Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[C:19]([CH3:32])[C:3]=1[O:4][CH2:5][CH2:6][NH:7][C@@H:8]([CH3:18])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[OH:10].Br[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[CH3:43].[F-].[Cs+].O1CCOCC1>O1CCCC1.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.C(O)C>[OH:10][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C@@H:8]([NH:7][CH2:6][CH2:5][O:4][C:3]1[C:19]([CH3:32])=[CH:20][C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=2[CH3:43])=[CH:22][C:2]=1[CH3:1])[CH3:18]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1cc(C)c(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(C)c1
Temperature: 100 °C
Yield: 22.6 %

Procedure:
A mixture of 4-((1R,2S)-2-{2-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethylamino}-1-hydroxypropyl)phenol (0.02 g), 4-bromo-3-methylbenzoic acid (0.020 g), tetrakis(triphenylphosphine)palladium (0.0027 g), cesium fluoride (0.041 g), 1,4-dioxane (0.75 mL), ethanol (0.25 mL) and water (0.15 mL) was stirred at 100° C. over night. After being cooled to room temperature, the reaction mixture was diluted with tetra hydrofuran (2.5 mL). The crude product was purified by SCX ion exchange column chromatography (Argonaut 1 g, preconditioning: tetra hydrofuran, washing solvent: tetra hydrofuran, eluent: 2 mol/L ammonia in methanol), followed by reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 120 Å, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.0046 g) as a white amorphous. The structure and physical data were shown in table 1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[O:58][CH3:59])C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([C@H:40]([O:58][CH3:59])[O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 76.4 %

Procedure:
To a solution of 54 (22 mg, 27 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (20 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 55 (9.3 mg, 76%). 1H NMR (300 MHz, CD3OD) δ 7.20 (s, 1H), 7.06 (s, 4H), 6.82 (s, 1H), 5.61 (s, 1H), 3.99 (s, 2H), 3.63-3.79 (m, 3H), 3.55 (s, 3H), 3.42-3.60 (m, 3H), 2.57 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H). LCMS m/z 451 (M+H), 473 (M+Na).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)=[O:5].[CH3:17][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4](=[O:5])[CH3:17])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of quinoline-6-carboxylic acid methoxy-methyl-amide (11.97 g, 55.35 mmol) in anhydrous THF (200 mL) was added MeMgBr (1.5 M in THF, 55 mL, 83 mmol) at 0° C. under nitrogen. The reaction was allowed to warm to ambient temperature over 16 hours. Sat. NH4Cl (20 mL) was added to quench the reaction. The reaction solution was then extracted with EtOAc (3×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give 1-quinolin-6-yl-ethanone (9.2 g, 97% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:26]([O:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 66.1 g. (0.25 mol.) of (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid and 250 ml. each of pyridine and acetic anhydride was stirred at 25°C. under N2 for 20 hours and stripped of solvent at 40°C. to give an orangebrown oil. To a suspension of this material in 500 ml. of H2O and 100 ml. of tetrahydrofuran was added 166 g. (2.0 mol.) of NaHCO3. The suspension was stirred at 25°C. for 4.0 hours, washed with ether, acidified with 2N-aqueous HCl and extracted with ether. The ether solutions were washed with saturated brine, dried over sodium sulfate and stripped of solvent to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as an orangeish resin. Crystallization from diethyl ether petroleum ether (b.p. 30°-60°C.) gave (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as a granular white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.ClC1SC(S(N(S(C2SC(Cl)=CC=2)(=O)=O)C2C3C(=CC=CC=3OC)N(C(OC(C)(C)C)=O)N=2)(=O)=O)=CC=1.[C:50]1(=O)[O:55][C:53](=[O:54])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([N:12]1[C:53](=[O:54])[C:52]3[C:51](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:50]1=[O:55])=[N:6][NH:7]2
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: O=C1OC(=O)c2ccccc21
Agent: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COc1cccc2[nH]nc(N3C(=O)c4ccccc4C3=O)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4-(Methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (500 mg, 3 mmol) and phthalic anhydride (680 mg, 4.6 mmol) (available from Aldrich) were dissolved in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 110° C. overnight, and then it was cooled and concentrated under reduced pressure. The residue was triturated and sonicated with 50 mL of ether. The solid was collected by filtration and dried in a vacuum oven to obtain a brown solid (711 mg, 81%). LCMS (System B) RT=2.82 min, ES+ve m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][CH:4]([CH2:18][OH:19])[CH2:3]1.Cl>[Zn].O>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][CH:4]([CH2:18][OH:19])[CH2:3]1
Reactant: CN1CC(CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CN1CC(CO)C[C@@H]2c3cccc4c3C(CN4)C[C@H]21

