Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(O)(C)C.[NH2:13][NH2:14]>C(OC)(C)(C)C.[Cl-].[Na+].O>[CH3:8][C:4]1[N:3]=[C:2]([NH:13][NH2:14])[CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: Cc1cccc(F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)O
Product: Cc1cccc(NN)n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A jacketed reaction flask was equipped with mechanical stirrer, nitrogen inlet, and reflux condenser and the jacket was cooled to 10° C. The reactor was programmed to automatically cool to 0° C. if at any point the internal temperature exceeded 80° C. The reactor was purged with a steady stream of nitrogen gas. To the reactor was charged 25 g (0.225 mol) of 2-fluoro-6-methylpyridine followed by 100 ml of isopropanol and the jacket temperature was adjusted to 73° C. (corresponding to an internal temperature of 70° C.). To the reactor was charged 44 g (0.90 mol) of 65% aqueous hydrazine and the mixture was stirred overnight with the jacket set at 70° C. The reactor contents were diluted with 125 ml of methyl t-butyl ether (MTBE) and 13 ml of saturated brine to give two layers which were separated. The aqueous layer was extracted with 2×60 ml of MTBE. The combined organic layers were combined and dried over sodium sulfate (anhydrous). The drying agent was removed by filtration and the organic filtrate was concentrated by rotary evaporation. The resulting oil solidified upon standing to give the desired product (21.1 g) as a white solid.
Reaction SMILES: [OH-:1].[Na+:2].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1>C(O)C.O>[OH2:11].[OH2:1].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([O-:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.[Na+:2]
Reactant: [OH-]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1

Procedure:
20% Aqueous solution of sodium hydroxide was added to a suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 15 g.) in a mixture of ethanol (8 ml.) and water (8 ml.) at room temperature to make a solution of pH 7.5. After filtration and washing, the filtrate and washings were combined (which contained 18.3 ml. of water) and added dropwise to ethanol (46 ml.) at 20° to 25° C. under stirring and stirred at the same temperature for 30 minutes. Ethanol (28 ml.) was added dropwise to the mixture over 30 minutes, and stirred at the same temperature for 2 hours. The precipitates were collected by filtration, washed with ethanol (20 ml.) and dried in vacuo at room temperature to give plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate dihydrate (syn isomer, 13.5 g.), mp 260° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][Br:33])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-(hydroxymethyl)benzoate (2.0 g, 8.2 mmol) and triphenylphosphine (4.28 g, 16.3 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (3.05 g, 17.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethylacete/hexanes) gave 2.1 g (83%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 4.42 (s, 2H), 3.90 (s, 3H). Mass spec.: 308.93 (MH)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[S:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[C:16]2[S:23]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:9]
Reactant: Cc1[nH]c2ccc(Cl)cc2c1SC1CCNCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1S(=O)C1CCNCC1
Reaction time: 4 h

Procedure:
Metachloroperbenzoic acid (2.79 g) is added in portions to a solution of 5-chloro-2-methyl-3-(piperidin-4-ylthio)-1H-indole (3 g, prepared in Example 18) in dichloromethane (25 ml) at -40° C. After 4 hours at room temperature, the insoluble material is filtered off. The filtrate is washed with sodium hydroxide and then with water. The aqueous phases are extracted with ether and then with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The oily residue obtained is chromatographed on silica gel (eluent: CH2Cl2 /MeOH/NH4OH:90/10/1) to give 5-chloro-2-methyl-3-(piperidin-4-yl-sulfinyl)-1H-indole in the form of an oil, which crystallizes on the addition of ether (0.4 g).
Reaction SMILES: C(OC(=O)CCN[C:10](=[O:33])[C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:14]=[CH:13][C:12]=1[N+:30]([O-:32])=[O:31])(C)(C)C.C([O:39]C(NCCC(O)=O)=O)(C)(C)C.NC1C=CC([N+]([O-])=O)=C(C=1)C(O)=O>>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:15]1[CH:14]=[CH:13][C:12]([N+:30]([O-:32])=[O:31])=[C:11]([CH:16]=1)[C:10]([OH:33])=[O:39])=[O:29])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1cc(NC(=O)CCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
For the preparation of the ester starting material, N-(t-butoxycarbonyl)-β-alanine and 5-amino-2-nitrobenzoic acid are coupled to give 5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoic acid, MS: 354 (17, M+H), and the latter is reacted with β-alanine t-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][OH:23]>O1CCCC1.CO>[OH:4][CH2:3][CH2:2][NH:20][CH2:21][C:22]([NH:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)=[O:23]
Reactant: NCCO
Reactant: Nc1cccnc1
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CNCCO)Nc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
Chloroacetyl chloride (2.2 mL, 27.6 mmol) was added dropwise over 10 minutes to a stirred, cooled (0° C.) solution of 3-pyridinamine (2 g, 21 mmol) and triethylamine (4 mL, 28 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to room temperature, then 2-aminoethanol (5 mL, 120 mmol) in methanol (5 mL) was added. The mixture was stirred at 60° C. for 4 hours, cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1), to give the title compound (2.53 g, 62%). m/z (ES+) 196 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:22][CH3:23])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:6]1[C:5]([C:3]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:4])=[C:10]([OH:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:23]
Reactant: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
3.3 gm (0.01 mol) of 2-ethyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 1.5 gm (0.015 mol) of 2-aminothiazole were reacted in 150 ml of xylene analogous to Example 40, yielding 1.0 gm (25% of theory) or 2-ethyl-4-hydroxy-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 261°-262° C (decomp.), after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.[H][H]>C(OCC)(=O)C.O.[Pt](=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)nc1Br
Yield: 98.7 %

