Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([OH:16])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([O:39][CH2:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]2[C:52]3[CH:53]=[CH:54][C:55]([C:57](=[O:60])[CH2:58]Br)=[CH:56][C:51]=3[CH2:50][O:49][CH2:48][C:47]=2[CH:61]=1)=[O:42])=[O:38])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH2:58][C:57]([C:55]2[CH:54]=[CH:53][C:52]3[C:46]4[CH:45]=[CH:44][C:43]([C:41](=[O:42])[CH2:40][O:39][C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][N:32]5[C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])=[O:38])=[CH:61][C:47]=4[CH2:48][O:49][CH2:50][C:51]=3[CH:56]=2)=[O:60])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(C(=O)CBr)ccc1-2
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(C(=O)COC(=O)C3C4CCC(C4)N3C(=O)OC(C)(C)C)ccc1-2
Reaction time: 10 h
Yield: 80.7 %

Procedure:
To the solution of 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.42 mmol) and triethylamine (50 μl, 0.36 mmol) in acetonitrile (2 ml) was added a solution of pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,e]oxepin-3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (136 mg, 0.24 mmol) in DMF (4 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{9-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-5,7-dihydro-dibenzo[c,e]oxepin-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester (142 mg). m/z: 731.3 (M−H)−, 755.2 (M+Na)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][S:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH2:1]([C:8]1[C:9]2[CH2:30][S:29](=[O:39])[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CSCC3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CS(=O)CC3)cc1
Reaction time: 2 h
Yield: 13.8 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (90 mg, 0.22 mmol) and mCPBA (56.3 mg, 0.33 mmol) was dissolved in DCM (4 mL). The reaction was completed after 2 h. The solvent was evaporated and the crude product was purified on preparative HPLC yielding 4-benzyl-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (13.0 mg, 13.0%). MS (ES+) m/z 430.0 (M+H)+
Reaction SMILES: C(C1C=CC([C@@H]2[C@]3(C4C(=CC=C(C(O)=O)C=4)NC3=O)C2)=CC=1)#N.C[O:25][C:26]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C@@:31]12[CH2:39][C@@H:38]1[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)=[O:27].[OH-].[Li+]>CO.O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C@H:38]2[C@@:31]3([C:30]4[C:34](=[CH:35][CH:36]=[C:28]([C:26]([OH:27])=[O:25])[CH:29]=4)[NH:33][C:32]3=[O:37])[CH2:39]2)=[CH:45][CH:44]=1
Reactant: COC(=O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2
Agent: N#Cc1ccc([C@H]2C[C@]23C(=O)Nc2ccc(C(=O)O)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@]1(C[C@H]1c1ccc(F)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
To a solution (1R,2S) and (1S,2R)-methyl-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylate (80 mg) (prepared as in Example 139) in methanol (1 mL) and water (0.1 mL) was added lithium hydroxide (10 mg) at room temperature. The mixture was stirred for 14 hours at room temperature. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound as white solid (30 mg). LC/MS m/e calcd. for C17H12FNO3: 297, observed (M+H)+: 298.2 LC/MS m/e calcd for C17H12FNO3297.08, observed (M−H)+: 296.1; 1HNMR (400 MHz, DMSO-d6) δppm 1.99 (dd, J=9.09, 4.80 Hz, 1 H) 2.35 (dd, J=8.08, 4.80 Hz, 1 H), 3.11 (t, J=8.46 Hz, 1 H) 6.65 (d, J=1.52 Hz, 1 H) 6.94 (d, J=8.08 Hz, 1 H) 7.14 (t, J=8.84 Hz, 2 H) 7.34 (dd, J=8.34, 5.56 Hz, 2 H) 7.72 (dd, J=8.08, 1.52 Hz, 1 H) 10.97 (s, 1 H) 12.36 (br. s., 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>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.C1(C)C=CC=CC=1>[CH3:9][NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH3:25]
Reactant: CNc1ccncc1Br
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 12.3 %

