Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCN3CCCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)pyrrolidine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (CDCl3) δ 12.80 (1H, br), 10.44 (1H, t, J=6 Hz), 8.60 (1H, d, J=1 Hz), 7.81 (2H, d, J=8.2 Hz), 7.30 (3H, m), 7.19 (2H, d, J=8.2 Hz), 7.06 (1H, s), 7.01 (2H, m), 5.41 (2H, br), 4.05 (2H, s), 4.02 (2H, q, J=6.6 Hz), 3.87 (2H, br), 3.36 (2H, t, J=7 Hz), 3.02 (3H, s), 2.89 (2H, m), 2.24 (2H, br), 2.10 (2H, br); HRMS calcd for C30H32N4O5S+H+: 561.2172. Found: 561.2166.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[CH2:11][S:12][C:13]([S:31][CH3:32])=[C:14]2[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:7])([CH3:4])[CH3:3].O1CCCC1.[H][H].Cl>CO>[CH3:4][C:2]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[CH2:11][S:12][C:13]([S:31][CH3:32])=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:1])[CH3:3]
Reactant: CSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Reactant: [H][H]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CSC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
1.45 g of (6RS) (7RS) (4-nitrophenyl)-methyl 7-[(1,1-dimethylethyl)-oxycarbonyl-amino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en 2-carboxylate, 30 ml of tetrahydrofuran, 30 ml of methanol and 1.45 g of 10% palladized carbon were hydrogenated under a pressure of 2 atmospheres of hydrogen, while being vigorously stirred. After one hour, the pressure was taken up to ambient, and under an inert atmosphere, 4 ml of N hydrochloric acid were added. After separation, the solvent was expelled under reduced pressure at 35° C. and the residue was taken up in 100 ml of distilled water. The mixture was extracted with methylene chloride and the organic phase was dried, and evaporated to dryness under reduced pressure to obtain 1.3 g of (6RS) (7RS) 7-[(1,1-dimethylethyl)-oxycarbonyl-amino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([OH:42])[C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2.Br[CH2:86][C:87]([O:89]C)=[O:88].CI>>[C:40]([C:38]1[CH:37]=[CH:36][C:26]2[NH:27][C:23]([CH:22]([C:3]3[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[C:8]4[C:4]=3[CH:5]=[CH:6][NH:7]4)[O:42][CH2:86][C:87]([OH:89])=[O:88])=[N:24][C:25]=2[CH:39]=1)#[N:41]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Solvent: CI
Product: Cc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) as described in Example 68 using methyl 2-bromoacetate as electrophile instead of methyl iodide. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 11.00 (br.s, 1H) 7.97 (s, 1H) 7.64 (d, J=8.33 Hz, 1H) 7.51-7.54 (m, 1H) 7.21 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.48-6.51 (m, 2H) 4.14 (A of AB, J=16.55 Hz, 1H) 3.99 (B of AB, J=16.55 Hz, 1H) 2.42 (s, 3H) 2.40 (s, 3H). HRMS calcd. for C21H18N4O3 (M+H)+ 375.1452. found 375.1465.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[CH3:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][NH:11][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CN
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)CCCCl
Yield: 73.7 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (6.8 g,94.9 mmol), methylamine hydrochloride (13.5 g,200 mmol), and potassium carbonate (27.6 g,200 mmol) were added in turn to ethyl acetate (500 ml). After the addition of N-benzyltrimethylammonium chloride (about 200 mg), the resultant mixture was stirred for 2 hours at room temperature and dried over anhydrous sodium sulfate. The mixture was filtered through a small amount of silica gel and the filtrate was concentrated in vacuo to give 12 g (74%) of crude N-methyl-3-chloropropylsulfonamide (intermediate 3b) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24]>ClCCl.CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][C:6]=2[CH3:11])=[O:10])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(C)ccnc2C)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To an ice cold solution of 2,4-dimethyl-3-pyridinecarboxylic acid (0.3 mmol, 45 mg) in dichloromethane (2 mL) containing one drop of DMF, was added oxalyl chloride (0.39 mmol, 49.5 mg) at 0° C. The reaction mixture was stirred for 30 min at this temperature, was allowed to warm to room temperature and was stirred for an additional 2 h. The solution was concentrated and the residue was dried under high vacuum. To a mixture of above acid chloride and 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (0.2 mmol, 88 mg) in dichloromethane (3 mL) was added diisopropylethylamnine (1 mmol, 0.175 mL) at room temperature. After the solution had stirred for 15 h, TLC analysis of the mixture did not detect any starting material remaining. The solution was diluted with water (20 mL) and dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL) and the combined organic extracts were washed with brine (300 mL). The dried (MgSO4) solution was filtered and evaporated to dryness and the residual material was purified by RP-HPLC to obtain 74 mg (65%) of 4-[[(2,4-dimethylpyridin-3-yl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 574.2389. Calcd. mass, 574.2409 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH:11]=[CH:12][O:13]CC[Si](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH2:11][CH:12]=[O:13]
