Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CS(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][CH:27]=2)=[CH:17][CH:16]=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:26][CH:27]=3)=[CH:19][CH:20]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: Cc1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 47 %

Procedure:
In substantially the same manner as in Working Example 8, 2-methylimidazole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[4-[3-(2-methyl-1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 47%. Recrystallization form ethyl acetate-hexane gave colorless prisms, mp 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH2:24][C:25]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=O)=O)[C:9]=2[CH3:33])=[CH:4][CH:3]=1.O1C=CN=C1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[S:48][C:25]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][N:23]=3)[C:9]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(C(=O)NCC(=O)C2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: c1cocn1
Solvent: C1CCOC1
Product: Cc1c(-c2ncc(C3CCCCC3)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 76.1 %

Procedure:
5-(4-chlorophenyl)-N-(2-cyclohexyl-2-oxoethyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (116 mg, 0.23 mmol) obtained in Step 3 of preparation of oxazole was added to a microwave reactor containing Lawesson's reagent (186 mg, 0.46 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 1860° C. for 30 min. The reaction product was purified by reverse-phase prep HPLC to provide the title compound (88 mg, 76%) as white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13](=[O:14])[C:6]=2[N:5]=1)[CH3:3]>CO.[Pd]>[CH3:3][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:6]=2[N:5]=1)[CH3:1]
Reactant: CC(C)c1nc2c(=O)ccccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1nc2c([nH]1)CCCCC2=O
Yield: 100.8 %

Procedure:
A solution of Intermediate 1 (3.4 g) in methanol (700 mL) was hydrogenated using the H-Cube (settings: room temp, 1.4 ml/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The solvent was concentrated under vacuum to give the title compound (3.5 g). LC/MS MH+ 193, Rt 0.42 min (2 minute run).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:12][C:13](N2[C@@H](C3C=CC=CC=3)[C@@H](C)N(C)C2=O)=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C[AlH]CC(C)C)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C[C@@H]1[C@H](c2ccccc2)N(C(=O)C[C@H](c2ccc(S(C)(=O)=O)cc2)c2cccs2)C(=O)N1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC=O)c2cccs2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
(4R,5S)-1-[(R)-3-(4-Methanesulfonyl-phenyl)-3-thiophen-2-yl-propionyl]-3,4-dimethyl-5-phenyl-imidazolidin-2-one (1.05 g, 2.18 mmol) was dissolved in dichloromethane (40 mL) under argon and the solution was cooled to −78° C. DIBAL solution (7 mL, 6.53 mmol) was then added dropwise and the solution stirred at −78° C. for a further 2 h. Crushed Glauber's salt (7 g) was then added and the reaction stirred vigorously at room temperature for 1 h. This was then filtered and stirred with basic alumina (7 g) for 4 h. Filtration and concentration gave the title compound (0.25 g, 38%) as a colourless oil; NMR (CDCl3): 3.05 (s, 3H), 3.24 (m, 2H), 4.96 (t, 1H), 6.85 (m, 1H), 6.93 (m, 1H), 7.20 (m, 1H), 7.48 (d, 2H), 7.90 (d, 2H), 9.76 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>ClC1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: C=C1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 130 g of chlorobenzene and the mixture is cooled to 0° C. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 0° C. for three hours and then added to ice water. The solid reaction product is filtered off and washed twice with water (50 ml). The product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 75% as a colorless, finely crystalline powder.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:22][OH:23])=[N:7]2.[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:13]([O:15][CH3:24])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:22][OH:23])=[N:7]2
Reactant: Cc1cc2nc(CO)ccc2c(Br)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of (S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (3.6 g, 9.4 mmol) in anhydrous dichloromethane and methanol (1:1, 20 mL) was added (trimethylsilyl)diazomethane (2 M in hexanes, 5.17 mL, 10.34 mmol) and the reaction was stirred at room temperature for three hours. An additional 2 mL of (trimethylsilyl)diazomethane was added and stirred for 2 hours, followed by an additional 1 mL of (trimethylsilyl)diazomethane for 1 hour, then 1 mL of (trimethylsilyl)diazomethane added and let go overnight. An additional 3.5 mL of (trimethylsilyl)diazomethane were added and stirred for 1 hour. The reaction was quenched with 30 mL of acetic acid and then stirred 15 minutes. The reaction was concentrated under reduced pressure and then absorbed onto silica. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow foam (2.37 g). LCMS-ESI+ (m/z): [M+H]+ calcd C18H23BrNO4: 396.07. found: 396.71.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:17]([C:21]1[CH:22]=[C:23]([SH:32])[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:20])([CH3:19])[CH3:18].CC1C=C(C)N=C(C)C=1>CC(C)=O.ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([S:32][C:23]2[CH:22]=[C:21]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[N:1]=1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Product: CC(C)(C)c1cc(Sc2nc(Cl)nc(Cl)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 0.1 mol of cyanuric chloride in 120 ml of acetone are added 3 g of anhydrous sodium sulfate and the mixture is cooled to 0° C. A solution of 0.1 mol of 3,5-di-tert-butyl-4hydroxythiophenol in 25 ml of chlorobenzene is then run in. Afterwards 12.7 g of s-collidine are added dropwise at 5° C. over 20 minutes to the reaction mixture. The reaction is brought to completion by stirring for 30 minutes at 5° C. and for 2 hours at room temperature. The reaction mixture is then filtered and, after washing with 100 ml of acetone, the filtrate is stirred into a mixture of 400 g of ice and 900 ml of water, acidified with dilute hydrochloric acid (weakly acid reaction to litmus paper), and extracted repeatedly with ethyl acetate. Conventional working up and recystallisation from hexane/acetone gives 16.9 g of 2,4-dichloro-6-(3',5'-di-tert-butyl-4'-hydroxyphenylsulfanyl)-s-triazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.IC.[C:25](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:25]
Reactant: O=C([O-])O
Reactant: Cc1cccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)c1C
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1C
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
A mixture of (4S,7R)-2-(2,3-dimethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 16; 4.07 g, 13.8 mmol) and iodomethane (1.5 mL, 24.1 mmol) in N,N-dimethylformamide (60 mL) in a sealed tube was heated to 105° C. and stirred for 1.5 h. The reaction mixture was allowed to cool and saturated sodium bicarbonate solution (200 mL) was added. A solid precipitated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), concentrated and purified by chromatography, eluting with 60-100% ethyl acetate/dichloromethane. Fractions containing the product were combined, evaporated, and recrystallized from ethyl acetate/hexanes to give (4S,7R)-2-(2,3-dimethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.12 g 49%) as a white solid. ES(+)-MS (M+H) 311.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[CH:15]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1cccnc1
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: [Na+]
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2cccnc2)cc1