Procedure:
A mixture of 1.26 g (6.75 mmol) (3-bromo-pyridin-4-yl)-methyl-amine, 13 ml toluene, 7 ml 2 N sodium carbonate solution, 234 mg (0.203 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.01 g (7.43 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (sodium sulfate) and evaporated. The residue was purified by flash chromatography to yield 164 mg (12%) of the title compound as a yellow oil.
Reaction SMILES: C([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:18][CH3:19])(=O)C.COC1C=C(C=C(OC)C=1O)C=CC(O)=O.P(Cl)(OCC)(OCC)=O.[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][NH:49][C@H:50]1[CH2:55][CH2:54][C@H:53]([CH3:56])[CH2:52][CH2:51]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][N:49]([C@H:50]1[CH2:51][CH2:52][C@H:53]([CH3:56])[CH2:54][CH2:55]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[C:6]([O:18][CH3:19])[C:5]([OH:4])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: COc1cc(C=CC(=O)O)cc(OC)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc(OC)c1O

Procedure:
Using 2.9 g of 4-acetoxy-3,5-dimethyoxycinnamic acid derived from 3,5-dimethoxy-4-hydroxycinnamic acid by the acetylation thereof, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 75 was carried out. As a result, 1.95 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,5-dimethoxy-4-hydroxycinnamamide (a compound of the present invention) was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=CCCCCCCCC
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Using the general procedure of Example 1, 225 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 65 ml of methanesulfonic acid and 188 ml of 1-decene are heated at 160° C. for a 5-hour period during which time anoher 564 ml of 1-decane is gradually added to the reaction mixture. The mixture is then cooled and the product isolated by the method described in Example 1 to give 183 grams of the above-named product as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7].[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:24]=[CH2:25])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)C(O)(CC(C)(C)c1ccc(I)cc1OC)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)CC(O)(C(=O)OC)C(F)(F)F)c(OC)c1
Yield: 43.7 %

Procedure:
1 g of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid methyl ester, 860 mg of tributylvinyl tin, 103 mg of palladium-dibenzylidene acetone complex and 30 mg of triphenylphosphine in 17 ml of THF are refluxed under argon atmosphere for 57 hours. It is filtered through diatomaceous earth and completely concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->2%), 339 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvaleric acid methyl ester is obtained. The latter is stirred with 56 mg of lithium aluminum hydride in 11 ml of diethyl ether at room temperature for 10 hours. It is added to saturated bicarbonate solution, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 148-mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoro-methylpentanol is obtained. The latter is hydrogenated in 4.3 ml of ethyl acetate with 14 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 127 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanol is obtained. The diol that is obtained is reacted with 0.29 ml of triethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 ml of DMSO at room temperature in 10 hours of reaction time. It is added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->3%), 94 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd].O>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
4-Nitro-N-(tert-octyl)benzamide (30 g, 0.108 mol) dissolved in 200 ml of ethyl acetate is hydrogenated, in a 500 ml hydrogenator, in the presence of 4.8 g of 10% palladium-on-charcoal containing 50% of water, as catalyst (hydrogen pressure: 8-10 bar), at a temperature of 70-75° C. for 1 hour and 15 minutes. After filtration, concentration of the solvent and drying under vacuum, 20.4 g (yield: 76%) of 4-amino-N-(tert-octyl)benzamide are obtained in the form of a light yellow powder, which is used as it is in the following stage.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][Mg]Br.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH:18]=[C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21]([CH2:29][OH:30])=[CH:20]4)[C@@H:15]1[CH2:14][CH2:13][CH2:12]2.C1C[O:34][CH2:33]C1>>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:33]([C@H:12]1[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19]([CH:20]=[C:21]([CH2:29][OH:30])[CH2:22][CH2:23]1)=[CH:18][CH2:17]3)[OH:34]
Reactant: FC(F)(F)CCC[Mg]Br
Reactant: C1CCOC1
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CC=C3C=C(CO)CC[C@]3(C)[C@H]1CC2
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(CO)CC[C@@]43C)[C@@H]1CC[C@@H]2C(O)CCCC(F)(F)F

