Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][OH:10].CN1CC[O:15][CH2:14]C1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.CCN(C(C)C)C(C)C.[CH2:40]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([N:47]1[CH2:52][CH2:51][N:50]([C:14]([O:10][CH2:9][CH:3]2[CH2:4][N:5]([CH3:8])[CH2:6][CH2:7][N:2]2[CH3:1])=[O:15])[CH2:49][CH2:48]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN1CCOCC1
Reactant: CN1CCN(C)C(CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C)C(COC(=O)N2CCN(Cc3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
1,4-dimethyl-2-hydroxymethyl piperazine (1.00 g, 6.94 mmol) was dissolved in DCM (50 mL) at room temperature and NMM (0.74 g, 7.29 mmol) was added. The reaction mixture was cooled to 0° C. and 4-nitrophenylchloroformate (1.4 g, 6.94 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then divided into two equal volumes. To one portion was added DIPEA (1.35 g, 10.4 mmol), 1-benzyl piperazine (0.61 g, 3.47 mmol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and 1.0M aq NaOH solution (100 mL). The organic layer was washed with 1.0M aq NaOH solution (5×100 mL), brine (100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was dissolved in DCM (100 mL) and isocyanate resin was added, the reaction mixture was shaken for 16 h, filtered and the solvents were removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 88 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give (1,4-dimethylpiperazin-2-yl)methyl 4-benzylpiperazine-1-carboxylate (0.32 g, 26.3%) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([CH2:11][NH2:12])[OH:10]>CCO>[CH:1]1([CH2:7][NH:12][CH2:11][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: NCCO
Solvent: CCO
Product: OCCNCC1CCCCC1
Temperature: 75 °C
Yield: 51.3 %

Procedure:
A mixture of cyclohexylmethylbromide (23.2 g, 131 mmol) and ethanolamine (47.9 g, 786 mmol) in EtOH (131 mL) was heated at 75° C. for 2 hours. NMR analysis of an aliquot showed the reaction was complete. The reaction was then concentrated to remove ethanol and the resulting residue was diluted with DCM. The organic layer was washed successively with water (3×100 mL) and brine (100 mL) and then dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a light yellowish oil (10.57 g). (m/z): [M+H]+ calcd for C9H19NO 158.16; found 158.2. 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.59 (t, J=5.4 Hz, 2H), 2.73 (t, J=5.4 Hz, 2H), 2.42 (d, J=6.6 Hz, 2H), 1.6-1.77 (m, 6H), 1.36-1.6 (m, 1H), 1.10-1.28 (m, 2H), 0.82-0.95 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9 L) at −78° C. was added over 30 minutes a 2.5 M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than −55° C. during the addition. The reaction mixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) 67 7.14-7.33(m, 10 H), 4.66 (m, 1 H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H),3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1 H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm−1; mp 102-104° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3].[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[N:1]([CH2:4][C@@H:5]([N:13]([CH3:22])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (30 mg, 0.11 mmol) in anhydrous THF (4 mL) at −78° C. was added 1.0 M LHMDS solution in THF (253 μL, 0.25 mmol), then stirred at this temperature for 30 min. To this mixture was added MeI (125 μL, 0.22 mmol), then the temperature was allowed to warm to 0° C., and stand for 12 hr in the refrigerator. The reaction mixture was quenched with saturated aq. NH4Cl, extracted with EtOAc (30 mL), the separated organic phase was washed with H2O (2×10 mL), brine, and dried (Na2SO4), and filtered. The filtrate was concentrated, the resulting slurry was purified through flash chromatography on silica gel (eluted with gradient system, 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate 31 mg, yield 100%. MS ESI+ve m/z 321 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH2:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16]O)[CH3:12].[Na]>C(O)(=O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[N:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:18])[CH3:12]
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: CCOC(=O)C=CO
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1
Reaction time: 3 h
Yield: 13 %

