Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]N1C(=O)CCC1.C[Mg]Br>C1COCC1.CC(=O)OCC>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCN(C)c1ncc(C(=O)OC(C)C)cc1Cl
Reactant: CN1CCCC1=O
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(C)c1ncc(C(=O)OC(C)C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A solution of 5-chloro-6-(ethyl-methyl-amino)-nicotinic acid isopropyl ester (5.18 g, 20.1 mmol), NMP (3.0 g, 30.2 mmol) and Fe(acac)3 (498 mg, 1.41 mmol) in THF (150 mL) is put under argon before a methylmagnesium bromide (3.0 g, 25.2 mmol, solution in diethyl ether) is added dropwise. The dark red-brown solution turns yellow, then dark brown again. The mixture is stirred at rt for 2 h before another portion of methylmagnesium bromide (1.44 g, 12.1 mmol) is added. The dark mixture is stirred at rt for 16 h. Another portion of NMP (3.0 g, 30.2 mmol), Fe(acac)3 (498 mg, 1.41 mmol) and methylmagnesium bromide (1.44 g, 12.1 mmol) is added and stirring is continued at rt for one more hour. The reaction mixture is diluted with EA (200 mL) and carefully quenched with ice-water (100 mL). The suspension is basified by adding 1 N aq. NaOH solution (10 mL) and filtered over a small pad of Hyflo and silica gel. The org. phase of the filtrate is separated and collected and the aq. phase is extracted with DCM (3×100 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. MPLC on silica gel eluting with a gradient of EA in heptane to give 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid isopropyl ester (2.19 g) as a beige oil; LC-MS: tR=0.76 min, [M+1]+=237.20.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2([CH:11]3[CH2:12][C:8]4([C:13]([OH:15])=[O:14])[CH:9]([CH2:10]3)[CH:7]24)[C:4](=[O:16])[NH:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:14][C:13]([C:8]23[CH2:12][CH:11]4[C:5]5([C:4](=[O:16])[N:3]([CH2:22][C:21]6[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=6)[C:2](=[O:1])[N:6]5[CH2:22][C:21]5[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=5)[CH:7]2[CH:9]3[CH2:10]4)=[O:15])=[CH:20][CH:19]=1
Reactant: O=C1NC(=O)C2(N1)C1CC3C2C3(C(=O)O)C1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccc(F)cc2)C(=O)C2(C3CC4C2C4(C(=O)OCc2ccc(F)cc2)C3)N1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A solution of 1.1 g (5.0 mmole) of 2′,5′-dioxo-spiro{tricyclo[2.2.1.02,6]heptane-3,4′-imidazoline}-1-carboxylic acid in 30 mL of N,N-dimethylformamide was treated with an excess of p-fluorobenzyl bromide (4.73 g, 25 mmole) and potassium carbonate (3.45 g, 25 mmole) at 60° C. for 36 hours. After cooling to room temperature, the mixture was diluted to 500 mL with water and extracted with 2×250 mL of ethyl acetate. The extracts were washed with water, dried over sodium sulfate and concentrated in vacuum to give 2.7 g of the title compound, again as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:38]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:32][CH:33]=1
Reactant: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(O)C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.166 mmol) in DCM (5 mL) was added thionyl chloride (0.060 mL, 0.829 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (3 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (95 mg, 0.663 mmol) was added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH) in DCM to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (30 mg, 31.3% yield). MS, m/z (C33H44FN5O3): calcd, 577.3. found, 578.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(=O)([O-])O.[Na+].ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[S:29][CH:28]=[N:27][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1scnc1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.2 g), 4-benzenesulfonylthiazole-5-carbaldehyde (0.23 g) and 1,2-dichloroethane (7.0 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (2.2 mL), trifluoroacetic acid (0.6 mL) and 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with saturated aqueous sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:4 by volume) to afford the title compound as a white foam (0.20 g).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[CH3:14][CH:15]([CH3:20])[C:16]#[C:17][Mg]Cl.CC(C)C#C.C([Mg]Cl)(C)C>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]2[C:16]([CH:15]([CH3:20])[CH3:14])=[CH:17][N:3]=[N:2]2)[CH:9]=1
Reactant: [N-]=[N+]=Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)C#C[Mg]Cl
