Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[Cl-].[NH4+]>C(Cl)Cl.O>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (8.8 g, 47 mmol) in DCM (188 mL) at 0° C., triethylamine (7.8 mL, 56 mmol) was added in one portion. Then, neat methanesulfonyl chloride (4.38 mL, 56 mmol) was added via an additional funnel over 30 minutes. The resulting mixture was stirred at 0° C. for 1.5 h. Upon completion of the reaction, water (100 mL) and sat'd aqueous ammonium chloride (100 mL) were added respectively. The organic phase was separated and washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate as a pale yellow oil (12.5 g). This compound was used directly for the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12].[ClH:26]>>[ClH:26].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCNC(CN2CCCC2)C1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridylacetic acid with 4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 127-130° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-1.7 (4H, m), 2.0 (3H, s), 2.2-3.2 (9H, m), 3.4-4.8 (6H, m), 6.8-7.5 (3H, m), 8.4 (1H, m); MS (FAB) 331 (M+H)+; Anal. Calcd. for C18H26N4O2.2HCl.0.5NH4Cl: C, 50.27; H, 7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[CH3:12][N:13]([CH3:16])[CH:14]=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[CH3:12][N:13]([CH:16]=[N:3][C:2]1[NH:1][C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 30 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was added to 175.4 g (2.4 mol) of N,N-dimethylformamide, and then 23.0 g (0.15 mol) of phosphorus oxychloride was added drop by drop, followed by stirring at 30° C. for 1 hour. The reaction mixture was added to 500 ml of ice water, and then neutralized with 75.6 g (0.9 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and washed with 50 ml of water to yield 14.6 g (0.07 mol) of a white crystal of N-dimethylaminomethyleneguanine (yield 71%). Its properties are as follows:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[OH-].[Na+]>C(O)(=O)C.C(OCC)C>[Br:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of bromine (13.1mL, 256.6 mMol) in glacial acetic acid (45 mL) was added drop wise into a mechanically stirred suspension of 2-Methoxy-pyridine (19 mL, 183 mMol) in glacial acetic acid (88 mL) with the temperature kept at ten degrees. After complete addition the solution was allowed to stir overnight while gradually warming to room temperature. Upon arrival the reaction mixture was poured over ice and the pH adjusted to eight with solid sodium hydroxide. The material was then diluted with diethyl ether (150 mL) and filtered thru Celite. The aqueous layer was extracted with diethyl ether (2×100 mL) and ethyl acetate (2×100 mL) and all the organics combined. The solution was dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator to a dark brown oil. The oil was eluted thru a plug of silica gel with hexanes and concentrated to yield 22.6 g (66% yield) of 5-Bromo-2-methoxy-pyridine as a clear oil. 1H NMR (DMSO-d6): δ=8.29 (dd,1H,J=2.6,0.5 Hz), 7.89 (dd, 1H, J=8.8, 2,6 Hz), 6.84 (dd, 1H, J=8.8, 0.5 Hz), 3.84 (s, 3H). LC/MS (Method A), rt=1.35 mins., purity=76.5%, calculated mass=187,[M+H]+=188/190, [M−H]− 187/189. HPLC (Method C): rt=8.1 mins., purity=88.0% @ 210-370 nm and 88.3% @ 286 nm.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[N:11][CH:12]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 51 %

Procedure:
Bromine (0.99 ml) was added dropwise to a stirred suspension of sodium acetate (1.59 g) and 2-methoxypyridine (1.93 ml) in acetic acid (10 ml). The reaction mixture was stirred at room temperature for 25 minutes, then at 80° C. for 2.5 h. The mixture was then allowed to cool and poured into ice-water, neutralised with 2M sodium hydroxide and extracted with ether. The combined extracts were dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with 5% ethyl acetate in hexane to give 5-bromo-2-methoxypyridine as a colourless oil (1.75 g, 51%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11].[OH-].[K+]>C(O)C>[C:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(O)OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)OCCNC(C)(C)C
Temperature: 60 °C
Reaction time: 120 h
Yield: 75.6 %

