Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:17][CH:18](OC)OC)[CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:18]=[CH:17][N:15]([CH3:16])[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C=CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-methylglycinamide (1.9 Kg, 6.1 mol) and p-toluenesulfonic acid monohydrate (270 g) in toluene (29.4 L) was stirred at 80° C. for 4 hrs. The resultant reaction mixture was cooled to room temperature, washed with water (4×2 L), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluting with heptane-ethyl acetate. Concentration of appropriate fractions provide the cyclization product as off-white solid.
Reaction SMILES: ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]([O:16][CH2:17][CH2:18]O)([CH3:15])[CH3:14].Cl.[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl.CO.CC1(C)N([O])C(C)(C)CCC1>[CH:13]([O:16][CH2:17][CH2:18][NH:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28])([CH3:14])[CH3:15]
Reactant: CC(C)OCCO
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)OCCNc1nc[nH]c1C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
Trichlorocyanuric acid (1.23 g, 5.29 mmol) was added to a solution of 2-isopropoxyethanol (0.50 g, 4.80 mmol) in CH2Cl2 (3 mL). The reaction mixture was cooled to 0° C. and TEMPO (0.015 g, 0.09 mmol) was carefully added in small portions. The mixture was stirred at r.t. for 20 minutes and then filtrated through Celite and washed with CH2Cl2. The filtrate was kept cold, 0° C., during the filtration. The obtained aldehyde solution was added to a stirred mixture of 4-amino-1H-imidazole-5-carboxamide hydrochloride (0.78 g, 4.80 mmol), which was obtained from Example 3(b), at 0° C. in MeOH (5 mL). The mixture was stirred for 20 minutes, then NaCNBH4 (0.30 g, 4.80 mmol) was added. After stirring at r.t for 5 h the mixture was concentrated and purified by flash chromatography (CH2Cl2/methanol gradient; 0 to 5% methanol), to yield the title compound (0.39 g, 38%) as an oil.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([OH:17])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19].[H-].[Na+].IC>O>[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([O:17][CH3:2])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: C1CCOC1
Reactant: COc1cc(C(C)O)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(C(C)OC)cc(OC)c1Br
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (100 mL) solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (7.24 g, 27.7 mmol) was added sodium hydride (1.33 g, 33.2 mmol) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added dropwise iodomethane (1.90 mL, 30.5 mmol), and the mixture was stirred at room temperature for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 10/1 then 1/4) to obtain the title compound (7.39 g, 26.9 mmol).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]2[C:12]([CH2:20][CH2:21][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: c1ccccc1
Reactant: Cc1c(Cl)cccc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)ccc2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Thionyl chloride (10.0 mL, 1.5 eq) and 3-chloro-2-methyl-benzoic acid (commercially available from Aldrich) (15.6 g, 91.4 mmol) in benzene was refluxed until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to a solution of AlCl3 (12.2 g, 1.0 eq) in dichloroethane at 10–20° C. Ethylene was bubbled through the mixture for 4 h. and the mixture was stirred overnight. The mixture was quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extract was washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. Concentrated sulfuric acid was added and the mixture was stirred at 85° C. for 1 h. After cooling to rt, the reaction mixture was quenched with ice-water. The mixture was extracted with Et2O (3×250 mL) and the combined organic extracts were washed with H2O (3×200 mL), saturated NaHCO3 (3×200 mL), brine (1×100 mL), dried over MgSO4 and concentrated. Pure 6-chloro-7-methyl-1-indanone (11.9 g, 72%) was obtained after column chromatography using 20% EtOAc:hexane as eluant. Use of 6-chloro-7-methyl-1-indanone in Method NINETEEN produced 4-(5-chloro-4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 152).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
2-Ethylhexanol (50.51 g, 0.384 tool) and pyridine (260 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -5° C. and to it is added p-toluenesulfonyl chloride (89.63 g, 0.416 mol) in portions via Gooch tubing so as to maintain the reaction temperature -5°-5° C. After 3 h, (40 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 540 mL of ether. The layers are separated and the organic layer is washed with 5 M H2SO4 (2×140 mL), saturated CuSO4 solution (140 mL), water (2×140 mL) and saturated NaHCO3 solution (140 mL). After drying over MgSO4, the organic layer is filtered, and concentrated to leave a light yellow liquid as 2-ethyhexanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][C:39]([N:41]([CH2:43][CH3:44])[CH3:42])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][C:39](=[O:40])[N:41]([CH2:43][CH3:44])[CH3:42])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCN(C)C(=O)CN
Product: CCN(C)C(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-N-methyl-acetamide.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:28])[C:16]([O:26][CH3:27])([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)N.Cl(O)(=O)(=O)=O.[NH:34]=[N+:35]=[N-:36]>O1CCCC1.C(Cl)Cl>[N:34]([CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:28])[C:16]([O:26][CH3:27])([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)=[N+:35]=[N-:36]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(COC(N)=O)=CS[C@@H]21
Reactant: [N-]=[N+]=N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(CN=[N+]=[N-])=CS[C@@H]21
Reaction time: 9 h

