Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:46]=[CH:45][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=4)=[CH:20][C:19]=3[N:36](C)[C:37](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:47].O1CCOCC1>>[ClH:47].[C:32]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[OH:31])[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:46][CH:45]=3)[N:36]([CH3:37])[C:19]=2[CH:20]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(O)c(C(C)(C)C)c3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.75 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 14 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (1.11 g).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[Cl:13].C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>O1CCCC1>[Cl:13][C:3]1[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=[CH:12][C:2]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1
Reactant: FC1(F)Oc2ccc(Br)c(Cl)c2O1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2Cl)OC(F)(F)O3)OC1(C)C
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
5-Bromo-4-chloro-2,2-difluorobenzo[d][1,3]dioxole (1.0 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to −20 to −30° C. and treated in portions with isopropylmagnesium chloride-lithium chloride complex solution (1.3 M; 3.1 mL, 4.1 mmol). After 90 min at −20 to 0° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (830 μL, 750 mg, 4.1 mmol) was added, and stirring was continued at 0-20° C. for 90 min. The reaction was quenched by addition of saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (30 mL). The aqueous phase was extracted again with ethyl acetate (15 mL), and the combined organic phases were washed with saturated NaCl (15 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (1.2 g, ca. 100%): 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 1H), 6.99-6.94 (m, 1H), 1.36 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.62 (s); EIMS m/z 318.
Reaction SMILES: P(Cl)(Cl)Cl.P(Br)(Br)Br.P(F)(F)F.S(Cl)([Cl:15])=O.[NH2:17][C:18]1[N:22]([CH2:23][CH2:24]O)[N:21]=[C:20]([C:26]2[N:27]([CH3:34])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[C:19]=1[C:35]#[N:36]>CN(C)C=O.C1C=CC=CC=1>[NH2:17][C:18]1[N:22]([CH2:23][CH2:24][Cl:15])[N:21]=[C:20]([C:26]2[N:27]([CH3:34])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[C:19]=1[C:35]#[N:36]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nn(CCO)c(N)c1C#N
Reactant: O=S(Cl)Cl
Agent: BrP(Br)Br
Agent: FP(F)F
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nn(CCCl)c(N)c1C#N

Procedure:
The preparation of a 5-amino-1-(haloalkyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile is accomplished by reacting the corresponding hydroxyalkyl compound with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus trifluoride, thionyl chloride and the like. Thus, 5-amino-1-(β-hydroxyethyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile, is allowed to react with thionyl chloride in an inert solvent such as benzene, in the presence of a small amount of dimethylformamide to yield 5-amino-1-(β-chloroethyl)-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carbonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH2:19]([C:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[O:23][N:22]=1)C>>[CH3:19][C:21]1[CH:25]=[C:24]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:27])[O:23][N:22]=1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CCc1cc(C(=O)O)on1
Product: Cc1cc(C(=O)NCCCCc2ccc(-c3ccc(=O)[nH]n3)cc2)on1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and 3-ethyl-5-carboxyisoxazole in the same manner as in Example 87, 6-{4-[4-(3-methylisoxazole-5-ylcarbonylamino) butyl]phenyl}pyridazin-3(2H)-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[N:6][CH:7]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:3]2[N:13]=[CH:14][N:8]([CH:9]3[CH2:12][CH2:11][CH2:10]3)[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)cnnc1NC1CCC1
Product: Clc1cnnc2c1ncn2C1CCC1
Temperature: 140 °C
Yield: 54 %

Procedure:
A mixture of 5-chloro-N3-cyclobutylpyridazin-3,4-diamine (Preparation 98, 140 mg, 0.70 mmol) and triethyl orthoformate (4 mL) was heated at 140° C. for 4 hours. After evaporation in vacuo, the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 99:1 to afford the title compound as an off white solid in 54% yield, 80 mg.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:12]I.[OH-].[NH4+]>CN(C=O)C.O>[I:12][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: II
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 1H-pyrrolo[3,2-c]pyridine (20 g, 170 mmol) in DMF (100 mL) was added KOH (33.2 g, 593 mmol) and the mixture was stirred for 10 minutes. A solution of iodine (47.3 g, 186 mmol) in DMF (100 mL) was added at 0° C., and the reaction allowed to warm to room temperature over 1.5 hours. The reaction was poured onto an aqueous solution of Na2S2O5 (17.2 g) and ammonium hydroxide (35%, 170 mL) in water (2.5 L). The resulting precipitate was filtered, washed with water and dried to afford the title compound (33.5 g, 81%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCBr
Reaction time: 16 h
Yield: 94.9 %