Procedure:
736 g of tertiarybutylamine and 500 g of 2-chloroethoxyethanol were placed in 2 liters of ethanol and heated at 60° C. overnight. The temperature was then gradually raised to 80° C. and held for 5 days. The reaction mixture was cooled to 50° C. and then treated with 247 g of KOH. After 1 hour at refluxing the reaction was cooled, filtered, vacuum stripped and distilled. The yield of the distilled product, which calculates as a 75.6% yield, was 491 g, and it had a b.p. of 117° C. at 10 mm. Analysis calculated for C8H19NO2 : % C 59.63; %H, 11.80, %N, 8.70; Found: % C, 58.99, %H, 11.82; %N, 8.38.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[CH:9]=[CH:8]2.Cl>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 60 °C

Procedure:
To a mixture of 20 g. of sodium hydroxide and 400 ml. of methanol are added 24.5 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate. The resulting reaction mixture is heated to 60°C for 5 hours. The cooled mixture is neutralized by the addition of aqueous 1N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-methoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:27][CH2:26]3)[C:20]([O:22]C)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.[SH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]([OH:27])[CH2:26][S:35][C:36]3[S:37][CH:38]=[CH:39][N:40]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Sc1nccs1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nccs3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.7 g, 1.79 mmol) in benzene (5 mL) and Et3N (0.33 mL, 2.3 mmol) at room temperature is added slowly 2-mercaptothiazole (0.52 g, 4.48 mmol). The reaction mixture is stirred for 4 h at room temperature. The resulting mixture is diluted with water, and the mixture is then extracted three times with EtOAc. The combined EtOAc layer is consecutively washed with water, and brine, dried over MgSO4 and concentrated to an oil under reduced pressure. Purification is accomplished by column chromatography with hexane/EtOAc (4:1 to 7:3 to 6:4) eluent to give the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]1([C:14]2([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc(C2(N3CCNCC3)CCCCC2)cc1

Procedure:
1 benzyl 4 (1-phenylcyclohexyl)piperazine (0.47 q) was dissolved in 86 mL methanol and 14 mL 0.2 N HCI in methanol. The mixture was hydrogenated over palladium black (0.1175 g) and 3 atm. of hydrogen at room temperature for 1 hour. The reaction was filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1 (1-phenylcyclohexyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:21][CH3:22])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)O.C(N(CC)CC)C.S(Cl)(C)(=O)=O.C([O-])(=O)C=C.S([O-])(=O)(=O)C>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)C>[CH3:1][O:2][C:3](=[O:23])[C:4]([O:21][CH3:22])=[CH:5][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Agent: C=CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC
Temperature: 0 °C

Procedure:
The compounds of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (Example 291, Step 1) (4.06 g, 12.84 mmol), triethylamine (7.15 mL, 51.33 mmol) and 4-(N,N-dimethylamino)pyridine (0.157 g, 128 mmol) were dissolved in dichloromethane (20 mL) in a round bottom flask and then cooled to 0° C. under ice bath. Mesyl chloride (1.093 mL, 14.1 mmol) was added dropwise via syringe, and the mixture was stirred at room temperature until no starting aldol is observed by HPLC-MS (4 days, 0.2 additional mL of MsCl were added each day). The mixture was diluted with 200 mL of diethyl ether, washed with HCl (1N, 3×40 mL) and 40 mL of brine, and dried over MgSO4 Concentration of the mixture afforded 3.96 g. of a 2.5:1 mixture of the acrylate and a single isomer of the mesylate intermediate which was directly used in the next Step. 1H-NMR (CDCl3, 200.15 MHz): 7.46–7.26 (m, 8H), 6.99–6.93 (m, 1H), 5.10 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[CH:14]([OH:27])[N:15]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
A solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.62 g, 7.0 mmol) in dichloromethane (50 mL) was stirred on an ice bath and treated dropwise with diisobutylaluminum hydride (1.0 M in tetrahydrofuran, 21 mL, 21 mmol) over ca. 10 min. The solution was stirred on ice for 4 h 5 min, then was treated dropwise over 10 min with methanol (1.75 mL). The mixture was stirred on ice for 10 min, then was treated with water (2.75 mL) over ca. 1 min. The mixture was stirred at rt for 35 min, then was filtered and the gelatinous solid was triturated 3× with dichloromethane and filtered. The combined filtrates were combined and concentrated under vacuum to provide (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a sticky semicrystalline solid (2.41 g). MS found: (M+H—H2O)+=359.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=CC=1.[C:8]([OH:11])(=[O:10])[CH3:9].O=O>[Br-].C([N+](CCC)(CCC)CCC)CC.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:8]([OH:11])(=[O:10])[C:9]1[CH:1]=[CH:2][CH:3]=[N:4][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1cccnc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1cccnc1
Temperature: 210 °C