Procedure:
A mixture of 4-carboxybenzeneboronic acid (0.5 g, 2.9 mmol), 3-bromopyridine (0.46 g, 2.9 mmol), sodium carbonate (1.37 g), and tetrakis(triphenylphosphine)palladium(0) (0.1 g) in 50% aqueous 1,2-dimethoxyethane (70 mL) was heated to reflux for 16 h, cooled, acidified, and extracted with dichloromethane. The organic phase was dried and concentrated in vacuo to yield the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[O:17][C:18]([C:21](=[O:29])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:20]=1.O>O1CCCC1.C(OCC)(=O)C>[O:4]=[C:3]([CH3:5])[CH:2]([CH2:15][C:16]1[O:17][C:18]([C:21](=[O:29])[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=1)[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)o1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 67.9 %

Procedure:
To 9.6 g of tert-butyl acetoacetate was dissolved in 80 ml of tetrahydrofuran, and 2.33 g of 60% oil sodium hydride was added under cooling with ice under stirring. The resulting solution was stirred at the same temperature for 10 minutes. After addition of 13.6 g of 2-(chloromethyl)-5-(phenylcarbamoyl)furan obtained in Reference Example 2 in 80 ml of tetrahydrofuran, the solution was stirred at room temperature for 10 minutes and then at 60° C. for 13 hours under heating. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride successively and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1→3/1] to give 14.0 g of the title compound as a colorless oily substance.
Reaction SMILES: [NH3:1].C1COCC1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](Cl)=[O:23])[N:15]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH2:1])=[O:23])[N:15]=1
Reactant: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Saturated NH3/THF solution (130 ml) cooled to 0° C. via cannula slowly over 10 min is then added to a suspension of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoyl chloride (Compound A2, 8.0 g, 26.43 mmol) in anhydrous tetrahydrofuran (80 mL) cooled to −78° C. The mixture is stirred for 30 minutes, warmed to room temperature and stirred for 16 h. The solvent is concentrated in vacuo and the resulting white residue is washed several times with water. The wet solid is dried in a vacuum oven for two days to give 7.06 g (94%) of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzamide (Compound A3) as a white solid: mp 231-234° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.10 (br d, J=9.7 Hz, 2H) 7.28-7.39 (m, 2H), 7.64 (t, J=7.8 Hz, 2H), 8.07 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.5 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.58 (t, J=1.8 Hz, 1H); MS m/z 284.12, calcd for C15H10FN3O2 (MH+) 284.
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C>[N:31](=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[OH:32]
Reactant: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)=NO