Agent: C#CC(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cnnn1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A 30 mL scintillation vial was charged with 2-azido-4-chloro-1-nitrobenzene (200 mg, 1.0 mmol) and 0.75 M 3-methyl-1-butynylmagnesium chloride in THF (1.6 mL, 1.2 mmol; prepared by mixing 3-methyl-1-butyne (120 μL, 1.2 mmol) and iPrMgCl (1.5 mL, 1.0 M in THF) at room temperature, heating to 40° C. for 30 minutes then cooling to room temperature). The reaction was allowed to stir at room temperature for 1 hour after which the reaction was quenched with SiO2 and the solvent removed. The product (adsorbed to SiO2) was then loaded on a SiO2 column and purified to give 1-(5-chloro-2-nitro-phenyl)-5-isopropyl-1H-[1,2,3]triazole.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39]([O:45][CH2:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13]([C:49](=[O:50])[C:48]([O:47][CH2:46][O:45][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[O:52])[C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(=O)C(=O)OCOC(=O)C(C)(C)C)[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 99.4 %

Procedure:
tert-Butyl 3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}-ethyl)-4-oxo-2-azetidinyl]acetyl}benzoate (2.24 g) and triethylamine (1.11 g) were dissolved in dry methylene chloride (10 ml), and thereto was added dropwise a solution of [(2-chloro-2-oxoacetyl)oxy]methyl pivalate (10 mmol) in dry methylene chloride (10 ml) under ice-cooling. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and separated. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl 3-({(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)-1-[{[(2,2-dimethylpropanoyl)oxy]methoxy}(oxo)acetyl]-4-oxo-2-azetidinyl}acetyl)benzoate (3.152 g).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][NH2:21])[CH:13]=1>C(O)C>[CH3:1][NH:2][C:3]([NH:21][NH:20][C:14]1[CH:13]=[C:12]([C:11]([F:23])([F:22])[F:10])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(NN)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NNc1cc(C(F)(F)F)cc(OC)n1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
4.7 g of N-methyl-1-methylthio-2-nitroetheneamine, 6.6 g of crude 4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71) and 35 ml of ethanol were stirred for about 5.5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of methanol and then dried to obtain 2.7 g of N-methyl-1-(2-(4-trifluoromethyl-6-methoxy-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 98) having a melting point of 193° C. (decomposed).
Reaction SMILES: C1(CCO)CC1.[C:7]12([CH2:17][OH:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:35][C:36]1[C:37](F)=[CH:38][C:39]([F:49])=[C:40]([CH:48]=1)[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42]>>[C:7]12([CH2:17][O:18][C:37]3[C:36]([Cl:35])=[CH:48][C:40]([C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42])=[C:39]([F:49])[CH:38]=3)[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with adamantan-1-ylmethanol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1), the title compound was obtained as a colorless solid (0.20 g, 8%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2.0 Hz), 159.8 (d, JC-F=255 Hz), 158.3 (d, JC-F=11 Hz), 130.6 (d, JC-F=4 Hz), 116.8 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.7 (d, JC-F=28 Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES+) m/z 415.6, 417.6 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(=O)([O-])O.[Na+].CN(C)C(=O)C>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:17][CH2:16][C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCc1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccccc1NCc1ccco1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 15.7 parts of 1-chloro-2-nitrobenzene, 9.7 parts of 2-furanmethanamine, 8.4 parts of sodium hydrogen carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at about 120° C. The reaction mixture was cooled, water was added and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was triturated in petroleumether. The product was filtered off and dried, yielding 15 parts of N-(2-nitrophenyl)-2-furanmethanamine; mp. 85.6° C. (intermediate 1).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1(=[O:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.[Li]>C1COCC1.[I-].[Zn+2].[I-]>[OH:17][C:7]1([CH2:5][NH2:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCc2ccccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Li]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: NCC1(O)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Five and one-half g of trimethylsilylcyanide is added to a mixture of 7.3 g of 1-tetralone and 10 mg of zinc iodide. The mixture is stirred at room temperature overnight. It is dissolved in 25 ml dry THF and slowly added to a suspension of 2.3 g of lithium aluminumhydride in 40 ml of THF. Reaction is refluxed for three hours and upon cooling, carefully quenched with water. Precipitate is filtered and aqueous solution is diluted with 100 ml 1N NaOH. It was extracted with ether (3×100 ml), dried over anhydrous MgSO4, filtered, and ether evaporated yielding an oil which solidifies upon standing giving 6.4 g (73%) of (1-hydroxy-1,2,3,4-tetrahydronaphthyl)methylamine.