Procedure:
A suspension of 8.13 g. of 6-methyl-8-hydroxymethylergoline and 560 g. of zinc metal dust in 250 ml. of water was cooled to 5° C. in an ice-water bath and stirred. To the cold reaction mixture was added 2500 ml. of concentrated hydrochloric acid dropwise over 6 hours. The acidic aqueous reaction mixture was filtered and the filtrate was made alkaline by the addition of ammonium hydroxide. The aqueous alkaline reaction mixture was extracted with chloroform, and the combined chloroform extracts were washed with water, dried, and the solvent was removed under reduced pressure to afford an oil. The oil was crystallized from methanol,providing 2,3-dihydro-6-methyl-8-hydroxymethylergoline, M.P. 226°-228° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl.Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(CCl)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloromethylbenzoyl chloride (5.0 g) and pyrrolidine (2.2 mL) in dichloromethane (30 mL) at 0° C. was treated with ethyldiisopropylamine (5.2 mL). The resulting mixture was warmed to room temperature over 1 hour and then stirred at this temperature for 2 hours. The mixture was diluted with 1.0 M aqueous hydrochloric acid, extracted with dichloromethane and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 6.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc2cnccc12)c1ccccc1
Temperature: 0 °C
Yield: 103.6 %

Procedure:
To a solution of 5-hydroxyisoquinoline (15.0 g, 103 mmol) in dichloromethane (300 ml) was added triethylamine (10.9 g, 108 mmol), and the mixture was cooled to 0° C. Under stirring, benzoyl chloride (15.2 g, 108 mmol) was added dropwise and the temperature was raised to room temperature. After stirring for 6 hours at room temperature, dichloromethane was added. The solution was washed with saturated aqueous solution of sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and solvent was distilled off, thereby affording 26.6 g of the title compound as a light brown liquid. Yield quantitative. 1H-NMR (DMSO-d6, δ): 7.68(2H, t, J=7.3 Hz), 7.75(1H, d, J=5.9 Hz), 7.79-7.85(3H, m), 8.12-8.16(1H, m), 8.28(2H, d, J=7.3 Hz), 8.55 (1H, d, J=5.9 Hz), 9.45(1H, s).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:36])[CH2:21][NH:22][C:23]([C:25]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:27][N:26]=3)=[O:24])[CH2:16][CH2:15]2)[CH:8]=1>CO.O>[C:30]1([C:28]2[NH:27][N:26]=[C:25]([C:23]([NH:22][CH2:21][C:20]([N:17]3[CH2:16][CH2:15][CH:14]([O:13][C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[C:6]([OH:37])=[O:5])[CH2:19][CH2:18]3)=[O:36])=[O:24])[CH:29]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
LiOH.H2O (44 mg, 1.0 mmol) was added to a stirred mixture of 3-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid methyl ester (prepared by the method used to generate Example 92) (99 mg, 0.2 mmol) in MeOH: H2O (1:1, 4 mL) was added, and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. Cold water was then added and acidified it with 10% aqueous HCl and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with diethyl ether to afford 87 mg (97.7% Yield) 3-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid. LC/MS [M+H]+: 463, 96.9%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (b, 1H), 13.6 (b, 1H), 8.1 (b, 1H), 7.8 (q, 2H), 7.5 (m, 6H), 7.3 (m, 1H), 7.1 (b, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.7 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][CH2:7][C:8]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:11])=[O:9])=[O:5])[CH3:3].[N+:26]([O-])([O-:28])=[O:27].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[NH2:1][C@H:2]([C:4]([NH:6][CH2:7][C:8]([N:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:26]([O-:28])=[O:27])=[CH:14][C:13]=1[C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:11])=[O:9])=[O:5])[CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: C[C@H](N)C(=O)NCC(=O)N(C)c1ccccc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: C[C@H](N)C(=O)NCC(=O)N(C)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Temperature: -5 °C
Reaction time: 10 h
Yield: 51.5 %

