Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].Cl.[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47](Cl)(=[O:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Zn].C(Cl)(Cl)Cl>[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47]([OH:49])(=[O:1])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)O)c1
Reaction time: 0.5 h

Procedure:
87 ml of water and 18.2 ml (0.218 mol) of 12N-HCl were added to the solution of 87 ml of chloroform and 8.65 g (0.0121 mol) of the white solid containing 3,5-dihexadecyloxycarbonylbenzenesulfonyl chloride, and then 7.93 g of zinc was added thereto at 5° C. followed by stirring for 4 hours and 30 minutes. After the insoluble component was removed therefrom, the solution was extracted with 100 ml of chloroform, washed with saturated brine, and dried with Glauber's salt. After removing Glauber's salt, the solution was concentrated under reduced pressure, and the residue was recrystallized from hot hexane to obtain a colorless crystal of 3,5-dihexadecyloxycarbonylbenzenesulfonic acid. (Yield: 4.43 g, 48% (based on sodium 3,5-dimethyloxycarbonylbenzenesulfonate), m.p.: 63°-65° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[N:27]1[C:40]2C(=CC=C3[C:39]=2[N:38]=[CH:37]C=C3)C=CC=1.N1C=CN=C1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:38]3[CH:39]=[CH:40][N:27]=[CH:37]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-n3ccnc3)cc2)CC1
Temperature: 110 °C
Yield: 156.3 %

Procedure:
4-(4-Iodo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.194 g, 0.5 mmol), Cul (0.01 g), Cs2CO3 (0.326 g, 1.0 mmol), [1,10]Phenanthroline (0.027 g, 0.15 mmol) and imidazole (0.034 g, 0.5 mmol) were mixed in 3 mL dry DMF in a pressure vessel. The vessel was heated at 110° C. overnight. After cooling to rt, the insoluble was filtered and washed with CH2Cl2. The filtrate was concentrated and the crude was purified with prep TLC (7.5% MeOH-2M NH3/CH2Cl2) to yield the title compound (0.077 g). M+H 328.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].OS(C(F)(F)F)(=O)=O.[I:19]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:19])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=S(=O)(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (5 g, 35.43 mmol) in triflic acid (15.6 ml, 177.15 mmol, 5 eq.) at 0° C. was added N-iodosuccinimide (9.57 g, 42.5 mmol, 1.2 eq.) portionwise and the mixture was stirred at RT for 1 h. The mixture was quenched by the addition of water and extracted with diethylether (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to afford the compound in 66% yield (6.2 g). 1H NMR (300 MHz, DMSO-d6): δ 8.42 (dd, 1H), 8.18-8.13 (m, 1H), 7.46-7.39 (m, 1H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[P:14]([Cl:18])(Cl)(Cl)=[O:15]>C(Cl)Cl>[CH2:1]([P:14]([Cl:18])([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCP(=O)(Cl)CCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
223.6 Grams (1.2 mol) of dodecyl alcohol and 500 ml of methylene chloride were placed in 1-liter three-necked flask equipped with a condenser and a stirrer; then 55.8 g (0.6 mol) of phosphorus oxychloride was added dropwise over 30 min, with stirring, under cooling with ice with the internal temperature kept below 10° C.; and after the completion of the addition the stirring was continued for 20 min. The temperature of this reaction mixture was elevated to room temperature, then the reaction was continued for 1 hour under reduced pressure of 80 to 120 mmHg; and after the temperature was elevated to 50° C., the reaction was continued for 3 hours under ordinary pressures. The reaction mixture was cooled to room temperature, to obtain 246.6 g (yield: 87.6%) of a transparent liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:24]2[S:23][CH:27]=[CH:26][N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), thiazol-2-ylamine (27 mg, 0.27 mmol) and N,N-diisopropylethylamine (141 μL, 0.82 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-thiazol-2-yl-acetamide (71 mg, 62%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O4S2 [M+] 427.04, found 428 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.05 (d, J=3.5 Hz, 1 H, Ar), 7.52 (d, J=3.5 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.2 Hz, 1 H, Ar), 7.71 (d, Jm=1.2 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>CN(C=O)C>[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(F)c1F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,3-difluorophenylboronic acid (CAS RN 121219-16-7) and using DMF as reaction solvent. Off-white solid (14%). MS (ESI): m/z=461.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[NH:8][C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17].[CH2:19]1[O:21][CH2:20]1>CO.Cl>[CH3:1][NH:2][C:3](=[O:18])[O:4][CH:5]1[CH2:10][C:9]([CH2:12][CH3:13])([CH3:11])[N:8]([CH2:19][CH2:20][OH:21])[C:7]([CH2:15][CH3:16])([CH3:14])[CH:6]1[CH3:17]
Reactant: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CCC1(C)CC(OC(=O)NC)C(C)C(C)(CC)N1CCO
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of 5.1 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl methylcarbamate (Compound 66 - prepared as described in Preparation 4) in 8 ml of methanol were added 1.74 g of ethylene oxide and 1 drop of concentrated hydrochloric acid. The mixture was heated overnight at 100° C. in a sealed tube. When the reaction was complete, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel using a 1 : 1 by volume mixture of benzene and ethyl acetate as eluent, giving 3.0 g of Compound 84. The compound showed a single spot on thin layer chromatography on silica gel (developing solvent: benzene/ethyl acetate, 1 : 1 by volume), Rf value 0.51.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:17]=[CH2:18])[C:14]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH3:19][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([CH2:15][Cl:22])[C:13]([CH:17]=[CH2:18])=[CH:12][N:11]=1
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Reaction time: 1 h

