Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12]CC)=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask containing a mixture of ethyl imidazo[1,2-a]pyridine-2-carboxylate (1 g, 5.26 mmol), THF (5 ml) and water (5 ml), lithium hydroxide (0.378 g, 15.77 mmol) was added and stirred overnight at RT. The pH of the reaction mixture was adjusted to 2 with 2 M HCl and THF was evaporated. The remaining water phase was extracted with ethyl acetate and the combined ethyl acetate phases were dried. The product had precipitated into the water phase. Water was evaporated, and the remaining solid recrystallized from methanol. The product was used as a salt in the next step. 1H-NMR (400 MHz; DMSO-d6): δ 7.23-7.26 (m, 1H), 7.63-7.70 (m, 1H), 7.76 (dd, 1H), 8.72 (s, 1H), 8.73-8.77 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)[OH:9])=[C:5]([CH3:7])[N:6]=1.[Al]>O=[Mn]=O.O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(O)c2cnnn2C)s1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Product: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Reaction time: 1.5 h

Procedure:
To a 500 mL flask containing (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (10.5 g, 46.8 mmol, Intermediate 16: step a) was added 1,4-dioxane (400 mL) and the contents were warmed to form a homogeneous solution. Activated MnO2 (18 g, 207 mmol) was added and the dark brownish mixture was heated to reflux in an aluminum heating mantle under an atmosphere of N2. After 1.5 hours, the contents were filtered while still hot through Celite® and rinsed with warm THF. The resulting light orange solution was concentrated and passed through a silica gel column (25% acetone-DCM) to provide the title compound as a light orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][CH:18]([O:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22]Br>>[CH3:16][O:17][CH:18]([O:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][N:13]1[CH2:12][CH2:11][CH:10]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9])[CH2:15][CH2:14]1
Reactant: COC(CCCCBr)OC
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Product: COC(CCCCN1CCC(N(C)C(=O)OC(C)(C)C)CC1)OC

Procedure:
The title compound was prepared from the above amine and 5-bromopentanal dimethyl acetal using a similar method to that described for Example 8 (Step 2). δ (360 MHz, CDCl3) 1.34 (1H, m), 1.46-1.73 (19H, m and s), 1.98 (2H, m), 1.33 (2H, m), 2.73 (3H, s), 2.99 (2H, m), 3.31 (6H, s), 4.36 (1H, t).
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)(O)[O-].[K+].C(OCC)(=O)C>CS(C)=O.O>[CH2:14]([O:13][C:11]([CH2:10][N:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: c1cc2n(n1)CCN2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCn2nccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,3-dihydro-1H-imidazo[1,2-b]-pyrazole (19 g) in dimethylsulfoxide (95 ml) were added ethyl bromoacetate (20.4 ml) and potassium bicarbonate (30 g) under ice-cooling. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a mixture of ethyl acetate (1.5 l) and water (500 ml). The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-ethoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (20.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([Cl:12])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:12][C:6]1[C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[C:3]([OH:13])=[CH:4][CH:5]=1
Reactant: Nc1c(O)ccc(Cl)c1C(F)(F)F
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(O)ccc(Cl)c1C(F)(F)F)c1ccncc1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 0.75 g of 2-amino-4-chloro-3-trifluoromethylphenol, 0.84 g of WSC, 0.42 g of isonicotinic acid and 5 ml of pyridine was stirred while heating at 80° C. for three hours. To the reaction mixture, 0.1 g of isonicotinic acid was added, and the reaction mixture was stirred while heating for further three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[3-chloro-6-hydroxy-2-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: CCOCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: O=C(c1cccc(O)c1)c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
26 g of the ether obtained above in (1) and 60 cm3 of chlorobenzene are introduced into a 250 cm3 single-necked flask and 35 g of aluminium chloride are added a little at a time; the reaction mixture is then heated under reflux for 30 minutes, allowed to cool to about 60° C. and then poured onto a mixture of ice and concentrated hydrochloric acid (d=1.18); this mixture is stirred for 1 hour and the solid is then filtered; the latter is washed with petroleum ether to free it from the last traces of chlorobenzene; the phenol thus obtained (20 g) melts at 104° C. and can be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([CH3:7])[S:5][CH2:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].S(Cl)([Cl:15])(=O)=O>ClC1C=CC=CC=1>[ClH:15].[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: COC(=O)C1=C(N)C(C)SC1
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1
Product: COC(=O)c1csc(C)c1N
Product: Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 135.3 %