Procedure:
3 g of L-alanyl-N-(2-benzoylphenyl)-N-methylglycinamide were dissolved in 10 ml of anhydrous sulphuric acid at room temperature. The resulting mixture was cooled to -5° C and treated dropwise by the addition of a solution of 0.94 g of potassium nitrate in 3 ml of anhydrous sulphuric acid. The resulting mixture was stirred at 0° C for 10 hours and finally allowed to warm to room temperature overnight. The mixture was then poured into an excess of ice-water. The pH of the mixture was adjusted to approximately pH 9 by the addition of concentrated ammonium hydroxide, care being taken to maintain the temperature at ca 0° C. The mixture obtained was extracted with several portions of dichloromethane. The combined organic phases were washed successively with 2-N sodium carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue (ca 3 g) was dissolved in a minimum amount of chloroform and subjected to column chromatography on Florisil using mixtures of methanol in chloroform in increasing proportions. Fractions were collected using 5% (vol/vol) methanol in chloroform and evaporated in vacuo to give 1.75 g (52%) of pure L-alanyl-N-(2-benzoyl-4-nitrophenyl)-N-methylglycinamide as an almost colourless light-sensitive foam; [α]D20 = +2.1° (c = 1 in ethanol).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[N:44]=[CH:45][C:46]([C:49](OC)=[O:50])=[N:47][CH:48]=2)[CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1.O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][O:24][C:14]2[CH:13]=[C:12]([NH:11][C:49]([C:46]3[CH:45]=[N:44][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[CH:48][N:47]=3)=[O:50])[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 45.2 %

Procedure:
NaHMDS (1M solution in THF, 0.645 ml, 0.644 mmol, 1.5 eq) was added dropwise to a stirred suspension of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (150 mg, 0.429 mmol, 1 eq) and methyl 5-(4-methylpiperazin-1-yl)pyrazine-2-carboxylate (122 mg, 0.515 mmol, 1.2 eq) in dry THF (2.5 ml) under nitrogen. The reaction mixture was stirred at room temperature for 50 min, then neutralised with satd aq NH4Cl and diluted with water (5 ml). The aqueous phase was extracted with ethyl acetate (3×8 ml) and the combined organic extracts were dried over MgSO4, filtered and evaporated. The residual solid was purified by reverse-phase prep. HPLC using a gradient of 31-51% acetonitrile in water containing 1% ammonium hydroxide to afford the product as a white solid (88 mg, 45%).
Reaction SMILES: FC1C=C(CCC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)C=CC=1O.Cl.ClCCN(C(C)C)C(C)C.[F:42][C:43]1[CH:58]=[C:57]([CH2:59][CH2:60][C:61]2[CH:66]=[C:65]([O:67]C)[CH:64]=[CH:63][C:62]=2[CH:69]2[CH2:78][CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[C:74]([O:79]C)[CH:75]=3)[CH2:70]2)[CH:56]=[CH:55][C:44]=1[O:45][CH2:46][CH2:47][N:48]([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50]>>[CH:52]([N:48]([CH:49]([CH3:51])[CH3:50])[CH2:47][CH2:46][O:45][C:44]1[CH:55]=[CH:56][C:57]([CH2:59][CH2:60][C:61]2[CH:66]=[C:65]([OH:67])[CH:64]=[CH:63][C:62]=2[CH:69]2[CH2:78][CH2:77][C:76]3[CH:75]=[C:74]([OH:79])[CH:73]=[CH:72][C:71]=3[CH2:70]2)=[CH:58][C:43]=1[F:42])([CH3:54])[CH3:53]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)C2
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)c(F)c1)C2
Agent: Cl
Product: CC(C)N(CCOc1ccc(CCc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1F)C(C)C
Yield: 55.2 %