Procedure:
8-Bromooctanoic acid (2 g, 8.90 mmol, 1 equiv) was stirred in CH2Cl2 (15 mL) under N2 atmosphere and thionyl chloride (784 μL, 10.68 mmol, 1.2 equiv) added followed by DMF (few drops). The solution was stirred for 16 h and concentrated in vacuo to give 8-bromooctanoyl chloride (2.04 g, 95%) as a yellow oil which was used without further purification. Thiourea 4 (600 mg, 1.84 mmol, 1 equiv.) was stirred in CH2Cl2 (15 mL) under N2 atmosphere. 8-Bromooctanoyl chloride (532 mg, 2.02 mmol, 1.2 equiv.) was added, followed by triethylamine (256 μL, 1.84 mmol, 1 equiv.). The beige suspension was stirred at rt for 16 h and diluted with CH2Cl2 (20 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×20 mL), 10% aqueous sodium hydroxide (1×20 mL), and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 8-bromo-octanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (579 mg, 59%) as a yellow oil.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[C:16]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1CC(O)=[O:35].O>[Ni]>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:35])=[C:16]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Reactant: O=C(O)Cc1ccccn1
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Temperature: 45 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Sodium hypophosphite hydrate (986 g, 11.2 mol) and Raney nickel (500 g of a 50% aqueous suspension) were added to a solution of the product from Step B (790 g, 2.8 mol) in a 2:1:1 mixture of pyridine-acetic acid-water (7 L). The mixture was stirred at 45° C. for 7 h, then cooled to 25° C. overnight and filtered through a filter-aide rinsing with water and ethyl acetate. The filtrate was washed with saturated sodium hydrogenphosphate to pH 5, water and brine, dried over sodium sulfate and concentrated. During concentration, 4 L of heptane was added to azeotropically remove pyridine. After 8 L of solvent had been removed the product solidified. Heptane (5 L) was added and the solid was triturated, isolated by filtration and vacuum dried at 35° C. to yield the desired product (722 g, 90%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Yield: 96 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 2-(trifluoromethyl)phenylboronic acid (Aldrich 393606; 2.74 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue was taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (3.7 g, 96%) as a brown oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1>O1CCOCC1>[CH3:10][O:11][C:12]1[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][CH:19]=2)=[N:16][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cnc(-c2ccc(O)cc2)nc1N1CCOCC1
Solvent: C1COCCO1
Product: COc1cnc(-c2ccc(OC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 80 °C
Yield: 24.03 %

Procedure:
Phenyl isocyanate (0.03 ml, 2.0 eq) was added to a solution of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol (0.05 g, 1.0 eq) in dioxane (6 ml) and heated at 80° C. for 20 hrs. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers were washed with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a white solid (0.07 g, 24.03%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:14]#[N:15].O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:19]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]2[C:11](=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH2:10][O:27]1
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Reactant: CN(C)CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 95 %

Procedure:
A solution of 3-dimethylaminopropylmagnesium chloride (1.2 M in THF, 84 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (25.0 g) in a mixture of toluene (175 ml) and THF (50 ml) so that the temperature did not raise above −5° C. The mixture was stirred for 2 hours at 0° C. before water (100 ml) and saturated NH4Cl solution were added to adjust the pH to 9. The phases were separated and the aqueous phase was extracted twice with toluene (200 ml). The combined organic phases were washed with water (200 ml) and concentrated in vacuo to give a viscous oil (28,0 g, 95%). Spectral and analytical data were in accordance with the literature.
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>CO.Cl>[C:11]12([C:10]3=[C:5]([OH:4])[CH:6]=[CH:7][CH:8]=[C:9]3[O:15][CH2:14]1)[CH2:13][CH2:12]2
Reactant: COCOc1cccc2c1C1(CC1)CO2
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc2c1C1(CC1)CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 4-{[(methyloxy)methyl]oxy}spiro[1-benzofuran-3,1′-cyclopropane] (Intermediate 84, 118 mg) in methanol (5 ml), HCl 2N in water (0.286 mL, 0.572 mmol) was added and the reaction mixture was stirred overnight at 50° C. Combined solvents were removed under reduced pressure and the residue was re-dissolved in toluen (10 ml) and the solvent was removed. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a white solid (70 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:1]1([C:7]2[N:11]=[CH:10][N:9]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2cnc[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of 5-phenyl-1H-imidazole (504 mg, 3.5 mmol) in DMF (10 mL) was cooled to 0° C., and then NEt3 (530 mg, 5.25 mmol) was added, followed by the addition of (chloromethanetriyl)tribenzene (1.17 g, 4.2 mmol) in small portions. The resulting slurry was stirred at room temperature for 2 hours. The mixture was poured into ice-water (50 mL) and stirred until the ice melted. The resulting precipitate was collected and dissolved in DCM (100 mL). The solution was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to obtain 4-phenyl-1-trityl-1H-imidazole as a white solid (1.0 g). MS (ESI): m/z 387 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][C@@H:22]([N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1)[CH3:23]>>[CH3:19][O:20][CH2:21][C@@H:22]([N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1)[CH3:23]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC[C@H](C)N(C)c1ccc(N)cn1
Product: COC[C@H](C)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2—((S)-2-methoxy-1-methyl-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([O:25]C3OC(CO)C(O)C(O)C3O)=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.P([O-])([O-])([O-])=O>[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1
Reactant: Cc1cc(=O)oc2cc(OC3OC(CO)C(O)C(O)C3O)ccc12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.33 h