Procedure:
80.7 g of methyl 4-amino-5-methyl-2,5-dihydrothiophene-3-carboxylate (2) (338 mmol, content: 72.6%) were dissolved in 88 ml of chlorobenzene and cooled to −10° C. A solution of 50.2 g of sulfuryl chloride (372 mmol) in 59 ml of chlorobenzene in the temperature range of −10-0° C. was added dropwise to this solution over a period of 1 h. The reaction mixture was subsequently stirred at −10-0° C. for another 1 h and then warmed to room temperature. For workup, the reaction mixture was concentrated under reduced pressure. 95 g of methyl 4-amino-5-methylthiophene-3-carboxylate hydrochloride (5) were obtained (96% of theory, content: 58.7%, determined as the free amine). The product was characterized after release of the amine with NaHCO3 solution (m.p.: 65° C.; 1H NMR (400 MHz, d3-DMSO): 2.62 (s), 4.25 (s), 5.18 (bs), 8.22 (s)).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(=O)C.[Br:29]Br>>[Br:29][C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH:10]=2
Reactant: BrBr
Reactant: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Solvent: CC(=O)OC(C)C
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
The mixture of isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (84 g, 0.294 mol) and isopropyl acetate (1074 g) was cooled to between −10-0° C. Bromine (50 g, 0.312 mol) was added while the batch was maintained at −10-0° C. The resulting slurry was stirred at the same temperature for additional 30 min and quenched with a pre-cooled solution of sodium thiosulfate pentahydrate (13 g) and triethylamine (64.5 g) in water (240 g) while the temperature was maintained at 0-10° C. The mixture was heated to 40-50° C. and charged with methanol (664 g). After it was stirred at the same temperature for at least 0.5 h, the batch was cooled to 0-10° C. and stirred for another 1 hr. The precipitate was filtered, rinsed with 56 wt % methanol/water solution (322 g), and dried in vacuo (≦200 Torr) at 50-60° C. until the water content was ≦0.4% to give isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate as a beige solid (90-95 g, 80-85% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40](O)=[O:41])[N:34]=1)=[O:31]>C(Cl)Cl>[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]4[NH:13][N:14]=[N:15][N:16]=4)[CH3:10])[CH2:7][S:8][C@H:3]23)=[O:41])[N:34]=1)=[O:31]
Reactant: CON=C(C(=O)O)c1nccc(NC=O)n1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(NC=O)n1
Temperature: 25 °C

Procedure:
On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and trimethylsilylacetamide (11 g.) were added to methylene chloride (66 ml.) and the mixture was stirred at ambient temperature for an hour, and to this solution was added all at once the above activated solution of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid under cooling at -20° C. with stirring, and the stirring was continued at the same temperature for an hour and at ambient temperature for additional an hour. The reaction mixture was concentrated under reduced pressure and then ethyl acetate and an aqueous solution of sodium bicarbonate were added to adjust the solution to pH 7 to 8. After the aqueous layer was separated out, a proper quantity of ethyl acetate was added thereto. The mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid and then salted out. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The resultant foamy substance was pulverised in ethyl ether, collected by filtration and then dried to give 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (2.9 g.). Thus obtained product (0.6 g.) was dissolved in a mixed solution of methanol and ethyl acetate (5 ml.)(2:1 by volume), and the solution was poured into ethyl ether (40 ml.) and then the mixture was allowed to stand for a while. The precipitates were collected by filtration to give purified pale-yellowish powder of 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.5 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: COc1cc(-c2c[nH]c3ncccc23)ccc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(-c2c[nH]c3ncccc23)ccc1C(N)=O
Yield: 93.5 %

