Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1c(O)cccc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(O)cccc1C(F)(F)F
Yield: 87 %

Procedure:
A mixture of 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-3-trifluoromethyl-phenol (53 mg, 87%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([OH:21])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:35](=[O:36])[N:11]2[CH:12]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:13]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of methanesulfonyl chloride (0.145 ml, 1.87 mMol) in anhydrous CH2Cl2 (2 ml.) is added dropwise over 10 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (0.65 g., 1.44 mMol) and Et3N (0.30 ml, 2.16 mMol) in anhydrous CH2Cl2 (10 ml.). After stirring 15 more min. in the cold, the solution is diluted with ice-cold CH2Cl2 (10 ml.), washed with ice-cold H2O (10 ml.), ice-cold 5% HCl (10 ml.), and ice-cold 5% NaHCO3 (10 ml.), dried with MgSO4, and filtered. Evaporation of the solvent in vacuo leaves p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2)=[O:2].[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH3:21]>CCOCC>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC[Mg]Br
Reactant: COC(=O)c1cccc2cc(C=O)ccc12
Solvent: CCOCC
Product: CCCCCC(O)c1ccc2c(C(=O)OC)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of methyl 6-formyl-1-naphthoate (36 mg, 0.17 mmol) in THE (1.7 mL) was cooled to 0° C. and treated with n-pentylmagnesium bromide (0.1 mL of a 2.0 M solution in Et2O, 0.2 mmol). The cooling bath was removed and after stirring at room temperature for 1 h the reaction was quenched with 1 N aqueous HCl, diluted with water (10 mL) and extracted with EtOAc (3×10 The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 12 g silica gel (100% hexanes→40% EtOAc/hexanes, gradient) to afford 34 mg (71%) of methyl 6-(1-hydroxyhexyl)-1-naphthoate.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>CN(C)C=O.O>[C:21]1([C:19]([NH:18][CH:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)[CH:2]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:46][C:47]3[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=3)=[CH:34][CH:33]=2)[OH:1])=[O:20])[C:26]2[CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were added potassium carbonate (470 mg, 3.40 mmol) and methyl 4-(bromomethyl)-benzoate (780 mg, 3.40 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (361 mg, 47%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.Cl[C:28](Cl)([O:30][C:31](=O)[O:32]C(Cl)(Cl)Cl)Cl.CO>ClCCl>[CH3:28][O:30][C:31](=[O:32])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OC)cc3)nc21

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (150 mg, 0.43 mmol) in dichloromethane (5 mL) was treated with triphosgene (64 mg, 0.21 mmol). After the passage of 5 minutes, an excess of methanol was added to the mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide methyl{4-[1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate. MS (ES+): 409.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]2[C:30]3[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=3[NH:24][C:23]([CH3:35])=[C:22]2[C:36]#[N:37])[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.N1C=CC=CC=1.[CH2:44]([S:47](Cl)(=[O:49])=[O:48])[CH2:45][CH3:46]>ClCCl>[C:36]([C:22]1[CH:21]([C:4]2[CH:5]=[C:6]([O:18][CH2:19][CH3:20])[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[C:2]([NH:1][S:47]([CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])[CH:3]=2)[C:30]2[C:29](=[O:31])[CH2:28][CH:27]([CH2:32][CH2:33][CH3:34])[CH2:26][C:25]=2[NH:24][C:23]=1[CH3:35])#[N:37]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc(OC)c2)c(OCC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(NS(=O)(=O)CCC)c(OCc2cccc(OC)c2)c(OCC)c1
Reaction time: 17 h

Procedure:
To a solution of 4-[3-amino-5-ethoxy-4-(3-methoxy-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (220 mg) and pyridine (106 μl) in dichloromethane (5 ml) was added propane-1-sulfonyl chloride (94 mg). After stirring for 17 h, the mixture was diluted with dichloromethane and extracted with water and sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:19][C:20]1([CH3:36])[O:25][CH:24]([C:26]([NH:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:27])[C:23]([CH3:35])([CH3:34])[CH2:22][O:21]1>>[CH3:19][C:20]1([CH3:36])[O:25][CH:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:32])=[O:27])[C:23]([CH3:35])([CH3:34])[CH2:22][O:21]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCCCC(=O)NCCCO
Product: CCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 64.1 %

