Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)[CH2:2][CH3:3]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CCCOc1ccc(CCCCCC(=O)O)cc1
Yield: 91.9 %

Procedure:
This compound was synthesized from 6-(p-propoxyphenyl)-5-hexenoic acid (1.49 g, 6 mmol) and Pd/BaSO4 (150 mg) by a hydrogenation reaction. Crystallization (petroleum ether) yielded the product (1.38 g, 92%) as white crystals (mp 42-43° C.), IR: 3400-2500, 1715 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.55 (m, 8H), 2.40 (m, 4H), 3.90 (t, 2H), 6.95 (q, 4H), 7.90 (bs, 1H). Anal. Calcd. for C15H22O3 : C, 71.97, H, 8.86%; Found: C, 72.04, H, 8.88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35]([O:37]C)=[O:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].Cl>CO>[C:35]([CH:17]1[CH2:16][N:15]([S:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)(=[O:13])=[O:14])[CH2:20][CH2:19][N:18]1[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([OH:37])=[O:36]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 116.2 %

Procedure:
A mixture of 4-(6-chloronaphth-2-ylsulphonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.362 g), 1N aqueous sodium hydroxide solution (1.3 ml) and methanol (5 ml) was stirred and heated to reflux for 30 minutes. The mixture was acidified by the addition of 2N aqueous hydrochloric acid (2 ml) and evaporated. The residue was dried to give 2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.41 g);
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Br)[CH:23]=[CH2:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:24][CH:23]=[CH2:22])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Product: C=CCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.45 g (0.012 mol) of allylbromide, the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising syrup in a yield of 2.25 g (68.4% of theory) and with an Rf value of 0.66 (solvent mixture as specified in 4.7.1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H-].C([Al+]CC(C)C)C(C)C.[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)C>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(CBr)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(CO)ccc1CBr
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
A solution of methyl 4-(bromomethyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzoate (1.59 g, 4.2 mmol) from Preparation 14 in THF 15 mL), cooled to -78° C. is treated with diisobutylaluminum hydride (1M, 10.4 mL, 10.4 mmol). The reaction mixture is stirred for 3.5 hours. The reaction mixture is treated with 20 mL of a saturated potassium-, sodium-tartrate solution, diethylether (200 mL) and is allowed to warm to room temperature. The organic phase is separated, dried (MgSO4), and concentrated. The residue is purified by silica gel chromatography (1% MeOH/CH2Cl2). An oil of 4-(bromomethyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanol is obtained (1.02 g, 74%).
Reaction SMILES: [CH:1]1([CH:8]=[C:9]2[CH2:13][C:12](=[O:14])[CH:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:10]2=[O:24])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:8][CH:9]2[CH2:13][C:12](=[O:14])[CH:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:10]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cc(C)c(C2C(=O)CC(=CC3CCCCCC3)C2=O)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C2C(=O)CC(CC3CCCCCC3)C2=O)c(C)c1
Reaction time: 2 h
Yield: 74 %

Procedure:
To 5% w/w Pd/C (5 mg) was added a solution of 4-[1-Cycloheptyl-methylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (39 mg, 0.12 mmol) in MeOH (10 ml). The reaction was stirred under an atmosphere of H2 (1.5 bar) for 2 hours, filtered through a pad of celite and washed through with MeOH (20 ml). The solvent was removed under reduced pressure to give the desired product as a colourless oil (29 mg) without need for further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[CH2:14][CH2:15][N:16]([C:18]([C:20]4[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)=[O:19])[CH2:17][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:30])[C:3]=1[CH3:31].[OH-].[K+].Br[CH2:35][CH2:36][CH3:37]>CC#N>[CH3:30][C:4]1[C:3]([CH3:31])=[C:2]([O:1][CH2:35][CH2:36][CH3:37])[CH:7]=[CH:6][C:5]=1[C@@H:8]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[O:19])[CH2:17][C@@H:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1c(O)ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c1C
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCOc1ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c(C)c1C
Temperature: 60 °C
Reaction time: 20.5 h