Procedure:
The nitrile 30 (10 mg, 40 μmol) was dissolved in dimethyl sulfoxide (0.5 ml). To this was added potassium carbonate (20 mg) and 30% hydrogen peroxide in water (100 μl). The reaction was warmed to approximately 60 C for 15 minutes. The reaction was concentrated to dryness and triturated in water. The resulting precipitate was filtered and dried in-vacuo overnight to give 31 (10 mg, 93%). 1H NMR DMSO-d6 11.99 (s, 1H), 8.32 (d, 1H), 8.24 (m, 1H), 8.01 (m, 1H), 7.88 (d, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.37 (m, 2H), 7.15 (dd, 1H), 4.00 (s, 3H). LC/MS (M+1)=268.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[N:23]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:17])[NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:47][CH:46]3[CH2:44][CH2:45]3)=[CH:26][N:25]=2)[N:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid (0.18 g, crude), HATU (0.07 g, 0.18 mmol)), and DIEA (0.1 mL, 0.77 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. then cyclopropylamine (0.030 ml, 0.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. Purification by reverse phase HPLC furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.58-12.57 (d, 1H), 9.03 (s, 1H), 8.72-8.71 (d, 1H), 8.34-8.31 (m, 1H), 8.07-8.00 (m,2H), 7.44-7.38 (m, 2H), 7.22-7.12 (m, 2H), 5.17-4.95 (m, 2H), 4.61-4.55 (m, 1H), 3.59-3.52, (m, 2H), 2.95-2.90 (m,1H), 2.34-2.32 (m, 1H), 2.04-1.92 (m, 3H), 0.80-0.78 (m,4H); MS: 492.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH3:10].[C:11]([C:17](OC)=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:16][O:15][C:13]([C:12]1[CH2:11][C:17](=[O:18])[C:6]2[C:7](=[C:2]([Cl:1])[C:3]([CH3:10])=[C:4]([Cl:9])[CH:5]=2)[N:8]=1)=[O:14]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1c(Cl)ccc(N)c1Cl
Solvent: CO
Product: COC(=O)C1=Nc2c(cc(Cl)c(C)c2Cl)C(=O)C1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of 2,6-dichloro-3-aminotoluene (20.5 g, 0.11 mol) in methanol (300 mL) was added dimethyl acetylenedicarboxylate (15 mL, 0.12 mol) and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to a yellow solid. Diphenyl ether (350 mL) was heated to 230–240° C., and the yellow solid was added to it. The temperature was maintained at 230–240° C. for 20 minutes and the reaction mixture was cooled slowly to ambient temperature and diluted with petroleum ether (1 L). The solid was filtered and washed with hot ethyl acetate to afford a brown solid, 2-(methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 85%); NMR (CDCl3) 2.62 (s, 3), 4.04 (s, 3), 7.02 (s, 1), 8.24 (s, 1) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.Cl.[NH2:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18])[N:7]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)(CC)C(CO)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(CC)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(CO)=NO
Yield: 48.8 %

Procedure:
A suspension of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal=Cl) (2.3 g) in dry ethanol was treated with 3-amino-1-hydroxy-3-spirocyclohexylpropan-2-one oxime hydrochloride (IV) (2.5g) and dry triethylamine (2.7 g) and the mixture was refluxed for 7 h. The reaction mixture was filtered and the solid washed with hot ethanol. The solvent was removed from the filtrate and the resulting yellow oil was triturated with cold water giving a yellow solid which on recrystallisation from water in the presence of charcoal gave the nitropyrimidine (II) (1.85 g; yield 47.4%) as an off-white powder, m.pt >300° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[N:8]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:10]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: Cc1ccc(N)nc1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Product: COc1ccc(-c2cn3cc(C)ccc3n2)cc1OC