Procedure:
A mixture of the benzhydryl ester of 3-carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.212 g.), perchloric acid (0.36 g.) in tetrahydrofuran (6.0 ml.) and hydrazoic acid (28.0 ml., 0.18 N) in methylene chloride is stirred under a nitrogen atmosphere for nine hours. The reaction mixture is washed with a 5% aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and the solvent removed by evaporation. The crude product is purified by chromatographing through a column of silica gel G to yield the substantially pure benzhydryl ester of 3-azidomethyl-7-methoxy-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([C:16](=[CH:19]NC1C=CC=CC=1)[C:17]#[N:18])=[O:15]>C(O)C.CCCCCC>[NH2:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:19][C:16]=1[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][CH:29]=[C:11]([Br:10])[CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Solvent: CCCCCC
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) in ethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After 4 h, the reaction mixture was cooled to room temperature, diluted with hexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (9.7 g) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C@H:6]([C:2]2[N:1]([C:34]([O:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=3)=[O:35])[CH:5]=[CH:4][N:3]=2)[CH2:10]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1ncc[nH]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1nccn1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
To a solution of (2S,4R)-2-(imidazol-2-yl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of water (10 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (5 ml) under ice-cooling with stirring, keeping the pH between 9 and 10 with 4N aqueous sodium hydroxide. The mixture was stirred under the same condition for 1 hour, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (2S,4R)-4-hydroxy-2-[N-(4-nitrobenzyloxycarbonyl)imidazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (970 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][NH2:11].[CH2:20]1[C:22]2([CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]2)[CH2:21]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:18][CH3:19])[CH2:10][NH:11][CH2:28][CH:25]1[CH2:26][CH2:27][C:22]2([CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: O=CC1CCC2(CC1)CC2
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC1CCC2(CC1)CC2)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 μl) was added spiro[2.5]octane-6-carbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 μl, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for overnight. The mixture was quenched with 0.5 M NaOH and mixture was stirred at rt for 30 min. Evolution of gas was observed. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give 2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=O.[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:20][C:4]1[C:3]([CH:1]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Yield: 53.2 %

Procedure:
A solution of benzyl (3-formyl-2-methylphenyl)carbamate (8.00 g, 29.7 mmol), nitroethane (10.7 ml, 149 mmol), and ammonium acetate (11.5 g, 149 mmol) was heated in an oil bath at 95° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with a mixture of dichloromethane (150 mL) and water (75 mL) and basified with solid sodium bicarbonate slowly. The organic layer was collected, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%-65%-75%) afforded benzyl (2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol, 53% yield) as a pale yellow solid.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1>O>[CH:1]([O:3][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:2]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=COCc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Formic acid (1.24 ml) and acetic anhydride (0.62 ml) were mixed and stirred at 50° C. for 30 minutes. This solution was cooled to 0° C., added with 4-hydroxymethylbenzoic acid (500 mg) and stirred at room temperature for 4.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 536 mg of the title compound. Yield: 91%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[NH2:17])=O)C.C[O-].[Na+].[CH:21]([NH2:23])=O>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]2=[N:8][C:7]3[C:6]([C:4](=[O:3])[NH:23][CH2:21][N:17]=3)=[C:14]2[CH:13]=1
Reactant: CCOC(=O)c1c(N)[nH]c2ccc(OC)cc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
A solution of 2-amino-5-methoxy-1H-indole-3-carboxylic acid ethyl ester (2.15 g (9.2 mmol), sodium methoxide (0.5 g (9.3 mmol), and formamide (200 mL), is heated under N2 at 220° C. for 1.5 h. The solution is cooled to room temperature, stored for 2.5 days, and filtered. The solvent is evaporated by Kugelrohr distillation at 95° C./0.8 mm. The residual solids are washed with H2O, then heated in 35 mL of boiling N,N-dimethylformamide. The hot suspension is filtered hot over a pad of flash silica gel. The cooled filtrate is concentrated in vacuo to a solid that is sonicated in about 30 mL of MeOH. The solids are filtered, washed with MeOH, and dried to leave 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (1.71 g,72%) that is about 83% pure. 1H NMR (DMSO): δ12.16 (1H, br s, exchanges with D2O), 12.04 (1H, br s, exchanges with D2O), 8.08 (1H, d, J=3.4 Hz, exchanges to s with D2O), 7.46 (1H, d, J=1.9 Hz), 7.37 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=8.8, 2.5 Hz), 3.81 (3 H, s).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+].O>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 95.6 %