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30](O)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([Br:38])[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCC(O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-hydroxypropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (212.4 mg, 0.402 mmol) in CH2Cl2 (5 mL) was added CBr4 (333 mg, 1.00 mmol) and a solution of PPh3 (250 mg, 0.956 mmol) in CH2Cl2 (5 mL). The reaction was allowed to warm to room temperature. After 72 hours, the reaction was concentrated and purified by flash chromatography (10 to 50% EtOAc/hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-bromopropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=594.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.46 (m, 6H), 5.81-5.69 (m, 1H), 5.25-4.97 (m, 2H), 4.36-3.83 (m, 2H), 2.46-2.34 (m, 1H), 2.25-2.14 (m, 1H), 1.29-1.01 (m, 3H), 0.83-0.78 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]([OH:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:30][CH:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CC(O)c1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-1-(2-naphthyl)ethanol and DBU in DME. ES-MS m/e (%): 357 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 8 h
Yield: 200.1 %

Procedure:
To a solution of L-tert-leucine (5.12 g, 39 mmol, 1 equiv) in 1,4-dioxane (80 mL) and 1M NaOH (39 mL, 39 mmol, 1.0 equiv) at 0° C. was added benzyl chloroformate (6.24 mL, 43.68 mmol, 1.12 equiv). The reaction mixture was stirred at 23° C. overnight, then concentrated, poured into 1M HCl (80 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over Na2SO4 and concentrated to give crude CBZ-L-tert-leucine (20.7 g) as a clear oil: IR (cm-1) 3336, 1715, 1521, 1232; 1H NMR (CDCl3) δ 1.02 (s, 9H), 4.21 (d, 1H, J=9.9), 5.11 (s, 2H), 5.35 (d, 1H, J=9.0), 7.34-7.37 (m, 5H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:35])([CH:32]([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[CH:32]([F:34])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 24.1 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.453 g) was added to a solution of 4-{4-(2,2,3,3-tetrafluoropropoxy)phenoxy]-piperidine hydrochloride (0.69 g) in dichloromethane (25 ml) and triethylamine (1.7 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by column chromatography (using λ230 nm as the detecting wavelength) eluting with a 0-10% methanol and dichloromethane. Yielded a solid product, which was dried under vacuum at 50° C. to yield the title compound (0.24 g). NMR Spectrum: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 6.95 (m, 4H), 6.6 (tt, 1H), 4.5 (m, 2H), 4.4 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum M−H− 495.89
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: Cc1ccncc1-c1cc(NC(=O)Oc2ccccc2)ccc1C
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C)c(-c3cnccc3C)c1)CC2
Temperature: 100 °C
Yield: 46.2 %

Procedure:
Phenyl N-(4-Methyl-3-(4-methylpyrid-3-yl)phenyl)carbamate (D69) (0.5 g, 0.0016 mole) in dry dimethylformamide (20 ml) was treated with 5-methoxy-6-trifluoromethylindoline (D11) (0.34 g, 0.0016 mole) under argon and heated to 100° C. for 6 hrs. The mixture was allowed to cool and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and the solution washed with 10% aqueous sodium hydroxide solution (2×20 ml) and then with saturated aqueous sodium chloride solution (30 ml). The organic phase was then dried (Na2SO4) filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane. Trituration of the resulting residue with diethyl ether gave the title compound (E28) (0.326 g, 47%) m.p. 138-140° C.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:49]=[C:48]([NH:50][NH2:51])[CH:47]=[CH:46][N:45]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:10]2[N:50]([C:48]3[CH:47]=[CH:46][N:45]=[C:44]([Cl:43])[CH:49]=3)[N:51]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Br)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
600 mg (1.30 mmol) of the compound of Example 2A is reacted analogously to the synthesis of the compound of Example 20A with 257 mg (1.43 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 175 mg (34% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.215 ml 2-(3-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 4 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 465 mg light yellow oil (100%). MS (ISP) 302.3 (M+H)+.