Procedure:
4,4,4-trifluorobutyl magnesium bromide (0.25M in THF, 4.0 ml, 1.0 mmol) was added to a solution of (17β)-17-carboxaldehydo- androsta-3,5-diene-3-methanol (50 mg, 0.16 mmol) in THF at 0 degrees C. After 0.5 h the reaction was quenched with aqueous ammonium chloride, the aqueous layer was extracted with EtOAc, the combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (silica gel, 20% EtOAc) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[CH3:9])=[O:7])=[CH:4][C:3]=1[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>ClC1C=CC=CC=1>[CH:22]1([C:18]2[N:17]3[C:3]4[C:2]([NH:1][C:28](=[O:29])[C:21]3=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[CH3:9])=[O:7])[CH:4]=4)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOCCN(C)C(=O)c1ccc(N)c(-n2ccnc2C2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1
Product: CCOCCN(C)C(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 150 °C

Procedure:
4-Amino-3-(2-cyclohexyl-1H-imidazol-1-yl)-N-(2-ethoxyethyl)-N-methylbenzamide as synthesized in Production Example 50, 2.51 g, 1,1′-carbonyldiimidazole 1.32 g and chlorobenzene 32 mL were mixed, and under nitrogen atmosphere, the temperature outside the reactor was heated to 150° C. for 16 hours. Allowing the reaction liquid to cool off, the solvent was distilled off therefrom. To the residue ethyl acetate and brine were added and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling the solvent off, the residue was crystallized from t-butyl methyl ether. Further heat-suspending the crystals in ethyl acetate for purification, 993 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=2.P(Br)(Br)[Br:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:16][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: COc1ccc2ncc(Cl)c(O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(Br)c2c1
Temperature: 25 °C

Procedure:
3-Chloro-6-methoxy-quinolin-4-ol from above in dry DMF (80 mL) was cooled in ice and phosphorus tribromide (15.6 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 3.5 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (13.2 g). MS (ES) m/z 272/274/276 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH2:7]P(OCC)(OCC)=O)[CH3:2].[Li]CCCC.[CH:23]([C:26]1[C:27]([O:41][CH2:42][CH2:43][CH3:44])=[C:28]([C:35]([CH2:39][CH3:40])=[CH:36][CH:37]=O)[CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])[CH3:24]>CN1CCCN(C)C1=O.C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([CH3:16])[CH:7]=[CH:37][CH:36]=[C:35]([C:28]1[CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[O:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[CH3:2]
Reactant: CCCOc1c(C(=CC=O)CC)cc(C(C)C)cc1C(C)C
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCOc1c(C(=CC=CC(C)=CC(=O)OCC)CC)cc(C(C)C)cc1C(C)C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
To a solution of 4-(diethoxy-phosphoryl)-3-methyl-but-2-enoic acid ethyl ester (10.6 mL, 43.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 20 mL) and THF (80 mL) at −78° C. was added n-BuLi dropwise (1.6 M in hexanes, 27.2 mL, 43.6 mmol). After 10 min, 3-(3,5-diisopropyl-2-propoxy-phenyl)-pent-2-enal (Intermediate 6, 8.77 g, 29.0 mmol) in THF (15 mL and 5 mL rinse) was added slowly to the reaction. The mixture was stirred at −78° C. for 2h, was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2.5% EtOAc-hexanes) to yield the title compound as a yellow syrup (11.4 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[C:11]([OH:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:14]1COCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Oc1cnn(-c2ccc(Br)cc2)n1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COc1cnn(-c2ccc(Br)cc2)n1
Temperature: 60 °C

Procedure:
2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (200 mg, 0.833 mmol) was weighed into a 20 ml vial equipped with a septa cap. THF (10.0 ml) was added. To this was added cesium carbonate (814 mg, 2.5 mmol), followed by the addition of methyl iodide (65.8 uL, 1.04 mmol) via syringe. The reaction was heated at 60° C. for 16 hours. Water (20 ml) was added and the product was extracted with ethyl acetate (2×75 ml). Organic phases were combined, dried over potassium carbonate, filtered and concentrated to furnish a light tan solid (190 mg, 89% TY). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 3H) 7.30 (s, 1H) 7.56 (d, J=8.98 Hz, 2H) 7.84 (d, J=8.98 Hz, 2H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[Mg].[Mg].CI.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](Cl)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC.C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 55.8 %