Procedure:
α-Gal A was assayed using 4-methylumbelliferyl-α-D-galactopyranoside (4-MU-α-Gal) as previously described (Bishop, et al., 1980, In Enzyme Therapy in Genetic Diseases: 2. Desnick, R. J. (Ed.). Alan R. Liss, Inc. New York, p. 17). Briefly, a stock solution of 5 mM 4-MU was prepared in 0.1M citrate-phosphate buffer, pH 4.6 solubilized in an ultrasonic bath. The reaction mixtures containing 10-50 μl of enzyme preparation or cell extracts and 150 μl substrate, were incubated at 37° C. for 10-30 min. The reactions were terminated with the addition of 2.33 ml of 0.1M ethylenediamine. One unit of activity is that amount of enzyme which hydrolyzes 1 nmol of substrate/hour.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:29])[CH2:24][NH:25][CH2:26][CH2:27][OH:28])[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:14]([OH:13])[CH:23]([OH:29])[CH2:24][NH:25][CH2:26][CH2:27][OH:28]
Reactant: CC1(C)OC(C(O)CNCCO)[C@H](CC2CCCCC2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H](CC1CCCCC1)C(O)C(O)CNCCO
Yield: 111.8 %

Procedure:
38.5 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-(2-hydroxyethylamino)ethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. The mixture was treated in the same manner as in Example 17 to obtain 25.8 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-(2-hydroxyethylamino)-2,3-pentanediol as colorless oily substance.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.BrC1C([F:42])=CC(C(F)(F)F)=CN=1>>[F:42][C:30]1[C:25]([NH:24][CH2:23][C@@H:3]2[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])=[N:26][CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C@H:37]3[CH2:41][O:40]C(C)(C)[O:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FOC(=O)C(F)(F)F>ClCCl>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C@H:37]([OH:38])[CH2:41][OH:40])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@H]3COC(C)(C)O3)c2)cc1
Agent: O=C(OF)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@H](O)CO)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 285A was treated with tetrafluoroacetic acid (0.20 mL) and dichloromethane (1.8 mL). The reaction mixture was stirred for 3 hours at room temperature, then dried in vaccuo, and purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 7.23 (m, 8 H), 7.04 (m, 1 H), 6.94 (m, 4 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.95 (m, 1 H), 3.81 (m, 1 H), 3.75 (m, 1 H), 3.41 (m, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H); MS (APCI+) m/z 563.2 (M+H)+.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:11][CH:10]=1>[C].[Pd].CO>[ClH:1].[NH:4]1[CH2:5][CH2:6][N:2]=[C:3]1[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(/C=C/C2=NCCN2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccc(C=CC2=NCCN2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
10% Palladium—carbon (200 mg) was added to a methanol suspension of N-[4-[(E)-2-(4,5-dihydro-1H-imidazol-2-yl)ethenyl]phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride (80 mg, 0.198 mmol) obtained in Example 124, which was stirred under hydrogen atmosphere at 60° C. for 2 hours. After a catalyst was filtered off, the solvent was distilled out under reduced pressure. Diethyl ether was added to the resulting residue, to give the titled compound (52 mg) as a colorless powder.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1>[N+:10]([C:6]1[CH:5]=[C:4]([N:1]2[CH:18]=[C:17]([Si:14]([CH3:16])([CH3:15])[CH3:13])[N:3]=[N:2]2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: C#C[Si](C)(C)C
Reactant: [N-]=[N+]=Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cn(-c2cccc([N+](=O)[O-])c2)nn1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Azido-3-nitro-benzene (CAS:1516-59-2, 11.8 g, 72 mmol) were dissolved in 20 ml THF and 30 ml trimethylsilylacetylene. The reaction mixture was stirred at 60° C. for 3 days. The solvents were evaporated off and the title compound was obtained as a brown solid (16.9 g, 90%), mp 75-78° C.