Procedure:
A solution of 4-chloro-2-aminobenzaldehyde (15 g, 96 mmol, 1 equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 g, 48 mmol, 0.5 equiv) in glacial acetic acid (175 mL), was heated at reflux for 3 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (6.65 grams, 48 mmol, 0.5 equivalents) was added and the reaction was heated at reflux for another 2.5 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for an additional 12 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (4 g, 28.8 mmol, 0.3 equiv) was added and the reaction was heated at reflux for 4 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The organic layer was then washed with brine (200 mL), dried over sodium sulfate, and treated with activated charcoal (Darco G-60®) (20 g). The mixture was filtered through diatomaceous earth. Silica gel (15 g) (EM Science, Gibbstown, N.J., 230-400 mesh, 0.04-0.06 mm particle size) was added to the solution and stirred for 3 hours. The slurry was filtered, rinsed with toluene (100 ml) and then 10% ethyl acetate in toluene (200 mL). The combined organic layers were concentrated and the resulting solid was stirred in isopropanol overnight to yield 7-chloro-quinoline-3-carboxylic acid ethyl ester (3 g, 13% yield) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P(Cl)(Cl)([Cl:20])=O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([Cl:20])=[N:7][C:6]=2[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Nc2ccccc21
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of amide 9 (1.39 g, 5.70 mmol), phosphorus oxychloride (1.6 mL, 17.1 mmol) and N-dimethylaniline (2.9 mL, 22.8 mmol) in benzene (10 mL) was heated at reflux for 2 hours. The reaction mixture was then cooled to room temperature and excess of phosphorus oxychloride, N-dimethylaniline and benzene were removed at reduced pressure. The resulting residue was dissolved in dioxane (20 mL) and 2 M Na2CO3 (30 mL 0.06 mol) and then heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and dioxane was removed at reduced pressure and the resulting aqueous solution was extracted with EtOAc (30 mL). The organic phase was washed with water, brine, dried (Na2SO4), filtered and solvent evaporated. The resulting crude residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford title compound 10 (869 mg, 58%) as an orange solid. LRMS (ESI): (calc) 262.01 (found) 263.1 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.Br[CH2:37]C1C=CC=CC=1C.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[CH3:22][C:18]([CH3:23])([CH2:17][S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[CH3:37])[C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[N:15][CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Cc1ccccc1CBr
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: Cc1ccccc1COCCN(C(=O)Nc1ncc(SCC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-methyl-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: OCc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3cccc(CO)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 58.5 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 250 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (70 mg, 0.110 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.55 mL, 1.1 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C34H31ClN4O3S: 611.2 (M+H+); Found: 612.2 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.83 (d, J=5.2 Hz, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.08 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (s, 2H), 5.59 (s, 1H), 5.38 (s, 1H), 3.91 (s, 3H), 2.73 (s, 3H), 2.60 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.O.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(O)(C)C>[C:12]1([C:9]2[C:8]3=[C:18]4[C:4](=[CH:5][CH:6]=[C:7]3[S:11][CH:10]=2)[NH:2][C:24]2[CH2:25][CH2:26][NH:21][CH2:22][C:23]4=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: c1ccc(-c2csc3ccc4[nH]c5c(c4c23)CNCC5)cc1

Procedure:
28 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride are dissolved in 300 ml of isopropanol and the solution is combined with 20 g of 4-piperidone hydrochloride monohydrate under an inert gas. After boiling the mixture for 3 hours, the solvent is evaporated off, the residue is taken up in isopropanol and the product is precipitated with the addition of isopropyl ether. The precipitate is filtered off and taken up in water; a layer of methylene chloride is introduced under the solution and the mixture is shaken with NaOH solution. The organic phase is separated off and worked up. Melting point: 228° C. (decomposition)
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:1])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:3][CH2:4][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC1(c2cccnc2)OCCc2cc(O)ccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)c1cccnc1
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-1-(3-pyridyl)-6-isochromanol (5.0 g), described in Example 22, and acetic anhydride (50 ml) is heated on the steam bath for 4 hr. The mixture is poured upon ice, left at room temperature for 1 hr, rendered basic with sodium bicarbonate and then extracted with chloroform. The extracts are washed with brine, dried, evaporated, and the residue is crystallized from isopropanol to give the title compound, m.p. 113°-115° C.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][OH:8].[C:9]([CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1)#[N:10].O>CS(C)=O>[NH2:10][C:9](=[N:7][OH:8])[CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=NO)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 108.1 %

