temperature for 6 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic solutions were washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 30 to 40% ethyl acetate in hexanes as the eluent, to afford trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 as an oil (2.0 g, 37%). 1H NMR(CDCl3) δ1.77 (d, 1H), 1.83-1.97 (m, 1H), 2.13-2.22 (m, 1H), 2.94-3.05 (m, 2H), 3.78 (s, 3H), 3.90 (d, 1H), 3.98-4.07 (m, 1H), 6.59-6.70 and 7.16-7.39 (m, 8H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([CH3:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37][CH:38]=C)[CH3:36])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])[CH2:7][CH2:6]1)[CH:2]=C.C(OC1(C)CCN(C2N3N=C(C4C=C(C5C(O[C@H](CC=C)C)=CC=C(F)C=5C)C=CC=4)C=C3N=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH2:2][CH2:38][CH2:37][C@H:35]([CH3:36])[O:34][C:27]2[CH:28]=[C:29]([CH3:33])[C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([OH:44])=[O:43])([CH3:49])([CH3:50])[CH3:48]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)c(C)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5C)c4)nn23)CC1
Product: Cc1cc2c(cc1F)-c1cccc(c1)-c1cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Yield: 9 %

Procedure:
Prepared from a 2:1 mixture of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-fluoro-2′-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate using the same procedures as intermediates 170 and example 81 in 9% yield. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.92-6.82 (m, 2H), 6.78 (s, 1H), 5.54 (s, 1H), 4.62-4.43 (m, 2H), 3.83 (d, J=10.5 Hz, 1H), 3.67-3.58 (m, 1H), 3.38 (d, J=6.8 Hz, 1H), 2.87 (d, J=12.2 Hz, 1H), 2.58 (s, 3H), 2.24 (s, 3H), 1.93-1.84 (m, 3H), 1.78-1.59 (m, 5H), 1.57-1.42 (m, 3H), 1.14 (s, 12H), 1.02 (d, J=5.9 Hz, 3H). LCMS (M+1)=659.6.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[C:29]([O:31]CC)=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Yield: 71.2 %

Procedure:
Ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.38 g, 0.53 mmol) and sodium hydroxide (170 mg, 4.2 mmol) were added to an ethanol/water mixture (2:1, 15 ml), followed by heating under reflux for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, the solvent was distilled off and the resulting residue was diluted with water, adjusted to pH 2-3 with 1N hydrochloric acid, and then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid (260 mg, Yield 87%) as a colorless foam.
Reaction SMILES: O[C:2]([CH3:36])([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C:2]([CH3:35])([CH3:36])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(C)(C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C)(C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.1 %

Procedure:
N-(2-Hydroxy-2-methylpropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (307 mg, 0.594 mmol) synthesized in Example (36a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (160 mg, 0.918 mmol) and triethylamine (0.25 mL, 1.79 mmol) were added, followed by stirring at room temperature for 4 days under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (187 mg, yield 63%) as a white solid.