Procedure:
A mixture of 1.0 g. of ethyl 4-(6-oxohexadecylamino)benzoate, 207 mg. of hydroxylamine hydrochloride, 244 mg. of sodium acetate and 20 ml. of 95% ethanol is stirred under reflux for 3 hours and filtered. The filtrate is evaporated and a methylene chloride solution of the residue is washed with water, dried over magnesium sulfate, and evaporated to yield ethyl 4-(6-oximinohexadecylamino)benzoate as a white solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a 250 mL flask which contained a suspension of NaH (60% in mineral oil, 500 mg, 12 mmol) in DMF (50 mL) was added 4-iodo-phenol (2200 mg, 10 mmol), at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3600 mg, 10 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 2000 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (2480 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.81-2.07 (m, 4H), 3.27-3.48 (m, 2H), 3.70-3.95 (m, 1H), 4.00-4.19 (m, 2H), 6.66-6.69. (m, 2H), 7.53 (d, J=8.4 Hz, 2H):
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:28])[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(CCCC2CC(c3ccccc3)=NO2)CC1
Yield: 73.3 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (27.3 mg, 0.124 mmol), 1-(o-tolyl) piperazine (20.0 mg, 0.113 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (72.1 mg, 0.340 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 30.1 mg (73.1%) of the target compound was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[CH2:9][O:8][C:7]3[N:12]=[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:6]2=3)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[NH2:32][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([C:13]3[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:10](=[O:11])[CH2:9][O:8][C:7]=4[N:12]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CC3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CC3)C(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 92.8 %

Procedure:
tert-Butyl 1-(4-(1-(cyclopropylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (40 mg, 0.076 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (30 mg, 73% yield).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12].Br[CH2:14][CH3:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[C:5]([F:12])[C:6]=1[F:11])[CH3:15]
Reactant: Oc1ccc(Br)c(F)c1F
Reactant: CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(Br)c(F)c1F
Temperature: 80 °C
Yield: 104 %

Procedure:
Sodium hydroxide (75.9 g) was added to a water (400 ml) solution of 4-bromo-2,3-difluorophenol (T-1) (195.0 g), bromoethane (196.2 g) and tetrabutylammonium bromide (hereinafter abbreviated as TBAB) (24.2 g), and the mixture was heated at 80° C. for 6 hours with stirring under an atmosphere of nitrogen. After the reaction had been completed, the reaction mixture was extracted with heptane and the organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to give a black oil. The oil was purified by distillation to give 1-ethoxy-2,3-difluorobromobenzene (T-2) (230.0 g, 97% yield) as a colorless oil.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CNCCO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
In a 500-mL round-bottom flask, 2-benzyl 4-tert-butyl morpholine-2,4-dicarboxylate (7.94 g, 25 mmol) was dissolved in DCM (200 mL). It was then cooled to 0° C. TFA (15 ml, 198 mmol) was added via pipet, and the solution was allowed to warm naturally to ambient temperature in the ice bath, whereupon it was stirred for 14 h. The mixture was concentrated to afford the title compound (50% by weight with the remainder assumed to be TFA, 10.86 g, 24 mmol). MS m/z 222 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]6)=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Yield: 100.7 %

Procedure:
A solution of 48 (1.456 g, 2.35 mmol) and TFA (15 mL) in DCM (50 mL) was stirred at RT for 5 hr. The TFA was removed by co-evaporation with DCM, the residue was diluted with water, and the pH was adjusted to ˜12-13 with 1N NaOH. The resultant suspension was sonicated for 15 min. The solid was collected by filtration, rinsed with water and dried under high vacuum to afford the title compound 49 (1.227 g, traces of TEA) as an off-white fluffy solid. 1H NMR (400 MHz. DMSO-d6) δ (ppm): 8.76 (bs, 1H), 8.54 (d, J=1.4 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.5, 2.3 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=10.2 Hz, 1H), 6.64 (d, J=5.5 Hz, 1H), 6.62 (bs, 1H), 3.58-3.48 (m, 2H), 2.73-2.64 (m, 4H), 2.59-2.52 (m, 1H), 2.38-2.25 (m, 4H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H), one NH is missing. MS (m/z): 519.6 (M+H).