Reactant: Cc1nc2ccccn2c1C=COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nc2ccccn2c1CC=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.7 %

Procedure:
To a solution of 2-methyl-3-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-imidazo[1,2-a]pyridine (1.8 g, 6.56 mmol) in a mixture of acetonitrile and water (1:1 by volume, 16 mL) in a 100 mL plastic bottle was added HF (8 mL, 48% solution in water). The reaction mixture was stirred at room temperature for 96 h and solid sodium bicarbonate was added in batches until the mixture reached pH 6. The mixture was washed twice with ether, basified to pH 8 with solid sodium hydroxide, and extracted three times with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and concentrated in vacuo to give (2-methyl-imidazo[1,2-a]pyridin-3-yl)-acetaldehyde (922 mg) as a deep brown semi-solid that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH3:12].[H][H]>C(O)(=O)C.[Pt]>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH2:9])=[C:6]([F:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1cc(N)c(F)cc1Cl

Procedure:
A solution of 2-chloro-4-fluoro-5-nitrotoluene (30.0 g, 0.158 mole) in glacial acetic acid (150 ml) was added to a 250 ml Parr bottle which contained platinum IV oxide (0.4 g). The Parr bottle was placed on a Parr hydrogenation apparatus and charged with hydrogen. The reaction mixture was allowed to shake until hydrogen absorption ceased. The catalyst was removed by vacuum filtration. The filtrate containing 4-chloro-2-fluoro-5-methylaniline was used in the following step. This reaction was repeated several times.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[O:12]1[CH:16]=[CH:15][CH2:14][CH2:13]1.O>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:14]3[CH2:15][CH2:16][O:12][CH:13]3[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Reactant: C1=COCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C2=NOC3OCCC23)cc1Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 3,4-dichlorobenzaldehyde oxime (1 eq) in DCM (10 vol) was added a 50% aqueous bleach solution (10 vol). 2,3-Dihydrofuran was then added and the resultant biphasic system was stirred vigorously at room temperature for 21 hours. Water (25 vol) and brine (25 vol) were added and the organic layer was separated. The aqueous phase was further extracted with (2×5 vol) DCM. The combined organic phases were washed with a 1:1 mixture of water and brine (50 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (eluent: EtOAc:heptane) to yield 3-(3,4-Dichloro-phenyl)-3a,4,5,6a-tetrahydro-furo[3,2-d]isoxazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[N:18][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:11]([O:10][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:19][N:18]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Reactant: O=Cc1ccc(F)cn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Temperature: 50 °C
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A solution of ethyl cis-2-amino-1-cyclopentane carboxylate hydrochloride (0.250 g, 1.29 mmol) in ethanol (10 mL) was treated with 5-fluoro-pyridine-2-carbaldehyde, glacial acetic acid (10 drops), sodium cyanoborohydride (0.162 g, 2.58 mmol) and stirred for 72 h at 50° C. The reaction was extracted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.179 g, 0.678 mmol, 52.5%), as a light yellow oil. LC-MS (ESI) calcd for C14H19FN2O2 266.14, found 267.2 [M+H+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(N)c1