Procedure:
2-Bromo-3-methoxy-6-nitropyridine (Desc. 5; 9.0 g, 38.6 mmol) and platinum (IV) oxide hydrate (250 mg) in ethyl acetate (250 ml) was hydrogenated at 20 psi hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate concentrated to give the product as a yellow solid (7.73 g, 38.1 mmol, 99% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[C:15](O)(=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)N.NC1C=CC=C(C)C=1>CN(C)C=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:19][CH:17]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(CC(=O)Nc2ccccc2C(=O)O)c1
Temperature: 0 °C
Yield: 57 %

Procedure:
N(chloroacetyl)anthranilic acid 6.4 g (15 mmol) (synthesized from anthranilic acid by the same procedures as those of Example 9) and m-toluidine 9.5 ml (0.09 mol) were dissolved in 60 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction mixture was poured into ice water and extracted with ether. The resulting ether solution was extracted with 10% sodium hydroxide and the resulting aqueous solution was neutralized with 10% HCl solution. The neutralized solution was extracted with ether, and the ether solution was washed with water and dried. The solvent of dried solution was distilled off and the residue was recrystallized from benzene-hexane to obtain N[(3-methylphenyl)acetyl]anthranilic acid 4.7 g (yield: 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[C:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[CH:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:14][CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CN=C(c3cccnc3F)C2(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2CNC(c3cccnc3F)C2(F)F)cc1
Reaction time: 3 h

Procedure:
To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 6.35 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][N:28]([CH2:30][CH:31]1[CH:36]([NH2:37])[CH:35]2[CH2:38][CH2:39][N:32]1[CH2:33][CH2:34]2)[CH3:29]>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:37][CH:36]2[CH:35]3[CH2:38][CH2:39][N:32]([CH2:33][CH2:34]3)[CH:31]2[CH2:30][N:28]([CH3:29])[CH3:27])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN(C)CC1C(N)C2CCN1CC2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1C2CCN(CC2)C1CN(C)C
Temperature: -55 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.22 g, 11 mmoles) and triethylamine (1.12 g, 11 mmoles) in anhydrous methylene chloride (35 ml) under nitrogen was cooled (0° C.) and treated dropwise with ethyl chloroformate (1.2 g, 11 mmoles). After 45 minutes at 0° C., the solution was cooled (-55° C.) and treated dropwise with 2-(dimethylaminomethyl)-1-azabicyclo[2.2.2]octan-3-amine (2.11 g, 11.5 mmoles) in 7 ml of methylene chloride. The solution was warmed to 25° C. over one hour, stirred for one hour, and diluted with methylene chloride to a total volume of 100 ml. The organic solution was washed with 1.0N sodium hydroxide (2×35 ml), saturated aqueous sodium bicarbonate (35 ml), and brine (35 ml), dried (Na2SO4), and concentrated in vacuo to provide 2.94 g (73%) of an oil.
Reaction SMILES: C[NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.CCOCC>[NH:2]1[C:3]2=[C:12]3[C:7](=[CH:6][CH:5]=[CH:4]2)[CH:8]=[CH:9][CH:10]=[C:11]3[NH:13][CH2:14]1
Reactant: CNc1cccc2cccc(NC)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 170.7 %

Procedure:
The above aldehyde (1.47 g, 4 mmol) was treated with N,N'-dimethyl-1,8-diaminonaphthalene (4.2 mmol), and para-toluenesulfonic acid (5 mg) in tetrahydrofuran (15 mL) for 20 min at room temperature. The solution was diluted with ether, washed with dilute sodium carbonate, and concentrated. The residue was recrystallized from hexane-ethyl acetate to give the 2,3-dihydroperimidine 7 (1.22 g, 59%): mp 89-90° C.; NMR 7.5-6.75(m, 12H), 6.34(d, 2H), 4.24(t, 1H), 3.9(2t, 4H), 3.02(s, 6H), 1.8-1.2(m, 16H), 0.85(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.O[CH:49]1[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:21]([S:18]([C:13]1[N:12]=[C:11]2[N:10]([CH:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[C:9](=[O:28])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:17][C:16]2=[CH:15][N:14]=1)(=[O:20])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN1CCC(O)CC1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Product: CN1CCC(N2C(=O)N(c3ccccc3Cl)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A mixture of sulfone 9.1 (1.0 g, 2.4 mmol), diphenyl-2-pyridylphosphine (1.9 g, 7.23 mmol) and 4-hydroxy-1-methylpiperidine (0.555 g, 4.8 mmol) was dissolved in anhydrous tetrahydrofuran under an atmosphere of nitrogen. To this solution was added di-tert-butylazodicarboxylate (1.67 g, 7.23 mmol) and the resulting mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by column chromatography on silica gel using 9:1 dichloromethane/methanol as eluant. The column fractions containing product were combined and concentrated in vacuo to give 354 mg of 7-benzylsulfonyl-3-(2-chlorophenyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>CS(C)=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]([CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:23]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CCOC(=O)CBr
Solvent: CS(C)=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 30.0 g. of 5-chloro-3-phenyisoindole-1carboxylic acid ethyl ester in 300 ml. of dimethylsulfoxide is treated with 66.8 g. of bromoacetic acid ethyl ester and 27.6 g. of finely triturated, dry potassium carbonate and intensively stirred at room temperature for 17 hours. The mixture is poured into 750 ml. of ice-water and the separated product, after the addition of 50 g. of sodium chloride, is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and concentrated to dryness. The resulting oil crystallizes on trituration with ether and pentane, and there is obtained 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid ethyl ester; melting point 100°-101° C. Recrystallization from ethanol increases the melting point to 103°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=O)cc1
Product: CCOC(=O)C=Cc1ccc(OC)cc1
Product: COc1ccc(C=CC(=O)O)cc1

