Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>ClCCl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[N:29]([O:30][CH3:31])[CH3:28])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl; 86.4 g) in dichloromethane (900 mL) was stirred at ambient temperature, then N,O-dimethyl hydroxylamine hydrochloride (35.3 g) and triethylamine (150 mL) were added. The resulting mixture was stirred at ambient temperature for 3 days. Water was added and most of volatiles were removed in vacuo. The residue was partitioned between DCM and aqueous NaHCO3. The organic layer was washed with 3M aqueous HCl, subsequently with brine before it was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (compound L; 28.2 g) as a white solid sufficiently pure for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)#[CH:2].[N:15]([CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[N:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][CH:4]=[C:3]2[C:1]1[N:17]=[N:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH:2]=1
Reactant: [N-]=[N+]=NCCCN1C(=O)c2ccccc2C1=O
Reactant: C#Cc1ccnc2ccc(OC)nc12
Solvent: Cc1ccccc1
Product: COc1ccc2nccc(-c3cn(CCCN4C(=O)c5ccccc5C4=O)nn3)c2n1
Yield: 45.9 %

Procedure:
A mixture of 8-ethynyl-2-methoxy-[1,5]naphthyridine (184 mg, 1.0 mmlole) and 2-(3-azido-propyl)-isoindole-1,3-dione (230 mg, 1.0 mmole) were refluxed in toluene (5 mL) for 12 hours. Upon cooling the product precipitated. The mixture was diluted with ether (5 mL) filtered, and the solid product was washed with ether and dried to give 190 mg (46%) of 2-{3-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)-[1,2,3]triazol-1-yl]-propyl}-isoindole-1,3-dione as a grey solid as single regioisomer.
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]([CH3:29])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:30])C.[CH3:32][CH2:33][Mg+].[Br-].O[C:37](C)(C)[CH2:38]OC1C=CC(C(C2C=CC(OCC(O)=O)=C(C)C=2)(CC)CC)=CC=1C>CCOCC>[CH2:37]([C:4]([OH:31])([CH2:33][CH3:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]([CH3:29])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:30])[CH3:38]
Reactant: CCOC(=O)COc1ccc(C(CC)(CC)c2ccc(OCC(=O)O)c(C)c2)cc1C
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(C)(C)O)c(C)c1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(OCC(=O)O)c(C)c2)cc1C
Yield: 59 %

Procedure:
The title compound 13 was prepared from compound 4 (91.2 mg, 0.2128 mmol) and EtMgBr (227 μL of a 3.0 M solution in Et2O, 0.681 mmol, 3.2 equiv.) following the same procedure as that for compound 12. Purification by column chromatography (1:10:90→2:15:85 AcOH/EtOAc/CH2Cl2) afforded the title compound 13 (55.2 mg, 59%)
Reaction SMILES: Cl.Cl[CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Br.BrC1C2NC(=[O:26])C=CC=2CCC1>O>[OH:26][CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=c1ccc2c([nH]1)C(Br)CCC2
Reactant: O=c1ccc2c([nH]1)C(Cl)CCC2
Agent: Br
Agent: Cl
Solvent: O
Product: O=c1ccc2c([nH]1)C(O)CCC2