Procedure:
To a solution of 0.1 mole of 3-benzyloxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. of benzene is added dropwise with cooling a solution of 0.11 mole of thionyl chloride in 50 ml. benzene. The reaction mixture is stirred for 1 hour and then filtered to give 2-methyl-3-benzyloxy-4-chloromethyl-5-vinylpyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18](O)=[O:19])=[CH:14]2.Cl.C[N:34](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:34])=[O:19])=[CH:14]2
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.2 %

Procedure:
A mixture of 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (940 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (817 mg), 1-hydroxybenzotriazole ammonium salt (648 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate-diethyl ether to give the title compound (640 mg, yield 68%) as a pale-yellow solid. MS 441 (MH+).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[CH:12]1[CH2:16][CH:15]=[CH:14][CH:13]=1>>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([C:4]([Cl:9])=[C:5]1[Cl:8])[CH:15]1[CH:16]2[CH:12]=[CH:13][CH2:14]1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: C1=CCC=C1
Product: ClC1=C(Cl)C2(Cl)C3CC=CC3C1(Cl)C2(Cl)Cl

Procedure:
In particular, the condensation reaction is a Dieis-Alder addition of hexachlorocyclopentadiene and cyclopentadiene to yield 4,5,6,7,8,8,-hexachloro-3a,4, 7,7a-tetrahydro-4,7-methanoindene which is oxidized with selenium dioxide to 1-exo-hydroxy-4,5,6,7,8,8-hexachloro-3a,4,7,7,a-tetrahydro-4,7-methanoindene. The composition of the heptachlor-hapten was verified by physical analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc(F)c1
Product: CCC(NC(=O)Cc1cccc(F)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH2:26][CH:27]1[CH2:29][CH2:28]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:27]1([CH2:26][C:6]2[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:12])([F:13])[F:14])[CH:9]=[C:8]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)[N:7]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1

Procedure:
In analogy to the procedure described in example 43D], 2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 21 g of 1-hydroxy-4-bromo-2,5-difluoro-benzene in 2-butanone (300 ml) and was added potassium carbonate (20.8 g) and benzylbromide (24 mL). The reaction mixture was boiled while stirring for 1.5 hours. After cooling to room temperature the mixture was partitioned between ethyl acetate and water. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was then purified by column chromatography (heptane/silica gel) to give 25.3 g of the title compound.
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>CCOCC>[F:31][C:22]([F:21])([F:30])[C:23]1[CH:24]=[C:25]([S:29][CH:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[CH3:7])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FC(F)(F)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Sc1cccc(C(F)(F)F)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 98.3 %

Procedure:
To a 250 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (11 g, 35.8 mmol), 3-(trifluoromethyl)benzenethiol (7.6 g, 43 mmol), K2CO3 (9.9 g, 72 mmol) and 80 ml dimethylformamide. The reaction mixture was heated at 50° C. for 36 hr under N2, then cooled down to room temperature, 150 ml ether was added. The resulting mixture was sequentially washed with 250 ml water, 100 ml 5% KOH solution and 75 ml brine. The organic layers were dried over sodium sulfate, filtered and concentrated to give 13.7 g crude product. It was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][N:13]1[CH2:17][C@@H:16]([CH3:18])[C@@:15]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])([C:19](=[O:33])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([F:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:14]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:9])[F:10])[C:3]=1[CH2:12][N:13]1[CH2:17][C@@H:16]([CH3:18])[C@@:15]([CH2:34][C:35]([OH:37])=[O:36])([C:19](=[O:33])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([F:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:14]1
Reactant: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3C(F)(F)F)C[C@H]2C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)O)CN(Cc3c(Cl)cccc3C(F)(F)F)C[C@H]2C)CC1
Reaction time: 0.58 h
Yield: 88 %

