Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[CH2:12][CH2:11]1
Reactant: Fc1ccccc1Br
Reactant: CNC1CCN(C)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCC(NCc2ccccc2F)CC1
Yield: 24.8 %

Procedure:
Mix 1-bromo-2-fluorobenzene (3.50 g), 1-methyl-4-(methylamino)piperidine (2.56 g), Pd2(dba)3 (0.366 g), racemic BINAP (0.498 g) and sodium t-butoxide (2.70 g) in toluene (40 mL) and heat at reflux for two days. Filter through a Celite® bed, partition between dichloromethane and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (35 g), using a gradient of dichloromethane-2M NH3 in methanol to give 1.1 g of the title intermediate.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2)(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Cl
Product: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 85 °C
Yield: 97.2 %

Procedure:
A mixture of 259 mg (1.16 mmol) of 5-acetamido-6-nitroindan in 4 mL of 2 N HCl was heated at 85° C. for 9 h and cooled to room temperature. The solid precipitate was filtered, washed with water, and dried to leave 201 mg (97%) of a crystalline yellow solid. 1H NMR (CDCl3), 2.068 (m, 2), 2.843 (m, 4), 6.00 (sb, 2), 6.650 (s, 1), 7.942 (s, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30](O)[CH2:29][CH2:28]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:34])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.C(N(S(F)(F)F)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]4[CH2:32][CH2:31][CH:30]=[CH:29][CH2:28]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:34])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc([C@H]3CC[C@H](O)CC3)n12
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc(C3CC=CCC3)n12
Reaction time: 2 h
Yield: 8.4 %

Procedure:
A mixed solution of 87 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one and 2.8 mL of dichloromethane was cooled to −70° C., and 48 μL of N,N-diethylaminosulfur trifluoride was added thereto, followed by stirring at the same temperature for 2 hours. To the mixed reaction liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by extraction with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 1.5 mL of methanol to give a mixed solvent, and then warmed and washed. The precipitate was collected by filtration and dried under reduced pressure to obtain 7 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-(cyclohex-3-en-1-yl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]3[O:19][C:18]([NH2:20])=[N:17][CH2:16]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:24])[C:22]#[CH:23]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]3[O:19][C:18]4=[N:20][C:21](=[O:24])[CH:22]=[CH:23][N:17]4[CH2:16]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1=NCC(CCc2ccc(C3CCCCC3)cc2)O1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: O=c1ccn2c(n1)OC(CCc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To a stirred solution of 5-[2-(4-cyclohexyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine (0.134 g, 0.493 mmol) in 5 ml of ethanol was added 50 μL (0.494 mmol) of ethyl propiolate. The mixture was stirred at 80° C. for 6h and allowed to cool to room temperature. The mixture was concentrated to a solid which was purified by chromatography on silica gel eluting with ethyl acetate followed by methanol/ammonia/dichloromethane to provide 70 mg of the title compound.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC)c(I)c1
Reaction time: 4 h

Procedure:
Silver sulfate (3.47 g, 11.12 mmol) and iodine (0.576 mL, 11.12 mmol) were added successively to a solution of ethyl (1S,2S)-2-(4-methoxyphenyl)cyclopropanecarboxylate (2.45 g, 11.12 mmol) in EtOH (55.6 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (100 mL), washed with water (2×25 mL), aq. NaHSO3 (2×25 mL), and brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 2088 mL) to afford ethyl (1S,2S)-2-(3-iodo-4-methoxyphenyl)cyclopropanecarboxylate, as a colorless oil. Rf=0.61 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.50 (d, J=2.3 Hz, 1H); 7.04 (dd, J=8.5, 2.3 Hz, 1H); 6.71 (d, J=8.5 Hz, 1H); 4.15 (q, J=7.2 Hz, 2H); 3.83 (s, 3H); 2.44-2.39 (m, 1H); 1.82-1.78 (m, 1H); 1.55-1.50 (m, 1H); 1.27 (t, J=7.2 Hz, 3H); 1.25-1.19 (m, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])O.[NH4+]>O.C(#N)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(C#N)c1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H](Cc1cccc(C#N)c1)NC(C)=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 47.4 %