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)/C=C\C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 9.96 g (92 mmol) of 1,3-phenylenediamine and 250 ml of tetrahydrofuran. A solution prepared by dissolving 9.03 g (92 mmol) of maleic anhydride in 27 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 1 hour, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was separated by filtration, and the filtrate was condensed to dryness, to obtain 16.68 g of coarse (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid. To 16.68 g of coarse (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid was added 450 ml of tetrahydrofuran, and the mixture was refluxed with heating for 1 hour, then, the deposited crystal was isolated by hot filtration, and dried to obtain 7.58 g of coarse ((Z)-3-(3-aminophenylcarbamoyl)acrylic acid. Further, to this crystal was added 30 ml of methanol, and the mixture was stirred at room temperature for 1 hour, then, the deposited crystal was isolated by filtration, and dried to obtain 6.94 g of (2Z)-4-[(3-aminophenyl)amino]-4-oxo-2-butenoic acid as a yellow-white solid. Yield: 36.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[Br-].[C:15]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH2:15])=[CH:5][CH:4]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 7-methoxy-1-tetralone H4.1 (26.9 g, 153 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and triphenylmethylphosphonium bromide (65.4 g, 183 mmol) in THF (550 mL) was added potassium tert-butoxide (1.0 M solution in THF)(183 mL, 183 mmol) via addition funnel over 1 hour. The resulting mixture was stirred at room temperature for 60 minutes after addition. The reaction was then concentrated and resuspended in hexanes (250 mL). The mixture was passed through a silica gel plug (25 g silica) and rinsed with 250 mL of hexanes. Removal of solvent gave H4.2 (24.5 g, 92% yield). MS ESI (pos.) M/E: 175 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.1 %

Procedure:
trans-4-Aminocyclohexanecarboxylic acid (314 mg, 2.19 mmol) was gradually added to sodium bis(2-methoxyethoxy)aluminum hydride-toluene solution (65 wt %, 3.0 mL) in toluene (3 mL) at 75° C., and the reaction mixture was stirred for 7 hours. The reaction mixture was allowed to cool to room temperature and stirred with 1 M aqueous sodium hydroxide (20 mL) at 80° C. for 10 minutes. The reaction mixture was allowed to cool to room temperature and partitioned between water and toluene, and the aqueous layer was extracted with chloroform three times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (170 mg, yield 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1ccccc1F
Reactant: BrCc1ccc2ccccc2c1
Product: Fc1ccccc1C1CCN(Cc2ccccc2)CC1OCc1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(2-fluorophenyl)-piperidin-3-ol with 2-bromomethyinaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(2-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a yellow oil; MS: 284 (M-C11H9)+. By cleavage of the benzyl protecting group with 2,2,2-trichloroethyl chloroformate in an analogous manner to that described in Example 12 (c) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-(2-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 509 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:11])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene under protective gas, 19.2 g of chlorine gas are introduced while illuminating with a mercury lamp at 30° C. within 4 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 30° C. for a further 20 minutes. The reaction solution is cooled to 5° C. and the solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 87%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:10][CH:9]=1>C1COCC1.C(OCC)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:18])[CH2:15][OH:16])=[CH:12][CH:13]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CO)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Lithium aluminium hydride (29.8 ml of a 1.0M solution in THF, 29.8 mmol) was added dropwise to a stirred solution of 4-fluoro-α-methylphenyl acetic acid (5.0 g, 29.8 mmol), in diethyl ether (100 ml), which had been cooled to -10° C. The mixture was warmed to +25° C. and stirred for 1 h before quenching with methanol (20 ml) and 4M NaOH (20 ml). The mixture was filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-(4-fluorophenyl)propyl alcohol (3.65 g, 79%). To a solution of the preceding alcohol (3.65 g, 23.7 mmol) and carbon tetrabromide (9.82, 29.62 mmol), in dichloromethane (75 ml), was added triphenylphosphine (9.31 g, 35.5 mmol), portionwise. The mixture was stirred for 1 h at room temperature and diethyl ether (50 ml) then added. The precipitated triphenylphosphine oxide was filtered off and the solvents removed in vacuo. The residue was chromatographed through silica gel eluting with ethyl acetate/hexane (1:2) to afford the desired bromide (3.05 g, 60%), δ(250 MHz, CDCl3) 1.40 (3H, d, J=6.8 Hz, Me), 3.06-3.20 (1H, m, CH), 3.42-3.61 (2H, m, CH2), 6.97-7.26 (4H, m, Ar--H).