Procedure:
A solution of [(6R,9aS)-6-(4-hydroxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-methanone (1.54 g, 3.55 mmol) in CH3CN is treated with powdered KOH (400 mg, 7.10 mmol, 1.5 eq) and 1-bromopropane (5.33 mmol, 2.0 eq) and heated in a sealed tube reactor with stirring in a 60° C. oil bath for 20.5 h. After cooling, the mixture is filtered through a CELITE pad. The pad is washed with CH2Cl2 and the solution is concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluting with 50%-40% hexanes/EtOAc to yield {(6R,9aS)-6-(2,3-dimethyl-4-propoxyphenyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl}-(6-(trifluoromethyl)pyridin-3-yl)methanone. LC/MS: 476 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[N+](C1C=CC=CC=1S[NH:34][CH2:35][C:36]([O-:38])=[O:37])([O-])=O>ClCCl.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[NH2:34][CH2:35][C:36]([O-:38])=[O:37]
Reactant: O=C([O-])CNSc1ccccc1[N+](=O)[O-]
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)[O-]

Procedure:
THC N-(2-nitrophenylsulfenyl)glycinate (6.1 mg, 0.0116 mmol) was dissolved at ambient temperature in dry dichloromethane containing 10% (v/v) of thiophenol and 1.5% (v/v) of TFA (100 μL). After S min the mixture was quenched by addition of 120 μL 3% triethylamine in DCM (at 0° C.). The solution of crude product was chromatographed directly on silica gel with dichloromethane-methanol (gradient 1:0, 20:1, 10:1, 5:1). The combined fractions containing the product were diluted with chloroform, concentrated at 25° C. to ˜3 mL, diluted with chloroform and concentrated again to ˜0.5 mL. The solution of product was diluted with chloroform again (˜5 mL) and concentrated to dryness. Remaining oil was immediately dissolved in chloroform, concentrated to dryness (2.49 mg, 58%), and immediately dissolved in chloroform to afford a stock solution of THC glycinate (ALL00130) stored at −20° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[NH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[F:17][CH:15]([F:16])[C:12]1[NH:13][CH:14]=[C:9]([OH:8])[C:10](=[O:18])[CH:11]=1
Reactant: O=c1cc(C(F)F)[nH]cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)[nH]cc1O
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
5-Benzyloxy-2-difluoromethyl-1H-pyridin-4-one (300 mg, 1.19 mmol) was dissolved in methanol (20 mL) to give clear a yellow solution. Pd/C (55 mg) was added at RT. After purging with hydrogen gas, the mixture was hydrogenated at 50 psi H2 pressure for 15 min. The reaction mixture was filtered through a short pre-treated CELITE™ bed. The filtrate was collected, and the solvent was removed in vacuo to give the title compound as an off-white solid (170 mg, 88%) with an HPLC purity (peak percent area) of 98.8%. HPLC Method 1 is used (see Example 1). 1H NMR (300 MHz, DMSO-D6) δ (ppm): 10.3 (br s, 1H), 7.97 (s, 1H), 6.98 (s, 1H), 6.72 (t, J=55.4 Hz, 1H); MS (m/z) 162.2 [M+1]+, 142.1 (100%).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:19]([O:38][CH3:39])=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[C:19]([O:38][CH3:39])=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)nc2OC)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2nc(OC)c(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxy-2-methoxypyridin-3-yl)methoxy)phenyl)propanoate (120 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure. The crude crystals were recrystallized (ethyl acetate/hexane) to give the title compound (98 mg) as a colorless amorphous solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:37][C:38]1[N:47]=[C:46](Cl)[C:45]2[C:40](=[CH:41][C:42]([O:51][CH3:52])=[C:43]([O:49][CH3:50])[CH:44]=2)[N:39]=1.[Cl-].[Na+]>O1CCCC1.Cl[Pd]Cl.O>[Cl:37][C:38]1[N:47]=[C:46]([C:13]2[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[C:45]2[C:40](=[CH:41][C:42]([O:51][CH3:52])=[C:43]([O:49][CH3:50])[CH:44]=2)[N:39]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To 634 g of sodium carbonate (5.98 mol) was added 2.91 kg of water under a nitrogen atmosphere, followed by stirring for dissolution. To the solution were added 3.0 L of tetrahydrofuran, 431 g of 3-aminophenyl boronic acid monohydrate (2.78 mol), 30.4 g of triphenylphosphine (0.116 mol) and 26.0 g of dichloropalladium (0.116 mol) in this order. To the mixture was dropwise added a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (600 g; 2.32 mol) in tetrahydrofuran (12.0 L) over 2 hours while stirring at 60° C., followed by stirring at the same temperature for 16 hours. To the mixture were added 3.0 kg of a 5% sodium chloride solution and 12.0 L of tetrahydrofuran in this order, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was transferred to separatory funnel and the organic layer was separated. To the separated organic layer were added 150 g of anhydrous magnesium sulfate and 60.0 g of activated carbon, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the residue was added 6.0 L of water, and the mixture was stirred at room temperature for 1 hour, and precipitated crystals were collected by filtration. The collected crystals were dried at 50° C. under reduced pressure to give 730 g (content rate 62.2%) of a target product. Yield: 62.1%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N(C)C)=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CN(C)C(=Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Into a 200 ml four-necked flask equipped with a thermometer, a stirrer and a reflux condenser, 15.5 g (50 mmol) of 1-(4-fluorophenyl)-2-(4-trifluoromethylphenyl)-N,N-dimethylethenylamine, 80 ml of acetic acid and 30 ml of concentrated hydrochloric acid were charged and reacted with stirring for two hours under refluxing under heating by an oil bath. After completion of reaction, 500 ml of water was added, and precipitated crystals were collected by filtration and washed with a 2% sodium hydrogen carbonate aqueous solution and water. Then, the crystals were further washed and purified with 20 ml of n-hexane and then vacuum-dried to obtain 12.7 g (yield: 90.3%) of the desired compound (melting point: 93-95° C.) as slightly yellow crystals.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[CH:15][C:14]=1[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[C:32]([CH2:41][CH3:42])[CH:31]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:39]([N:36]([CH2:37][CH3:38])[C:33]1[CH:34]=[CH:35][C:30]([C:14]2[CH:15]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=3)[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:31][C:32]=1[CH2:41][CH3:42])[CH3:40]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Yield: 53.5 %