Procedure:
Starting materials for the preparation of the ketone of the invention are 8-chloro-5,6,7,8-tetrahydro-2-quinolone hydrochloride or 8-bromo-5,6,7,8-tetrahydro-2-quinolone hydrobromide, which are hydrolyzed with the 4- to 8-fold amount of water, at a temperature of from 50° to 100° C., preferably 80° to 100° C., to form 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone which, after cooling of the neutralized solution (neutralization for example by means of ammonia) precipitates in crystallized form as trihydrate. In order to prepare the ketone of the invention, it is however required to oxidize the anhydrous 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone with manganese dioxide. The necessary dehydration of the trihydrate formed first is generally carried out by distillation removal of the hydration water as azeotropic mixture with, for example, butyl acetate, chloroform, butanol, toluene or cyclohexanone. Butyl acetate and cyclohexanone have proved to be especially suitable as agents for forming an azeotropic mixture (=water entrainers), because they allow particularly economic operations due to their good dissolving power, relatively high boiling point and minimal miscibility with water.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:20]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cncc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Clc1cncc(C#Cc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (980 mg, 6.0 mmol) and CuI (230 mg, 1.2 mmol) were combined in DME (15 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (4.2 mL, 30 mmol) and PdCl2(PPh3)2 (420 mg, 0.60 mmol) were added, then 3-chloro-5-ethynylpyridine (820 mg, 19 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS analysis showed starting material remaining. The reaction mixture was heated at reflux for 2 h. The mixture was filtered through Celite.™., the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), and washed with water (100 mL), brine (100 mL), dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 9:1 hexane:ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridi-ne which contained some dimer. This material was crystallized from hot ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridine (300 mg 23% yield) as light orange crystals M.p. 124-125° C. 1H NMR (CDCl3, 300 MHz) Δ8.70 (d, J=1.5 Hz, 1H), 8.59 (d, J=3.0 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.88)t, J=2.0 Hz, 1H), 7.48 (d, J=3.0 Hz, 2H). MS (ESI) 221.1 (M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:37])[CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[CH:18][CH:17]=1)(C)(C)C.[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:37][C:40](=[O:41])[N:24]([C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)[CH2:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc(NCC(O)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc(OC)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc(N2CC(c3ccc(C(=O)Nc4ccccc4N)cc3)OC2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added 1,1′-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirred at room temperature for 16 h. DCM was removed under reduced pressure, AcOEt and a solution of sat. NH4Cl were added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (Hexane/AcOEt: 30/70) to afford the desired compound (80 mg, 0.14 mmol, 58% yield). 1H NMR (DMSO) δ (ppm): 9.39 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J=8.4 Hz, 1H), 4.24 (t, J=8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3C)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Yield: 105.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (5.00 g) and 4-nitro-2-methylphenol (6.85 g) were suspended in monochlorobenzene (25 ml) to prepare a suspension which was then heated under reflux overnight. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate, was filtered, and was dried. Next, the resultant crystal was suspended in an aqueous sodium hydroxide solution to prepare a suspension. The suspension was then filtered, followed by drying to give 6.89 g of 4-(2-methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline. 4-(2-Methyl-4-nitrophenoxy)-6,7-dimethoxyquinoline (1.36 g) was dissolved in ethyl acetate/N,N-dimethylformamide/triethylamine (25 ml/25 ml/5 ml). Palladium hydroxide (0.4 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give the title compound (1.31 g, yield 91%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)C(C)C)(C)C.[F:28][C:29]([F:39])([F:38])[C@H:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:40][CH:41]([S:43]([C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=1)[C:50]([CH2:66][N:67]1[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([CH3:74])[CH2:68]1)=[C:49]2[C:75](O)=[O:76])(=[O:45])=[O:44])[CH3:42].CCCP(=O)=O>C(OCC)(=O)C.ClCCl>[CH3:42][CH:41]([S:43]([C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:65])[F:64])[CH:57]=1)[C:50]([CH2:66][N:67]1[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([CH3:74])[CH2:68]1)=[C:49]2[C:75]([NH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:29]([F:38])([F:39])[F:28])=[O:76])(=[O:44])=[O:45])[CH3:40]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)O)CCC1=O
Agent: CCCP(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
T3P (propylphosphonic anhydride) (0.698 mL of a 50% solution in ethyl acetate, 1.185 mmol), N,N-diisopropylethylamine (0.478 mL, 2.73 mmol), and [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.251 g, 1.185 mmol) were added to a suspension of 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.5 g, 0.911 mmol) in dichloromethane (14.02 mL) at 0° C. After 90 min, additional T3P (propylphosphonic anhydride, 0.349 mL of a 50% solution in ethyl acetate, 0.593 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride (30 mL), and the solution was washed with 10% Na2CO3, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was loaded onto florisil and purified using column chromatography (ISCO, 12 g silica, 5-40% ethyl acetate/hexanes) to afford 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.431 g, 67% yield). MS (m/z) 706.3 (M+H+).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.FC(F)(F)C(O)=O>>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:5])[OH:10]
Reactant: C=CCOC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
FmocAsp(OtBu)Oallyl (40 g, 88.7 mmol) was treated with 25 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 min. The solvent was stripped off on a rotary evaporator. The residue was dried in vacuo. FmocAsp(OH)Oallyl was obtained as a yellow oil (33.9 g, 97%). ES(+)-MS: 395.2 (M+H)+
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.S(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1
Reactant: COc1cc2cc(CO)ccc2c(OC)c1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2cc(CCl)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Hydroxymethyl-5,6,7-trimethoxynaphthalene (781 mg) was dissolved in chloroform (6 mL), and thionyl chloride (561 mL) was added dropwise to the solution. After stirring at room temperature for 5 hours, the reaction mixture was poured into ice water, and sodium hydrogencarbonate was added to adjust the pH of the reaction mixture to 8 to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: O.[CH3:2][N:3]1[C:8](=[O:9])[CH2:7][C:6](=O)[NH:5][C:4]1=[O:11].O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[NH:5][C:4](=[O:11])[N:3]([CH3:2])[C:8](=[O:9])[CH:7]=1
Reactant: CN1C(=O)CC(=O)NC1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)cc(Cl)[nH]c1=O
Temperature: 80 °C
Yield: 71.6 %