Procedure:
An autoclave having a stirrer, a gas introducing tube and a refluxer for generated steam was charged with 50 parts by weight of 3-methylpyridine, 0.76 part by weight of cobalt acetate, 0.54 part by weight of manganese acetate, 2 parts by weight of tetrapropylammonium bromide and 150 parts by weight of acetic acid having a 5 wt % water content as a solvent, and the mixture was continuously stirred at a temperature of 210° C. under a pressure of 25 kg/cm2G with feeding air at a rate of 60Nl (normal liter)/hour. The mixture was allowed to react for about 3 hours until no oxygen absorption was found, and then the reaction mixture was cooled to 0° C. A precipitated nicotinic acid crystal was recovered by filtration, washed with acetic acid and dried to give 43.4 parts by weight of crude nicotinic acid. The mother liquor was analyzed by gas chromatography to show that it contained 6.5 parts by weight of raw material 3-methylpyridine and 9.5 parts by weight of nicotinic acid. The conversion of the 3-methylpyridine was 87.0 mol %, the selectivity to the nicotinic acid was 92.1 mol %, and the yield of the nicotinic acid 80.1 mol %. The crude nicotinic acid had a bromine concentration of 470 ppm and showed a dissolved b value of 5.10.
Reaction SMILES: Cl.C(OC([NH:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:20][CH2:19]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12])=O)(C)(C)C.[OH-].[Na+]>CC(C)=O.O>[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:19][CH2:20]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](N)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 50 °C
Yield: 59.3 %

Procedure:
Add concentrated hydrochloric acid (36.94 mL, 430.11 mmol) to a solution of (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (82.24 g, 215.06 mmol) in acetone (822.4 mL), and stir the mixture at 50° C. After 1.5 hours cool the mixture to 0° C. and add 50% sodium hydroxide in water to pH=3.6-3.8. Stir the solid obtained for 1 hour, filter and wash with water. Dry under vacuum for 48 hours to yield the title compound as a white solid (36 g, 127.53 mmol). MS (m/z): 283 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(O)(=O)C.[CH3:22][NH2:23]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:23][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC1CCN(Cc2ccccc2)CC1=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a stirred solution of 1-benzyl-4-methyl-piperidin-3-one (2.3 grams, 11.5 mmol), prepared by the methods of Iorio, M. A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified using 5% methanol as a co-solvent), both references are incorporated by reference in their entirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran was added 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirred in a sealed tube for 16 hours at room temperature. Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3×80 mL with ether, the combined ether layers dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Al].CCOCC>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Solvent: CCOCC
Product: C[C@H]1CC2(C[C@@H]3CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@]31C)OCCO2
Yield: 93.3 %