Procedure:
A mixture of the chiral form of tert-butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 1l (153 mg, 0.252 mmol), trifluoroacetic acid (2 ml, 26.9 mmol) and dichloromethane (dehydrated) (2 ml) was stirred at mom temperature for two hours and 35 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title compound (122 mg, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=Cc1c[nH]cn1
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(NCc2c[nH]cn2)cc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 3,4-difluoroaniline (0.60 g, 4.65 mmol) in 1,2-dichloroethane (5 ml) were added 4-formylimidazole (0.67 g, 6.97 mmol), sodium triacetoxyborohydride (1.97 g, 9.29 mmol) and acetic acid (0.05 ml). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield an off-white solid (284 mg, 29%); MS (ISP): 210.1 ((M+H)+.).
Reaction SMILES: [OH:1][CH:2]1[C:6](=O)[N:5]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][C@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].B>O1CCCC1>[OH:1][CH:2]1[CH2:6][N:5]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:4][C@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Agent: B
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(O)[C@@](C)(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 30.5 %

Procedure:
To a solution of tert-butyl (3S)-4-hydroxy-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (5.13 g, 16.1 mmol) in tetrahydrofuran (100 mL), 1.17M solution of borane in tetrahydrofuran (45.3 mL, 53.1 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 13 hours. After concentrating the reaction mixture under reduced pressure, water (10 mL), ethanol (100 mL), and triethylamine (5 mL) were added to the concentrate, and the mixture was heated under reflux in an oil bath at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (200 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (200 mL×2). The resulting organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1→1:2) to obtain 1.50 g (31%) of the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccn1)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-pyridin-2-ylethanone (6.27 g 29 mmol) in methanol (100 ml) was added a solution of hydroxylamine hydrochloride (9.6 g 130 mmol) and sodium acetate (15.6 g) in water (80 ml) and the reaction was stirred at room temperature for 24 hours. The resulting precipitate was filtered off and dried to give the title compound as a white solid (5.83 g 87%). (M-H2O)H+: 213; NMR: (CDCl3): δ 4.42 (2H, s) 7.00 (2H, t) 7.14 (1H, m) 7.28 (1H, d) 7.59 (1H, dt) 7.72 (2H, m) 8.55 (1H, m) 8.96 (1H, br).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][O:17][CH2:18][C:19]([NH2:21])=O)=[CH:13][CH:12]=1)[CH3:9].CCOCC>O1CCCC1>[CH3:9][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][O:17][CH2:18][CH2:19][NH2:21])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CN(C)Cc1ccc(COCC(N)=O)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1ccc(COCCN)s1
Yield: 74.8 %

Procedure:
A suspension of lithium aluminium hydride (0.38 g) and [[5-(N,N-dimethylaminomethyl)2-thienyl]methoxy]acetamide (2.28 g) in a mixture of dry ether (25 ml) and dry tetrahydrofuran (5 ml) was heated at reflux for 4 hr. The reaction was then quenched with water and evaporated. The residue was extracted with chloroform. The organic phase was dried and distilled to afford a colourless oil (1.6 g) b.p. 110°-120° (0.1 mm). NMR (CDCl3), 8.43, s, (2H); 7.72, s, (6H); 7.12, t, (2H); 6.46 t, (2H); 6.38, s, (2H); 5.32, s, (2H), 3-3.3, m, (2H).
Reaction SMILES: [CH2:1]([O:3][Si:4]([CH2:11][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].C([Li:26])(C)(C)C>>[CH2:17]([O:16][Si:12]([CH:11]([Li:26])[Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])([O:19][CH2:20][CH3:21])[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCO[Si](C[Si](OCC)(OCC)OCC)(OCC)OCC
Reactant: [Li]C(C)(C)C
Product: [Li]C([Si](OCC)(OCC)OCC)[Si](OCC)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A commercially available bis(triethoxysilyl)methane (BTM) was lithiated by the following procedure. To 300 mL of freshly distilled dry tetrahydrofuran (THF) in a 3-neck flask attached to a bubbler was added 3.07 g (9.00 mmol) BTM and the solution was flushed for 5 minutes with nitrogen that had been passed through a drying column packed with CaCl2 and Drierite. The solution was cooled down to −78° C. and then 5.2 mL, 1.7 M (9 mmol) of t-butyllithium was added dropwise over 10 minutes. The solution was stirred for 30 minutes at −78° C. after which a very, faint yellowish solution resulted. Then the temperature of the solution was raised to room temperature (RT) and stirring continued for 30 minutes at RT after which the solution turned colorless.