Procedure:
The process of claim 1 wherein p-methoxy benzaldehyde is reacted with ethyl acetate in step (a); ethyl p-methoxycinnamate is formed in step (b) and ethyl p-methoxycinnamate and p-methoxycinnamic acid are reacted with a C8 alkanol in step (e) to produce a C8 alkyl p-methoxycinnamate as the product of the process.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[NH3:17]>C(O)CO>[NH3:7].[CH3:9][OH:10].[NH2:17][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1NC(=O)C(C)(C)C
Agent: N
Solvent: OCCO
Product: CO
Product: COc1ccc(N)nc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h
Yield: 1 %

Procedure:
A pressure tube was charged with 6-bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34) (0.287 g), ethylene glycol (3 mL) and Cu2O (0.028 g) and cooled to −78° C. To this mixture, 1 mL of liquid ammonia was collectyed (at −78° C.), the pressure tube was sealed and then stirred at room temperature for 24 hours. The reaction mixture was again cooled to −78° C., the seal was removed and the reaction mixture diluted with water (10 mL). The aqueous solution was extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and solvent was removed under a reduced pressure. The resulting residue was chromatographed (silica gel, CH2Cl2 then 1% 2N NH3/MeOH in CH2Cl2 to obtain 6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35). LCMS: purity: 94%; MS (m/z): 224 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/C(N=[N+]=[N-])=O.C1([O:23][C:24]2C=CC=CC=2)C=CC=CC=1.[N:30](CCCC)(CCCC)CCCC>CCCCCC>[C:24]1(=[O:23])[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]=2[CH:10]=[CH:11][NH:30]1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCCCN(CCCC)CCCC
Reactant: [N-]=[N+]=NC(=O)/C=C/c1cc2ccccc2s1
Solvent: CCCCCC
Product: O=c1[nH]ccc2sc3ccccc3c12
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A suspension of (2E)-3-(1-benzothien-2-yl)acryloyl azide in diphenyl ether (9.2 equiv) and Bu3N (1.1 equiv) was heated to reflux for 1 h. A solution resulted. The mixture was cooled to 40-50° C. Hexane was added; the mixture was stirred for 30 min, filtered, and washed with hexanes to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[OH:16])=[C:12]([OH:17])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:24]([C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:15]=1[C:14]([O:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[O:16][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([O:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cccc2cc3cccc(O)c3c(O)c12
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1cccc2cc3cccc(OC(=O)c4ccccc4Oc4ccccc4)c3c(OC(=O)c3ccccc3Oc3ccccc3)c12)c1ccccc1Oc1ccccc1
Reaction time: 2 h

Procedure:
1,8,9-Trihydroxyanthracene (4 g.), benzene (125 ml.) and pyridine (12 g.) were stirred under nitrogen until a clear solution resulted. 2-Phenoxybenzoyl chloride (17 g.) was added and the mixture was stirred for 2 hours, filtered and evaporated under reduced pressure to a thick oil. This was dissolved in toluene and the solution was added dropwise with stirring to petroleum ether (b.p. 40°-60° C.) to yield a pale yellow-green solid (13 g., 90%), m.p. 110° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[NH4+].[OH-].[CH3:18]O>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:18])=[O:9])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A resealable pressure bottle was charged with cis-4-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol), MeOH (100 mL), and sulfuric acid (7.45 mL, 140 mmol). The vessel was sealed and the mixture stirred at 80° C. for 24 hours. The mixture was cooled to 0° C. via an ice bath and made basic with NH4OH to a pH of approximately 10. The aqueous layer was extracted with DCM (4×50 mL) and the organic layers combined, dried over sodium sulfate and concentrated to afford cis-methyl 4-aminocyclohexanecarboxylate (9 g, 82% yield) as a colorless oil. MS m/z=158.2 [M+H]. Calc'd for C8H15NO2: 157.1.