Procedure:
Morphine of 89.0% purity 320 parts (1 mole part), potassium carbonate 552 parts (4 moles part), water 65 parts and trimethylphenylammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene (4000 parts) at 45° to 120° C. for 2 to 8 hrs. to yield 296 parts codeine (95.6% yield after workup as in Example 1.
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl>C(O)=O>[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: NC(N)=O
Agent: Cl
Solvent: O=CO
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To 100 g of 1-bromo-3,5-dimethyl adamantane and 86 g of urea, adding 72 ml of 94 wt % formic acid, heating to 120° C. and holding for 2 hours. Cooling to the room temperature and adding 385 ml of 10% hydrochloric acid to hydrolyze at 100° C. for about 1 hour. Adjusting with 30% sodium hydroxide solution to a pH of 12, extracting with butyl acetate twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150 ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with water to yield 60.4 g of pure Memantine Hydrochloride. The yield is 68.1% (GC 99.1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[C:20]([F:26])([F:25])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:20]([F:26])[O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(OC(F)F)c2)C1
Temperature: 120 °C
Yield: 69.5 %

Procedure:
(3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 300 mg, 1.19 mmol) and methyl 2-chloro-2,2-difluoroacetate (258 mg, 1.78 mmol) were dissolved in dry DMF (2 mL). Potassium carbonate (328 mg, 2.38 mmol) was added and the reaction was heated to 120° C. under microwave irradiation for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 20% hexanes in ethyl acetate to 100% ethyl acetate to afford the title compound as a yellow oil (250 mg, 67.3%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:32][CH2:33][O:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=4)[O:46][C:47]=3[CH3:48])[CH2:36]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH2:32][CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH:37]([O:41][CH2:42][C:43]4[N:44]=[C:45]([C:49]5[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=5)[O:46][C:47]=4[CH3:48])[CH2:36]3)[C:9]2=[CH:10][N:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1CCOC1CCCC(OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
66 mg of ethyl 5-(2-methoxyethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are dissolved in 2 ml of dry DMF, and 12 mg of 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:2). This gives ethyl 5-(2-methoxyethoxy)-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate as a yellowish solid. C33H41N3O7 (591.71), MS (ESI): 592 (M+H+).
Reaction SMILES: O1CCOC1[N:6]1[N:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[NH:7]1.[C:23](=O)(O)[O-:24].[Na+]>O1CCCC1.Cl.[Cl-].[Na+].O>[CH3:14][S:11]([C:9]1[N:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([CH:20]=2)[CH:23]=[O:24])[N:7]=[N:6][N:10]=1)(=[O:12])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccc(N2NN(C3OCCO3)N=C2S(C)(=O)=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C=O

Procedure:
1-(3-[1,3]Dioxolan-2-yl(4-methoxy-phenyl)-5-methanesulfonyl-1H-tetrazole (800 mg) in tetrahydrofuran (13 ml) and hydrochloric acid (2N, 7.5 ml) was stirred at room temperature for 1.5 h. The solution was basified with sodium bicarbonate solution (8%), saturated with brine (50 ml), extracted with ether (3×50 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (307 mg).