Procedure:
Synthesized from 2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-{2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}diisopropylamine (199 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (104 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:11]2([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:31][O:32][CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[F:27][C:25]([F:28])([F:26])[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=2)[C:11]2([OH:17])[CH2:16][CH2:15][N:14]([CH2:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][O:32][CH3:31])=[CH:43][CH:42]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COCCOc1ccc(C=O)cc1
Reactant: OC1(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCOc1ccc(CN2CCC(O)(C(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 2.2 grams (0.0050 mole) of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol, 1.1 grams (0.0061 mole) of 4-(2-methoxyethoxy)benzaldehyde and 1.35 grams (0.0064 mole) of sodium triacetoxyborohydride in 25 mL of methylene chloride was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 200 mL of water and stirred at ambient temperature for 5 hours. The phases were separated. The organic phase was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride:1%-5% methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=[CH2:3].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Solvent: c1ccncc1
Solvent: O
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of nucleoside 2 (35.0 g, 7.31 mmol) in anhydrous pyridine (23 cm3) at 0° C. was added methanesulphonyl chloride (1.69 cm3, 21.89 mmol). The reaction mixture was stirred for 1 h at room temperature, water (100 cm3) was added and extraction was performed using dichloromethane (3×150 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×200 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane/methanol (99:1) as eluent to give 3 as a white solid material (3.64 g, 89%). δH (CDCl3) 8.95 (1 H, br s, NH), 7.71 (1 H, d, J 1.1, 6-H), 7.39-7.25 (10 H, m, Bn), 6.52 (1 H, d, J 8.0, 1′-H), 5.90 (1H, m, 2″-H), 5.34 (1 H, d, J 7.9, 2′-H), 5.20-5.09 (2 H, m, 3″-Ha, 3″-Hb), 4.91 (1 H, d, J 11.2, Bn), 4.68 (1 H, d, J 11.3, Bn), 4.64 (2 H, s, Bn), 4.33 (1 H, br s, 4′-H), 3.81 (1 H, dd, J 2.5, 11.1, 5′-Ha), 3.73 (1 H, dd, J 1.1, 11.1, 5′-Hb), 3.08 (1 H, dd, J 5.5, 5.7, 1″-Ha), 2.99 (3 H, s, CH3), 2.68 (1 H, m, 1″-Hb), 1.51 (3 H, d, J 0.8, CH3). δC (CDCl3) 163.4 (C-4), 150.8 (C-2), 137.9, 136.3 (Bn), 135.5 (C-6), 131.0 (C-2″), 128.8, 128.3, 127.5, 127.2 (Bn), 119.3 (C-3″), 111.6 (C-5), 84.1, 83.6, 82.4, 82.2 (C-1′, C-2′, C-3′, C-4′), 73.7, 68.9 (Bn), 66.2 (C-5′), 38.7 (CH3), 33.0 (C-1″), 11.9 (CH3) Found: C, 60.5; H, 5.8; N, 4.9. C28H32N2O8S requires C, 60.4; H, 5.8; N, 5.0%).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.N1C=CC=CC=1.[FH:23]>ClCCl>[F:23][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](F)C1
Reaction time: 8 h

Procedure:
benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.5 g, 47.9 mmol) and pyridine-hydrogen fluoride (14.2 g, 144.0 mmol) were added to a Teflon bottle containing dichloromethane and stirred vigorously overnight. After 20 hours, the reaction was slowly and carefully quenched with excess saturated solution of NaHCO3 over several minutes and allowed to stir for one hour, and then the organic layer was isolated and washed with NaHCO3 and a solution of brine. The combined organic layers were dried over MgSO4, filtered and evaporated to yield an oil. This crude oil was purified on silica gel using ethyl acetate-hexane to produce 2.0 g (17% isolated yield) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([O:18][CH3:19])[CH2:16][CH3:17].ClC1(Cl)C(O)CC2C1CCC2CCCCC(OC)CC>C(O)(=O)C.[Zn]>[CH3:19][O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][CH:9]([OH:10])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC
Agent: CCC(CCCCC1CCC2C1CC(O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(O)CC12)OC

Procedure:
The reactions of this example can also be conducted using an equivalent amount of 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo [3.3.0]octan-7-one {1-1-dichlorohexahydro-4-(5-methoxyheptyl)-2 (1H)-pentalenone} to first prepare 6,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo[3.3.0]octan-7-ol {1,1-dichlorooctahydro-4-(5-methoxyheptyl)-2-pentalenol} which is then treated by the zinc in glacial acetic acid to produce 2-(5-methoxyhept-1-yl)bicyclo [3.3.0]-octan-7-ol {octahydro-4-(5-methoxyheptyl)-2-pentalenol}.