Procedure:
55 g of 3,3-ethylenedioxy-17β-hydroxy-1α-methyl-5α-androstane in 550 ml of toluene and 110 ml of cyclohexanone were treated at boiling with a solution of 5.5 g of aluminium isopropylate in 55 ml of toluene and the mixture was heated for 3 hours with slow distillation. The mixture was then treated with ether, washed with ice-cold dilute sulphuric acid and water, evaporated and the residue steam-distilled. After extraction with methylene chloride, the resulting product was recrystallised from diisopropyl ether to give 51 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one of melting point 155.5°-156.6° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=[O:1]
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate (2.0 g, 9.25 mmol) in chloroform (40 ml) was added manganese dioxide (4.0 g), and the mixture was stirred at room temperature for 2 hrs. Manganese dioxide was filtered from the reaction solution using celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give methyl 4-formyl-1-naphthalenecarboxylate (1.41 g, 85%).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.CO.C(Cl)(=O)C>[Pd].C(Cl)(Cl)Cl>[NH2:26][C:18]1[C:17]2[N:27]=[C:14]3[CH2:13][O:12][CH2:11][C@H:10]([CH2:9][OH:8])[N:15]3[C:16]=2[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Agent: [Pd]
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Reaction time: 96 h
Yield: 49.3 %

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (4.5 g, 12 mmol) was added to a mixture of methanol (177 mL) and acetyl chloride (1.3 mL, 19 mmol) in a pressure bottle. Palladium on carbon (10%, 900 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 4 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were treated with 2 mL of 50% aqueous NaOH solution and the mixture was concentrated under reduced pressure to afford an oily solid. Chromatography (SiO2, 0-30% CMA/CHCl3) afforded an oil that was concentrated with acetonitrile to give 1.6 g of [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methanol as a tan solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])(=[O:3])[CH3:2].C1(C=CC(O)=CC=1)[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:5]1(=[O:14])[O:4][C:1](=[O:3])[CH2:2][CH2:6]1.[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])(=[O:3])[CH3:2]
Reactant: Oc1ccc(O)cc1
Agent: CCOCCOCCOC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CCC(=O)O1
Temperature: 115 °C

Procedure:
A reflux condenser, a thermometer, a bleed tube, and a stirrer were set to a four-necked flask. In order to prepare a reaction solution, 919 parts by mass of bisphenol A epoxy resin (jER1004 (item number) available from Mitsubishi Chemical Corporation, epoxy equivalent weight: 919), 470 parts by mass of diethylene glycol monoethyl ether acetate, 0.2 parts by mass of hydroquinone, 300 parts by mass of ω-carboxy-polycaprolactone (n≈2) monoacrylate (Aronix M-5300 (trade name) available from TOAGOSEI CO., LTD., the number average molecular weight: 290), and 3 parts by mass of triphenyl phosphine were added to the four-necked flask. The reaction solution was heated at 115° C. for 12 hours with air bubbled therein to cause the addition reaction. Subsequently, into thus-obtained solution in the four-necked flask, 249 parts by mass of succinic acid anhydride and 322 parts by mass of diethylene glycol monoethyl ether acetate were added, and then thus-obtained solution was heated at 110° C. for 5 hours to react them. Consequently, a 65 mass % solution (carboxyl group containing resin solution A-1) of resin containing a carboxyl group was obtained, the resin having the number average molecular weight of about 3700.
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH2:11][C@@H:10]2[C@H:15]1[CH2:16][NH:8][CH2:9]2)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Yield: 86.7 %

Procedure:
The preparation comprises dissolving [1S,6S]-8-benzyl-2-tertbutyloxycarbonyl-2,8-diazabicyclo[4,3,0]nonane (target product of Embodiment 5, 5.0 g, 15.8 mmol) in methanol (50 mL), adding 10% Pd/C (1.0 g) as catalyst for hydrogenation under 3 atm for 10 h, filtering to remove the catalyst, concentrating the filtrate, adding petroleum ether to solidify the product, filtering, and drying obtained filter cake to give [1S,6S]-2-tertbutyloxycarbonyl-2,8-diazabicyclo[4,3,0]nonane(3.1 g, 86.8%), [α]20D=−70.2° (C=4).