Procedure:
N-(3-Hydroxypropyl)dodecanamide (2.57 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.19 g of the title compound (yield: 64%)
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16])[CH3:10]>O.C(O)C>[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[N:2][OH:3])[C:15]1=[O:16])[CH3:10]
Reactant: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(CN1C(=O)C(=NO)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of 5.38 g of hydroxylamine hydrochloride and 5.38 g of sodium acetate in 40 ml of water was added to a suspension of 11.1 g of 1-(2,2-diethoxyethyl)isatin in 100 ml of ethanol. The mixture was stirred at room temperature for 1 hour, followed by concentration. The concentrate was diluted with chloroform and washed with an aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous sodium sulfate and concentrated, and the residue was recrystallized from ethyl acetate to obtain 7.10 g (61%) of 1-(2,2-diethoxyethyl)-3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:14][CH:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.61 g, 4.32 mmol) and tert-butyl azetidin-3-ylmethylcarbamate (0.886 g, 4.76 mmol) in dimethylformamide (8.65 ml) was treated with potassium carbonate (0.896 g, 6.48 mmol) and the suspension was heated at 55° C. (12 pm) for 3 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered. The solid was washed with water and dried to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1F
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1F

Procedure:
prepared by reaction of 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.89 min; [M+H]+=252.0.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:24])([OH:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: C[Mg]Cl
Reactant: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Yield: 96 %

Procedure:
To a stirred solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)propan-2-one (3.81 g, 10.0 mmol) in toluene (100 mL) at 21° C. was added a 3.0 M solution of methylmagnesium chloride in THF (5.0 mL, 15 mmol) in one portion. The temperature of the resulting solution rose to 34° C. and was stirred without any temperature control. After a total of 60 min the reaction mixture was quenched by addition of saturated ammonium chloride (50 mL). The resulting mixture was vigorously stirred for 20 min, then transferred to a separatory funnel and shaken. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to afford the title compound as an orange oil (3.79 g, 96%) that slowly crystallized on standing.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([N+:25]([O-])=O)=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reaction time: 1 h

Procedure:
A mixture of 2-(2-(2-acetoxyethyl)-5-nitro-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (350 mg, 0.00093 mol), ethanol (20 mL, 0.3 mol), ammonium chloride (496.1 mg, 0.009275 mol) and water (10 mL, 0.6 mol) was added at 85° C. Iron (207 mg, 0.00371 mol) was added in two portions five minutes apart and the reaction was stirred at that temperature for 1 hour. The reaction mixture was then poured into methylene chloride (100 mL) and the layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and used for the next reaction without purification. MS m/z=348.5 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.Cl.[CH3:13][O:14][C:15]([C:17]1([NH2:20])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.C(O)(=O)C>C(O)C.C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1([N:20]2[C:2]3[N:3]=[CH:4][N:5]=[C:6]([Cl:11])[C:7]=3[CH:8]=[CH:9]2)[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1(N)CC1
Reactant: O=CCc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(=O)C1(n2ccc3c(Cl)ncnc32)CC1
Temperature: 100 °C
Yield: 35 %

Procedure:
To a stirred solution of (4,6-dichloro-pyrimidin-5-yl)acetaldehyde (Preparation 208, 2 g, 10.5 mmol) and 1-Amino-cyclopropane-carboxylicacidmethylester hydrochloride (1.33 g, 11.6 mmol) in ethanol (30 mL) was added triethylamine (4.4 mL, 31.6 mmol) and the mixture heated in a sealed tube at 100° C. for 10 hours. Acetic acid (1.21 mL, 21.1 mmol) was then added and the mixture heated at 100° C. for additional 16 hours. The reaction mixture was cooled to room temperature and diluted with DCM (200 mL). The organic layer was washed with water (2×50 mL), brine (50 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 90:10) to afford the title compound as a solid in 35% yield, 900 mg.
Reaction SMILES: [CH:1]1([N:4]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(N)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CN(C)C=O.ClCCl.CCN(CC)CC>[CH:1]1([NH:4][C@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:14][C@H:13]2[F:18])[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Agent: CC(C)(C)OC(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: F[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@@H]1NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-cyclopropyl-N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate (100 mg), 2-chloro-5-trifluoromethylpyridine (141 mg) and Et3N (78 mg) in N,N-dimethylformamide (2 mL) is heated in a microwave reactor at 130° C. for 3 h. After concentration the residue is purified by chromatography on silica gel eluting with 0% to 30% ethyl acetate/hexane to give the intermediate product [LC (method 20): tR=3.19 min; mass spectrum (APCI): m/z=404 [M+H]+]. The Boc-amine is dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) is added and the solution is stirred at r.t. for 1 h. After concentration dichloromethane (3 mL) and 2 M NaOH (2 mL) are added and the organic layer is separated, dried over MgSO4 and concentrated to give the title compound. LC (method 20): tR=1.99 min; Mass spectrum (APCI): m/z=304 [M+H]+.