Reaction SMILES: [CH2:1]([O:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[Na+:24].[CH2:25]([OH:43])CCCCCCCCCCCCCCC(C)C>>[CH2:1]([O:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18].[Na+:24].[C:25](=[O:43])=[O:19]
Reactant: CC(C)CCCCCCCCCCCCCCCO
Agent: CC(C)CCCCCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: O=C=O

Procedure:
Into a piston front part (window side) in the variable-volume high-pressure cell, 0.143 g (0.386 mmol) of sodium isostearylsulfate (containing 13.9% of isostearyl alcohol as an impurity) obtained in Example 1 was charged and the apparatus was closed tightly, followed by drying the inside of the variable-volume high-pressure cell using a vacuum pump. Next, the temperature inside of the variable-volume high-pressure cell was set at 35° C. and into the piston front part of the variable-volume high-pressure cell, 20 g (sodium isostearylsulfate concentration (relative to carbon dioxide): 0.08% by mol) of carbon dioxide (manufactured by Nippon Ekitan Corporation; purity: 99.99% or more) was pressed. Then, the temperature inside of the variable-volume high-pressure cell was elevated to 75° C. and the pressure in the piston rear part of the variable-volume high-pressure cell was set to 37 MPa, followed by stirring the mixture in the variable-volume high-pressure cell to obtain a transparent and homogeneous sodium isostearylsulfate/carbon dioxide solution. Next, to the sodium isostearylsulfate/carbon dioxide solution, 40 μL of a 0.1% by weight sodium p-toluenesulfonate aqueous solution prepared by a method including: dissolving 0.0392 g of p-toluenesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) in 40 mL of water and neutralizing the resultant solution with sodium hydrogen carbonate (manufactured by Wako Pure Chemical Industries, Ltd.); utilizing a six-ports valve and a high pressure pump, was added as the marker solution and the resultant mixture was stirred. At the time when a homogeneous one liquid phase was obtained, an UV-Vis absorption spectrum was measured by a spectrophotometer (manufactured by Hitachi High-Technologies Corporation; U-2810) through a pressure resistant spectrum cell (manufactured by L. TEX Corporation; light path length: 10 mm) having a quartz window that was connected to the apparatus. By repeating the addition of 40 μL of a sodium p-toluenesulfonate aqueous solution, the stirring of the reaction mixture, and the measurement of the UV-Vis absorption spectrum, the data until W0=86.5 (W0c=71.5) were collected.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].[Cl-].[Na+].C(OCC)(=O)C>C(O)C.[Ti]>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:21])[CH3:22])[N:7]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [Ti]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Reaction time: 6 h
Yield: 91.3 %

Procedure:
A solution that consists of 230 mg (0.45 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid diethylamide and 0.132 ml (0.58 mmol) of titanium tetraethylate in 14 ml of ethanol is mixed with 135 mg (3.55 mmol) of sodium borohydride. After 6 hours at room temperature, the reaction is halted by adding saturated sodium chloride solution and ethyl acetate. The precipitate that is produced is suctioned off on Celite. The filtrate is washed with saturated sodium chloride solution, and it is dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-70%), 220 mg (92%) of the product is obtained.