Procedure:
17.6 g of indole in solution in 100 ml of ether were added to a magnesium methyl iodide solution prepared from 6.5 g magnesium and 38.6 g methyl iodide in 150 ml ethyl ether. Heating under reflux took place for 2 hours and the solution was cooled to 0° C. before adding, drop by drop while stirring, a solution of 36.3 g of 1-benzyloxycarbonyl-4-piperidyl-acetyl chloride (U.S. Pat. No. 4,064,255) in 300 ml toluene. The solution was stirred for 2 hours at 10° C. and then hydrolyzed with 170 ml of 2 N hydrochloric acid. 25.8 g of 2-(1-benzyloxycarbonyl-4-piperidyl)-1-(3-indolyl)- ethanone melting at 122° C. were obtained and then converted into a tosylated derivative by the action of 15.7 g of tosyl chloride in the presence of 27.8 g potassium carbonate in 400 ml of acetone. 34.5 g of 2-(1-benzyloxycarbonyl- 4-piperidyl)-1-(1-p-toluenesulfonyloxy-3-indolyl)-ethanone were obtained and put into suspension in 600 ml ethyl ether. This suspension was added, little by little, to a magnesium methyl iodide solution prepared from 3.1 g of magnesium and 18.5 g of methyl iodide in 200 ml of ethyl ether. The mixture was stirred over night at the ambient temperature and hydrolyzed at about 5° C. with 650 ml of a 20% by weight aqueous solution of ammonium acetate. 35.5 g of 1-(1-benzyloxycarbonyl-4-piperidyl)-2-(1-tosyl-3-indolyl)-2-propanol were obtained. The piperidine protective group was then eliminated by the action of cyclohexene in the presence of aluminum chloride and 10% palladized carbon; the reagents were added at or near 0° C. in an inert atmosphere. The process was completed by heating under reflux for 4 hours. After filtration, concentration under vacuum and purification by silica gel chromatography (eluant: toluene-ethanol-diethylamine=5-5-1), 10 g of 1-(4-piperidyl)-2-(1-p-toluenesulfonyloxy-3-indolyl)-2-propanol were obtained which were used as such for the preparation of 3-[2-(4-piperidyl)-1-methyl-ethyl]-indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Zn+]>C1COCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Zn+]c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 60 °C
Yield: 64 %

Procedure:
Next, a pure solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (18 g, 54 mmol) in THF (˜200 mL) was treated with 2-pyridylzinc bromide 0.5 molar solution in THF (from Aldrich, brown color) (124 mL, 62.5 mmol, 1.15 eq.) followed by Pd(PPh3)4 (from Strem Chemicals) (625 mg). The reaction mixture was heated at 60° C. for 90 minutes. The THF was removed by rotary evaporator. Ethyl acetate (300 mL) and 1 N NaOH (200 mL) were added to the residue, and the zinc salts were removed by filtration. The organic layer was separated and washed with brine (300 mL), dried (MgSO4), and concentrated on the rotary evaporator to give brown oil. Purification by flash chromatography using Hexane:Ethyl acetate 6:4 as eluent gave 9.0 g (64% yield) of 3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 2.56 (m, 2H), 3.54 (t, 2H), 4.04 (m, 2H), 6.08 (m, 1H), 7.25 (dd, 1H), 7.56 (d, J=9 Hz, 1H), 7.77 (m, 1H), 8.54 (m, 1H); MS (DCI—NH3) m/z 259 (M+H)+, 277 (M+H+18)+
Reaction SMILES: [OH:1][C:2]1[CH:39]=[CH:38][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:41].O>O1CCOCC1>[OH:1][C:2]1[CH:39]=[CH:38][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:33])([F:34])[F:35])=[O:41])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-2,3-dihydro-4H-benzopyran (47 mg, 0.08 mmol) was dissolved in 1,4-dioxane (1 ml), methanol (1 ml) and water (0.25 ml). NaIO4 (20 mg, 0.093 mmol) was added dropwise thereto, and the reaction mixture was stirred for 12 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1→1:1) to obtain 35 mg (yield: 73%) of the title compound as a colorless oil.