Procedure:
In a manner similar to that of Example 2b, by reacting 660 mg of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate (1.1 mmol) in 25 mL of tetrahydrofuran with 1.2 mL of 1M tetrabutylammonium fluoride. 280 mg of ethyl 4″-diethylamino-3″-ethyl-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=52%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C:25]1([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:29]4[C:25]([CH3:31])([CH3:24])[CH2:26][CH2:27][C:28]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1(C)CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4(C)C)cc3)CC2)c(C)c1
Yield: 18 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (295 mg) described in Preparation Example 113 and 5,5-dimethylpyrrolidin-2-one (79 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (51 mg) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[CH2:14](Br)[CH:15]=[CH2:16]>O1CCCC1>[CH2:16]([O:13][C:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)([CH3:11])[CH3:12])[CH:15]=[CH2:14]
Reactant: CC(C)(O)c1ccc(F)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of sodium hydride (1.47 g) in dry tetrahydrofuran (60 ml) was added dropwise under an argon atmosphere a solution of 2-(4-fluorophenyl)-2-propanol (4.35 g) in dry tetrahydrofuran (10 ml). The resulting yellow suspension was stirred at room temperature for 10 min. A solution of allyl bromide (3.1 ml) diluted in dry tetrahydrofuran (10 ml) was added slowly. The reaction mixture was stirred for 30 min and quenched by addition of water. The solution was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give 1-(1-allyloxy-1-methyl-ethyl)-4-fluoro-benzene (3.30 g, 60%) as a light yellow liquid. MS (EI): 179.0 ([M-CH3]).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C(O)C>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCN(CCc2ccccc2)CC1
Agent: NN
Solvent: CCO
Product: NCC1CCN(CCc2ccccc2)CC1
Yield: 108.5 %