Procedure:
The process is performed as in Example 2, starting with 11.39 g of ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate, 17.39 g of ammonium hydrogen carbonate and 0.1 g of α-chymotrypsin in 200 cm3 of water and 70 cm3 of acetonitrile. After stirring for 24 hours at a temperature in the region of 20° C. and an identical work-up, 5.40 g of ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the form of a beige-colored solid. (Rf=0.76 in a 40/10/20 by volume mixture of n-butanol/acetic acid/water, on a Merck 60F254R silica plate).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Ethyl 4-fluorobenzoate (0.753 g, 4.48 mmol) was added to a solution of 1-cyclobutylpiperazine (0.571 g, 4.07 mmol) and potassium carbonate (0.563 g, 4.07 mmol) in DMSO (8 mL) under nitrogen. The resulting solution was stirred at 100° C. for 18 h and evaporated to dryness. The residue was triturated with diethyl ether, filtered, and evaporated and the crude product was purified by silica column chromatography, eluting with a gradient of 0 to 2.5% 2.5N MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.387 g, 32.9%) as a white solid.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.Cl>O1CCCC1.CCCCCC>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:5][CH2:4][CH2:3][OH:2])[CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1cccc(F)c1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCC=Cc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of 4.0 g of (3-hydroxypropyl)triphenylphosphonium bromide and 20 ml of tetrahydrofuran was cooled to 0° C., to which 12.5 ml of 1.6M n-butyl lithium (as a hexane solution) was slowly added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, to which a mixture of 1.24 g of 3-fluorobenzaldehyde and 10 ml of tetrahydrofuran was slowly added dropwise at the same temperature, followed by further stirring at room temperature for 6 hours. The reaction mixture was poured into ice-water, acidified by the addition of 10% hydrochloric acid, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.70 g of 4-(3-fluorophenyl)-3-buten-1-ol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.[C:23](=[O:25])=[O:24].Cl>O1CCCC1.CCCCCC.O>[Cl:13][C:14]1[C:19]([C:23]([OH:25])=[O:24])=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1
Reactant: O=C=O
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine 11.93 g in tetrahydrofuran 350 ml is dropped a 1.6M solution of n-butyl lithium in hexane 73.7 ml over a period of 20 minutes on dry ice-acetone bath, and the mixture is stirred for 30 minutes. Thereto is added 4,6-dichloro-2-methylthiopyrimidine 10.00 g in tetrahydrofuran 50 ml over a period of 1 hour on a dry ice-acetone bath, followed by further one hour agitation. The reaction mixture is poured into dry ice and the mixture is stirred for 1.5 hours at room temperature. The reaction mixture is made acidic with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and condensed in vacuo. The resulting solid is triturated with hexane to give 4,6-dichloro-5-carboxy-2-methylthiopyrimidine as a brown crystalline powder, 10.42 g. mp 151–158° C.(decomposition)
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:19])([F:18])[C:6]([F:17])([F:16])[C:7](=O)[CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([C:9]1[CH:8]=[C:7]([C:6]([F:17])([F:16])[C:5]([F:19])([F:18])[F:4])[NH:3][N:2]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(F)(F)C(F)(F)F)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
At room temperature, hydrazine hydrate (2.06 g) is added to a solution of 1,1,1,2,2-pentafluoro-6,6-dimethylheptane-3,5-dione (10.1 g) in ethanol (100 ml). The reaction mixture is stirred at room temperature overnight. After removal of the solvents under reduced pressure, 3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazole (7.9 g, 79%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3c2C1
Yield: 35.5 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 19.2 mg (0.101 mMol) 4-trifluoromethylbenzoic acid, 5.7 mg (35%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[C:5]=1[CH2:14][Br:16]
Reactant: COC(=O)c1cccc(C(F)(F)F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C(F)(F)F)c1CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.9 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-benzoic acid methyl ester (0.95 g, 4.35 mmol) in benzene (10 mL) was added N-bromosuccinimide (0.77 g, 4.33 g) and benzoyl peroxide (0.052 g, 0.21 mmol) and the resulting mixture heated to reflux for 4 h, cooled and stirred at room temperature for 48 h. The mixture was filtered, the filter cake washed with diethyl ether and the filtrate washed with a 1 N sodium thiosulfate solution (10 mL), brine and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF25-80 g column, 5→10% ethyl acetate/hexane gradient) to give 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (1.04 g, 3.50 mmol, 81%) as an off white solid; 1H NMR (300 MHz, DMSO-d6) δ ppm 3.72-4.16 (m, 3H), 5.03 (s, 2H), 7.47-8.32 (m, 3H).
Reaction SMILES: [CH:1]([C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]([CH3:15])=[CH:8][C:7]=1[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:2][C:3](=[O:5])[CH3:4].C(OC)(=O)[CH2:24][C:25](OC)=[O:26].[Na]>CO>[C:19]([CH2:18][CH2:17][CH2:16][C:7]1[C:6]([CH:1]2[CH2:24][C:25](=[O:26])[CH:4]=[C:3]([OH:5])[CH2:2]2)=[C:11]([CH3:12])[C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([OH:21])=[O:20]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=CC(C)=O
Agent: [Na]
Solvent: CO
Product: COc1c(C)cc(CCCC(=O)O)c(C2CC(=O)C=C(O)C2)c1C
Temperature: 60 °C