Procedure:
Water (2.7 mL) is added dropwise to a suspension of 1-methylpyrimidine-2,4,6(1H,3H,5H)-trione (14.2 g, 100 mol) in POCl3 (95 mL) at 0° C. The reaction mixture is then heated at 80° C. for 5 hours. The resulting brownish solution is cooled, and POCl3 is evaporated under reduced pressure. The residue is treated with MeOH, and the obtained solid is recrystallized from ethanol to give 11.5 g product (Yield: 71.6%). m.p.=279-282° C. (dec) [Lit.2: 280-282° C.]. 1H NMR (400 MHz, DMSO-d6) δ3.10 (S, 3H), 5.90 (S, 1H), 12.4 (br, 1H).
Reaction SMILES: [CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:17][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:24])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.54 mmol) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (207 mg, 5.4 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (75 mg, 37%). 1H NMR (400 MHz, CDCl3): δ=2.12-2.30 (m, 2H), 2.47 (m, 2H), 3.19 (m, 1H), 3.40 (m, 1H), 3.53 (m, 1H), 3.76 (m, 1H), 7.06 (m, 1H), 7.13 (m, 1H), 7.22 (m, 1H), 7.25-7.40 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([OH:12])[CH2:4][C:5]1([CH3:11])[O:10][CH2:9][CH2:8][CH2:7][O:6]1.C(OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[C:30]12([NH:40][C:41](=[O:49])[C:42]([F:48])([F:47])[S:43](F)(=[O:45])=[O:44])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.Cl>C(OCC)(=O)C.O1CCCC1>[C:30]12([NH:40][C:41](=[O:49])[C:42]([F:47])([F:48])[S:43]([O:12][CH:3]([CH2:4][C:5]3([CH3:11])[O:6][CH2:7][CH2:8][CH2:9][O:10]3)[C:2]([F:1])([F:13])[F:14])(=[O:44])=[O:45])[CH2:39][CH:34]3[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]3)[CH2:37]1)[CH2:31]2
Reactant: CC1(CC(O)C(F)(F)F)OCCCO1
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(F)(F)S(=O)(=O)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CC1(CC(OS(=O)(=O)C(F)(F)C(=O)NC23CC4CC(CC(C4)C2)C3)C(F)(F)F)OCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 200 ml round-bottom flask provided having a thermocouple and a dropping funnel was charged with 5 g (23 mmol) of 1,1,1-trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-2-ol and 40 g of diisopropyl ether. To the flask, 24.5 ml of 1 mol/L lithium diisopropylamide was added dropwise over 30 minutes in a nitrogen atmosphere at −30° C. or lower (thereby obtaining a solution “C”). The solution was stirred for 30 minutes after the termination of the dropwise addition, followed by increasing the temperature of the solution to room temperature and then stirring it for additional 1 hour. Another 200 ml round-bottom flask provided having a thermocouple and a dropping funnel was charged with 8.0 g of 2-(adamant-1-ylamino)-1,1-difluoro-2-oxoethanesulfonyl fluoride and 30 g of tetrahydrofuran and cooled to −30° C. in a nitrogen atmosphere. To this solution, the previously prepared solution “C” was added dropwise by using the dropping funnel to such an extent as not to exceed an inner temperature of −20° C. The solution was stirred for 30 minutes after the termination of the dropwise addition, followed by increasing the temperature of the solution to room temperature and then stirring it for additional 3 hours. Thereafter, 50 g of ethyl acetate was added thereto, and then 30 ml of 5% aqueous hydrochloric acid solution was added. An organic phase was separated by using a separatory funnel, followed by rinsing with 30 ml of a saturated aqueous sodium hydrogen carbonate solution and then repeating rinsing with 30 ml of water three times. Distillation of a solvent was performed, and then filtration was performed when crystallization was confirmed, thereby obtaining 8.9 g of a crude crystal. This crystal was recrystallized with 50 g of ethyl acetate thereby obtaining 7.1 g of a target 1,1,1-trifluoro-3-(2-methyl-1,3-dioxan-2-yl)propan-2-yl 2-(adamant -1-ylamino)-1,1-difluoro-2-oxoethanesulfonate (hereinafter referred to as “AA-3”). As a result of analyzing this compound by high performance liquid chromatography, it was confirmed that the purity was 98.8%. Additionally, the yield was 60%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=O)C.[CH3:27][NH:28][NH:29][CH3:30]>C1(C)C=CC=CC=1.O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:29]([CH3:30])[N:28]([CH3:27])[C:4](=[O:3])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CNNC
Reactant: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)n(C)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 53 %

