Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:2].[N:29]1C2C(=NC=CC=2)N(O)N=1.CCN=C=NCCCN(C)C.N>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23]([O:24][CH2:25][CH3:26])=[O:27])[C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:19]([NH2:29])=[O:21])[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2nc(C(=O)O)cs2)ccc1C
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2nc(C(N)=O)cs2)ccc1C
Reaction time: 1.17 h
Yield: 92.3 %

Procedure:
The compound (4.59 g, 11.3 mmol) of step A was dissolved in N,N-dimethylformamide (60 ml), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.97 g, 14.5 mmol) and WSC (2.80 g, 14.6 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 70 min. Then, to the reaction mixture was added 28% aqueous ammonia (10 ml), and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with a diethyl ether-hexane=1:1 mixed solvent, and dried under reduced pressure to give the title compound (4.23 g, yield 92%) as a colorless solid.
Reaction SMILES: CCOCC.O[CH:7]([CH2:17][C:18]([CH2:21][Si](C)(C)C)=[C:19]=[CH2:20])[CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:21]=[C:18]1[C:19](=[CH2:20])[C:10]23[O:16][CH:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:17]1
Reactant: C=C=C(CC(O)CC1CCCCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CC2CC3CCCCCC3(O2)C1=C
Temperature: -78 °C
Yield: 90.2 %

Procedure:
1.30 mL of ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cycloheptanone (95 mg, 0.32 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (58.4 μL, 0.32 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 59 mg of the product (90%).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([NH:18][NH2:19])=O>CO>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[NH:19][N:18]=1
Reactant: NNC(=O)c1cnccn1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: CO
Product: c1cc(-c2nc(-c3cnccn3)n[nH]2)ccn1
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
Sodium (0.4 grams) is added to pyridine-4-carbonitrile (8.3 grams, 0.08 mole) in methanol, and the solution is allowed to stand 30 minutes at room temperature. A suspension of pyrazine carboxylic acid hydrazide (9.6 grams, 0.07 mole) in methanol (160 ml.) is added, and the resulting solution is heated at reflux for 30 minutes. After cooling, the intermediate acylamidrazone is collected by filtration. The acyclic intermediate is then heated at 260° C. for 15 minutes, after which the reaction is cooled to room temperature. Upon recrystallization from acetonitrile-water, 3-pyrazinyl-5-(4-pyridyl)-1,2,4-triazole is obtained, m.p. 251°-252.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)=[N:19][CH:20]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: Clc1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccc(Cl)cn3)CC2)cc1
Yield: 113.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5 g), 1-(5-chloropyridin-2-yl)piperazine (1.5 g) and potassium carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at 70-80° C. for 8.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (3.1 g). The obtained brown solid was crystallized ethyl acetate to give the title compound (1.3 g) as pale-yellow crystals,
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].O=O.[CH3:8]OC.[C:11]([O:14]C)(=[O:13])[CH3:12].[CH3:16]OC.O=O.N#N>>[C:1]([O:4][CH3:5])(=[O:3])[CH:2]=[CH2:8].[C:11]([OH:14])(=[O:13])[CH:12]=[CH2:16]
Reactant: COC
Reactant: COC(C)=O
Agent: N#N
Agent: O=O
Product: C=CC(=O)O
Product: C=CC(=O)OC
Reaction time: 0 h
Yield: 4.6 %

Procedure:
The reactor was charged with a catalyst having the composition 50% K0.4 Ce0.58 Cu0.58 POx +50% Al2O3 (see Example 7). The testing procedure was essentially the same as that of Examples 2-10, except that the liquid feed consisted of methyl acetate alone, while the gaseous feed consisted of oxygen, nitrogen, and dimethyl ether. The composition of the gaseous feed and the respective flow rates of the liquid and the gaseous feeds were such that a reactant ratio methyl acetate/dimethyl ether/O2 /N2 =10/0.5/0.8/7.2 was obtained, and the average residence time in the reactor was 10 seconds. At the reaction temperature of 330° C., 45.2% ppc of methyl acrylate and 4.6% ppc acrylic acid were obtained, resulting in 49.8% ppc to total product. At 350° C. the yields were 82.1% ppc to methyl acrylate and 13.6% ppc to acrylic acid, resulting in 95.7% ppc to total product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
4-Aminopyridine (1.94 g, 20.6 mmol) was added to a solution of p-anisoyl chloride (3.5 g, 20.6 mmol) and triethylamine (8.6 mL, 62 mmol) in dichloromethane (100 mL) at 0° C. The mixture was stirred 3 h at RT, and then extracted successively with 1N NaOH, water and brine, dried over sodium sulfate, and concentrated. Chromatography on silica (gradient of 30% to 100% ethyl acetate-hexanes) gave 3.8 g (81%) of a colorless solid. 1H NMR (CDCl3, 400 mHz) δ 8.49 (m, 2H), 8.19 (br, 1H), 7.85 (m, 2H), 7.59 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H). MS (AP+) 229 (MH+).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].NN.[OH-].[K+].C(O)COCCOCCO>O>[CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)c1ccccn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCCCCCCCCCCc1ccccn1
Reaction time: 7 h
Yield: 58.6 %