Procedure:
Methyl 4-(2-(but-1-en-3-one-1-yl)-3,5-dimethyl-4-methoxyphenyl)butyrate (5.0 g) and sodium dimethyl malonate (6 g equiv) were stirred and heated at reflux in dry methanol (60 ml) for 6 hr. The solvent was evaporated under reduced pressure and the residue was heated at reflux with a 10% excess of an aqueous potassium hydroxide solution (60 ml) for 8 hr. The cooled mixture was extracted with diethyl ether. The aqueous fraction was heated to 60° C. and was acidified by slow addition of a dilute aqueous hydrochloric acid solution. The cooled mixture was extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated to give 5-(6-[3-(carboxy)propyl]-2,4-dimethyl-3-methoxyphenyl)-3-hydroxycyclohex-2-en-1-one as a pale yellow foam. Pmr spectrum (acetone-d6 ; δ in ppm): 1.6-3.7 (11H,m); 2.28 (3H,m); 2.43 (3H,s); 3.65 (3H,s); 5.52 (1H,s); 6.91 (1H,s); 8.6 (2H,brs).
Reaction SMILES: C([NH:8][CH:9]([CH3:39])[CH:10](C(OCC1C=CC=CC=1)=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)C1C=CC=CC=1.[H][H]>CO.[PdH2]>[C:25]([C:13]1[CH:12]=[C:11]([CH2:10][CH:9]([NH2:8])[CH3:39])[CH:16]=[CH:15][C:14]=1[OH:17])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(NCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [PdH2]
Solvent: CO
Product: CC(N)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
A suspension of 2.35 g (4.50 mmol) of N-benzyl-2-(4-benzyloxy-3-tert-butylphenyl)-1-methyl-N-(benzyloxycarbonyl)ethylamine and 0.50 g of a 20% palladium hydride on carbon catalyst in methanol (30 ml) was stirred overnight in a hydrogen atmosphere. After filtering off the catalyst, the solvent was distilled off under reduced pressure to give 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine in the amount of 0.90 g (96%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][C:36]([NH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:42])[CH3:41])=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)C>O1CCOCC1.O.CCOC(C)=O>[C:29]([O:28][C:26]([N:11]1[C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:33]2[CH:34]=[N:35][C:36]([NH:39][C:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)([CH3:41])[CH3:42])=[CH:37][CH:38]=2)[CH2:14][CH2:13][C@H:12]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(NC(C)(C)c4ccccc4)nc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(NC(C)(C)c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.340 g, 0.504 mmol) in dioxane (8 mL) and water (2 mL) was added 1M LiOH (1.51 mL, 1.51 mmol). The reaction was stirred vigorously at room temperature for 18 hours and then quenched with acetic acid (0.116 mL, 2.018 mmol). The reaction was diluted with EtOAc (125 mL) and washed with water (20 mL) and brine (20 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was taken up in CH2Cl2/heptanes and concentrated in vacuo to afford 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]pyrrolidin-2-yl}methyl)benzoic acid (319 mg, 96%). LC-MS=660.4 (M+1)+. 1H NMR (600 MHz, CD3OD) δ 7.90 (d, J=7.2 Hz, 2H), 7.79 (bs, 1H), 7.37 (bs, 2H), 7.28 (m, 1H), 7.02-7.12 (m, 5H), 6.13 (m, 1H), 5.31 & 5.12 (2 singlets, 1H), 4.00 (m, 1H), 3.84 (bs, 1H), 2.76 & 2.49 (2 multiplets, 1H), 1.14-1.96 (m, 20H), 0.88 (s, 9H), 0.08 (s, 3H), −0.06 (s, 3H).
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][CH2:7][CH3:8])(=O)=O.S([O-])([O:13][CH2:14][CH2:15][CH2:16]C)(=O)=O>>[C:14]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:13])[CH:15]=[CH2:16]
Reactant: CCCCOS(=O)(=O)[O-]
Reactant: CCCCOS(=O)(=O)O
Product: C=CC(=O)OCCCC