Procedure:
The title compound, MS: m/e=269.2 (M+H+), was prepared in accordance with the general method of example 8 from 5-methyl-pyridin-2-ylamine and 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:18][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(O)n2nc(C)nc2n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Temperature: 0 °C
Yield: 33.7 %

Procedure:
To an ice-cooled mixture of 30.5 g (0.15 mole) of 7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 300 ml of phosphorus oxychloride, 18.6 ml (0.15 ml) of N,N-dimethylaniline was added dropwise over 5 minutes and the mixture was stirred under reflux for 1 hour, followed by concentration. The residue obtained was dissolved in 300 ml of chloroform and washed with water, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated and n-hexane was added to the set residue. The crystals were collected by filtration and dried to obtain 11.19 g of the title compound (Yield: 33.7%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](N)C>>[CH2:9]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10])[CH3:11]
Reactant: CCN
Reactant: Cc1c(O)c(=O)ccn1C
Product: CCn1ccc(=O)c(O)c1C

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4-pyridinone was employed, starting with 70% ethylamine (4.6 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (4.2 g). Proton NMR (D20): 7.85 (d, 1H), 6.88 (d, 1H), 4.12 (q, 2H), 2.36 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3].[CH3:15]O>>[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:15])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3]
Reactant: CO
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Agent: Cl
Product: CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 15 °C

Procedure:
Hydrogen chloride was bubbled into a stirred solution of 4-ethoxy-2-hydroxybenzoic acid (10.10 g. 0.554 mol) in methanol (2000 mL) until the solution was saturated. The solution was heated under reflux for 3 days and then cooled to 15° C. This caused the product to crystallize out. The crystals were collected, rinsed with methanol and hexanes, and dried. Methyl 4-ethoxy-2-hydroxybenzoate was obtained as a pale amber solid (49.3 g) melting at 77°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[C@H:11]([CH3:22])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.N.[Li]>C1COCC1.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][C@@H:11]([CH3:22])[C@@H:12]1[OH:21]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]12
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](C)C[C@@H]32)C1
Temperature: -40 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A solution of 10.0 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17β-ol in 200 ml of absolute THF and 20 ml of tert.-butanol is dropped at -50° C. to about 500 ml of ammonia and then combined in incremental portions with 6.3 g of lithium. The mixture is agitated for 3 hours at -40° C., ammonia is allowed to evaporate overnight, the residue is taken up in about 1 liter of water, and extracted with ethyl acetate, thus obtaining 9.6 g of 3-methoxy-16α-methyl-2,5(10)-estradien-17β-ol as an amorphous crude product which is used in the subsequent stage without further purification.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[Br:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Br:21][CH2:22][C:23](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH2:24][OH:25]
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Reactant: O=C(CO)CBr
Solvent: C1CCOC1
Product: OCC(CBr)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-bromo-3-hydroxypropanone under nitrogen to give 2-[[2-bromo-1-(hydroxymethyl)ethylidene]-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OO)=O)[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=CC=1.[OH2:18]>C(Cl)Cl>[CH2:8]([N:12]1[CH2:15][CH2:16][C:17]1=[O:18])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccncc1
Reactant: O
Solvent: ClCCl
Product: O=C1CCN1Cc1ccccc1
Reaction time: 0.67 h

Procedure:
N-benzyl-2-azetidine carboxylic acid (2 mmol) was added slowly to excess oxalyl chloride at 0 degrees followed by gradual warming to 45 degrees (10 min.). The clear solution was then poured into cold, anhydrous ether, acidified with 10 drops of 70% perchloric acid and filtered to give N-benzyl-2-azetidinium perchlorate (95%). A suspension of this iminium salt in 10 ml of methylene chloride at 0 degrees was treated with 1 equivalent of 100% m-chloroperbenzoic acid followed by 2 equivalents of pyridine. The resulting reaction mixture was stirred for 40 min. and then poured into water. The organic layer was separated, washed with 5% NaHCO3 and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded N-benzyl-2-azetidinone as the sole product (70%).