Procedure:
3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)-3-oxo-propionic acid ethyl ester was dissoved in 20 ml of toluene and then 0.24 g of dimethyl hydrazine was added to the solution. The apparatus containing the mixture was heated and refluxed at 120° C. for 24 hours in the Dean-Stark trap apparatus. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The obtained organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was recrystalized with n-hexane to give 160 mg of the title compound as a yellow solid(yield 53%).
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[CH3:11]>C(O)(=O)C>[CH3:11][C:4]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][N+:3]=1[O-:1]
Reactant: Cc1cnc(C)c(C)c1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Reaction time: 8 h

Procedure:
420 ml of 30% hydrogen peroxide were added dropwise at room temperature to 246.4 g of 2,3,5-collidine and 2400 ml of glacial acetic acid. The solution was stirred at 80° overnight. The reaction mixture was then cooled to 40°, a further 420 ml of 30% hydrogen peroxide were added thereto and the mixture was heated to 80° for a further 24 hours. After evaporation in vacuo the residue was dissolved in 300 ml of water, whereupon the solution was made basic with concentrated sodium hydroxide solution while cooling, saturated with sodium chloride and extracted three times with 1 l of methylene chloride. The organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether/petroleum ether; there was obtained 2,3,5-trimethyl-pyridine 1-oxide of melting point 42°-44°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2]
Reactant: C=Cc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OC(C)(C)C)CC3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OC(C)(C)C)CC3
Yield: 70 %

Procedure:
To a stirred solution of 3-vinyl-N-(tert-butyloxycarbonyl)morphinan, 44 (10 mg, 0.028 mmol) in dry methanol (1 mL) was added Pd/C (4 mg) and the flask was charged with hydrogen gas in a balloon. After starting material disappeared on TLC, solvent was evaporated and column chromatography of the residue gave 7 mg (70%) of product: 1H NMR (300 MHz, CDCl3) δ7.06˜7.36 (3H, m); 4.37 (0.5H, s); 4.19 (0.5H, s); 3.88 (1H, dd); 3.11 (1H, m); 2.63 (2H, m); 2.59 (2H, m); 2.44 (1H, m); 1.60˜1.80 (4H, m); 1.40˜1.60 (9H, d); 0.90˜1.40 (9H, m).