Procedure:
Sodium hydrogen carbonate (872 mg, 10.38 mmol) was added to a suspension of hydroxylamine monohydrochloride (721 mg, 10.38 mmol) in DMSO (3 mL), and the mixture was stirred at 80° C. for 15 min. The precipitate was filtered off, and a solution of tert-butyl (6R,7R)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (500 mg, 1.30 mmol) in DMSO (4 mL) was added to the filtrate. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (588 mg). This compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5].[Br:11]Br>CO.C(O)(=O)C>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: BrBr
Reactant: COc1cccc(C)c1N
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Br)cc(C)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To an ice-water cooled solution of 2-methoxy-6-methylaniline (10 g, 72.9 mmol) in 30 mL of methanol and 10 mL of acetic acid was added dropwise bromine (3.75 mL, 72.9 mmol). The reaction mixture was allowed to stand for overnight. The solvent was removed under reduced pressure and the residue was suspended in 60 mL of IN NaOH and extracted with ethyl acetate and dried over sodium sulfate and evaporated to dryness to give reddish crude product, which was recrystallized from hexane to give pure product (14.3 g, 91%).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[OH2:7].C[N:9]1C[CH2:12][CH2:11][CH2:10]1>>[N:2]1([C:10]2[CH2:11][CH2:12][O:7][N:9]=2)[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: c1nc[nH]n1
Reactant: O
Reactant: CN1CCCC1
Agent: [Na]
Product: c1ncn(C2=NOCC2)n1
Temperature: 100 °C

Procedure:
A microwave reaction vial is charged with racemic ompound I-10 (1.0 equiv) and the sodium salt of 1,2,4-triazole (2.0 equiv). The reagents are dissolved in N-methylpyrrolidine (0.18 M with respect to compound I-10). The mixture was sealed and heated in a microwave reactor at 100° C. for 30 min. Excess water is added and a brown solid crashes out which is isolated using vacuum filtration and dried to provide the desired 3-(1H-1,2,4-triazol-1-yl)-4,5-dihydroisoxazole I-34a and I-34b. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M−H]−=306.1 m/z. Activity: C.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=O.C[N:23](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:14][C:9]1[CH:8]=[C:7]([C:5]2[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:3][NH:2][N:23]=2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CN(C)C=C(C(=O)c1ccc(F)c(F)c1)c1ccncc1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Product: Fc1ccc(-c2n[nH]cc2-c2ccncc2)cc1F
Yield: 90 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 2.54 g (8.81 mmol) of 3-dimethylamino-1-(3,4-difluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one obtained in Example 6-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 2.05 g of the title compound as a white powder. (Yield: 90%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2CNC(=O)C2)cc1O
Yield: 99.8 %

Procedure:
A mixture of 4-(3-Benzyloxy-4-methoxyphenyl)-2-pyrrolidone (3.5 g, 11.6 mmol) and 350 mg of 10% Pd/C in 50 mL of MeOH and 10 mL of CH2Cl2 was shaken on a Paar apparatus under a 20 psi atmosphere of hydrogen for 8 hours. The mixture was filtered through celite and concentrated to afford 2.4 g (99%) of 4-(3-Hydroxy-4-methoxyphenyl)-2-pyrrolidone that was used without further purification for the syntheses described in Examples 1-3. 1H NMR (300 MHz, CDCl3) δ 6.82 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.50 (s, 1H), 3.87 (s, 3H), 3.77 (t, J=8.4 Hz, 1H), 3.62 (t, J=8.0 Hz, 1H), 3.40 (t, J=8.4 Hz, 1H), 2.71 (dd, J=16.8, 8.8 Hz, 1H), 2.49 (dd, J=16.8, 9.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18]([I:22])[CH2:19][CH2:20][CH3:21]>C(#N)C>[I-:22].[CH2:7]([N+:6]([CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([OH:1])[CH:3]=1)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN(CCCC)Cc1cccc(O)c1
Reactant: CCCCI
Solvent: CC#N
Product: CCCC[N+](CCCC)(CCCC)Cc1cccc(O)c1
Product: [I-]

Procedure:
A mixture was prepared containing 10 g (0.042 m) of 3-hydroxy N,N-dibutylbenzylamine, 15 g (0.082 m) of butyliodide and 25 ml of acetonitrile. The mixture was heated to reflux overnight. The completion of the reaction was determined by high pressure liquid chromatography. After completion, the solvent was removed and the residue triturated with ether, filtered and dried. The desired N,N,N-tributyl-(3-hydroxybenzyl)ammonium iodide product was recovered as a white powder in a yield of 15.7 g. The product melted at 128° C.-130° C. and its elemental analysis is as follows:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4 g of 2,6-dichloropyrazine and 9.5 ml de DIPEA in 40 ml of n-butanol is heated at reflux for 3 hours. It is concentrated under vacuum, the residue is taken up in 100 ml of EtOH, the system is left to stand overnight and the crystalline product formed is isolated with suction. This gives 4.7 g of the expected product, m.p.=108° C.