Procedure:
The process is performed as in Reference Example 1, but arrangement is made for elimination of the butyl hydrogen sulphate by acid hydrolysis of the neutral butyl sulphate contained in the aqueous phase (A1). Experimentally, this reaction was carried out in two ways:
Reaction SMILES: C(O[SiH](OCC)OCC)C.[CH3:11][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1COCC1.[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.CCOCC>[CH3:11][CH:12]([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)O
Temperature: 60 °C
Yield: 61.6 %

Procedure:
A dry Schlenk tube under argon was charged with triethoxysilane (1.4 ml, 7.5 mmol) and 2-octanone (525 μL, 5 mmol) and heated to 60° C. Titanium (IV) isopropoxide (75 μL, 0.25 mmol) was then added. After stirring at that temperature for an hour the color changed to deep blue. After 12 hours the reaction mixture was cooled to room temperature and added to THF (5 mL). Aqueous NaOH (1 N, 15 mL) was then added to the solution. After vigorous stirring at room temperature for 1 hour, the reaction mixture was added to a water/ether mixture (100 mL each), shaken vigorously, and separated. The aqueous layer was washed with an additional 100 mL of ether, and the combined ether extracts were dried over MgSO4. Concentration in vacuo afforded 401 mg (63% yield, greater than 95% pure by NMR and GC) of 2-octanol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(Cc2cccc(CN)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(Cc2cccc(CNC(=O)OCc3ccccc3)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of methyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzyl)piperidine-4-carboxylate (1.67 mmol), benzyl chloroformate (0.48 mL, 3.36 mmol), and diisopropylethylamine (1 mL, 5.74 mmol) in dichloromethane was stirred at room temp. The resultant solution was diluted with dichloromethane, washed with aqueous sodium bicarbonate, and then brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as clear colorless gum.
Reaction SMILES: C(OC1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(=O)C=C.CS(Cl)(=O)=O.C(N(CC)CC)C.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[C:41]([CH2:46][CH2:47]C)C=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:39]([O:38][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:47]=1
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Agent: C=CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Specifically, 1.90 g (7.86 mmol) of 6-acryloyloxy-2-naphthoic acid was dissolved in 10 g of THF, to which 0.99 g (8.65 mmol) of methanesulfonyl chloride was added with ice-water bath cooling, and further 1.91 g (18.87 mmol) of triethylamine (TEA) was added dropwise. After stirring for 1 hour, 10 mg (0.08 mmol) of 4-dimethylaminopyridine (DMAP) was added, to which a solution of 2.00 g (8.25 mmol) of 4-benzyloxy-2-n-propylphenol dissolved in 7 g of THF was added dropwise. After stirring for 1 hour, the reaction mixture was allowed to warm to room temperature, the precipitates were removed by filtration, and the filtrate was washed with water. After removing the solvent by evaporation, the residue was purified by column chromatography (developing solvent: dichloromethane, SiO2) and recrystallized from acetone. Thus the target benzyl ether was obtained as a white solid (2.27 g, 61.9% yield).