Procedure:
A mixture of 1.31 g (3.8 mmoles ) of 2-[1-(2-phenylethyl)-4-piperidylmethyl]-1H-isoindole-1,3(2H)-dione (Example 2) and 0.25 mL (7.8 mmoles) of hydrazine in 20 mL of ethanol was heated under reflux for 4 hours. The solvent was removed and the residue was made basic with aqueous potassium hydroxide and extracted with chloroform to give 0.90 g of 1-(2-phenylethyl)-4-piperidinemethylamine as an oil. NMR (CDCl3): δ7.14-7.35 (m, 5H); 2.93-3.10 (d, 2H); 2.72-2.85 (m, 2H); 2.52-2.65 (m, 4H); 1.92-2.05 (t, 2H); 1.61-1.87 (m, 2H); 1.08-1.48 (m, 5H) .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([NH:15][CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12][N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:39](=O)(OC(Cl)(Cl)Cl)[O:40]C(Cl)(Cl)Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]3[CH2:16][CH2:17][N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:39]3=[O:40])[CH2:13][CH2:12][N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCCNc2ccccc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCN(c3ccccc3)C2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of the compound (0.21 g) obtained in step 3 and triethylamine (0.19 mL) in THF (10 mL) was added bis(trichloromethyl) carbonate (0.13 g) at 5° C. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give the title compound (0.04 g, 18%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](C3C=CC(Br)=CC=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29](C2C=CC(C)=CC=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][O:56][C:57]([C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][CH:64]=1)=[O:58]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[C:44]([C:47]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:45]([C:63]3[CH:62]=[CH:61][CH:60]=[C:59]([C:57]([O:56][CH3:55])=[O:58])[CH:64]=3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:11][C:10]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:9]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(Br)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2-c2ccccc2)c1
Yield: 38 %

Procedure:
Aryl halide 5 was coupled to 3-(methoxycarbonyl)phenylboronic acid on a 0.1 mmol scale via General Procedure H to yield 35 (39 mg, 38%): δH (400 MHz, CDCl3) 2.40 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.68 (s, 2H, CH2), 3.96 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.62 (s, 1H, CH), 6.70 (d, J=8.0 Hz, 1H, CH) 7.19 (d, J=8.0 Hz, 2H, CH), 7.26-7.34 (m, 10H, CH), 7.38-7.41 (m, 3H, CH), 7.54 (d, J=8.0 Hz, 2H, CH), 7.62 (d, J=8.4 Hz, 2H, CH), 7.68 (q, J=8.0 Hz, 4H, CH), 7.84 (t, J=8.0 Hz, 2H, CH), 8.03 (d, J=8.0 Hz, 1H, CH), 8.32 (s, 1H, CH); LRMS (ES+) Calcd for [C52H46N2O8S+H] 859.31. found 859.25.
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.[Br:10][C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[OH:20]>[2H]C(Cl)(Cl)Cl>[Br:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[OH:20]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Agent: C1=Cc2ccccc2C1
Agent: [2H]C(Cl)(Cl)Cl
Product: OC1c2ccccc2CC1Br

Procedure:
This was prepared from indene according to the known procedure. The n.m.r. spectrum in deuteriochloroform confirmed that the product was trans-2-bromoindan-1-ol.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])([F:10])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:6]1[CH2:7][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])([F:10])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCC1(F)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(F)CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
To a solution of 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (270 mg, 0.89 mmol) in THF (12 mL) and water (4 mL), was added lithium hydroxide monohydrate (45 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 16 hours. THF was removed under vacuum and the residue was taken up in ethyl acetate (150 mL), washed with 10% citric acid (100 mL) and brine (20 mL). Removal of solvent provided 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (260 mg, 100%).