Procedure:
A mixture of 21.5 g (87 mmol) of 2-n-undecanoylpyridine, 13.7 g (0.27 mol) of hydrazine.monohydrate, 10.1 g (0.18 mol) of potassium hydroxide, and 50 ml of triethylene glycol was heated at 110° to 125° C. for one hour, and further, at 180° to 185° C. for 7 hours. After cooling, 400 ml of water was added, the mixture was extracted with diethyl ether, washed with water and dried over anhydrous potassium carbonate. After concentration under a reduced pressure, the residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:9), and further, purified by distillation under a reduced pressure to give 11.9 g of the desired product (yield 58.7%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:12][OH:13].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:9]([O:8][CH3:7])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: COc1cc(COCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred suspension of finely powdered cesium carbonate (8.0 g, 24.5 mmol) was added 3-methoxy-4-nitrobenzyl alcohol (1.5 g, 8.18 mmol), followed by benzyl bromide, (2 mL, 16.4 mmol). After stirring at room temperature for 18 h, the suspension diluted with 100 mL diethyl ether, and washed with 3×50 mL water, then 50 mL brine. The organic phase was dried over MgSO4, filtered through a plug of silica, and concentrated. The resulting orange oil was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to give 1.87 g, (84%) of the benzyl ether. 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J=8.2 Hz, 1H) 7.3-7.4 (m, 5H), 7.26 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 4.59 (s, 2H), 3.96 (s, 3H).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:34]([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:35]1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OCC1CCNC1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCC(CO)C2)c(C(=O)O)c1
Yield: 25 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and rac-pyrrolidin-3-yl-methanol and obtained in 25% yield. MS (m/e): 313.0 MH−(100%).
Reaction SMILES: N[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(=O)O)c1Br
Temperature: 60 °C
Yield: 74 %

Procedure:
To 2-amino-3-(methyloxy)benzoic acid (4.00 g, 23.9 mmol) in 10% aqueous hydrobromic acid (54 ml) at 0° C. was added sodium nitrite (1.65 g, 23.9 mmol) in water (17 ml). To this solution was added dropwise a solution of copper (I) bromide (3.78 g, 26.3 mmol) in 48% hydrobromic acid (22 ml) and heated to 60° C. for 2 h. The mixture was cooled to 0° C., and the resultant precipitate was collected by filtration, washed with cold water and recrystallized from water to give pure 2-bromo-3-(methyloxy)benzoic acid (4.07 g, 74%). MS (EI) for C8H7BrO3: 232 (MH+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][CH:6]([CH3:14])[C:7](=O)[CH2:8][C:9](OC)=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>O.CO>[CH:6]([C:7]1[N:4]=[C:2]([SH:3])[N:1]=[C:9]([OH:10])[CH:8]=1)([CH3:14])[CH3:5]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(O)nc(S)n1
Temperature: 105 °C
Yield: 67.8 %

Procedure:
Thiourea (1.0 g, 13 mmol) was dissolved in 1.6 mL of water at 70° C. Methyl 4-methyl-3-oxopentanoate (2.8 g, 20 mmol) was added and followed by K2CO3 (2.7 g, 19 mmol). The reaction was heated at 105° C. open to air for 1 hour to boil off any remaining methanol. After being cooled to room temperature, water (6.6 mL) was added and followed by 6 mL of concentrated HCl. The white precipitate was collected by filtration and washed with water and 1 N HCl to afford 6-isopropyl-2-mercaptopyrimidin-4-ol as a white solid (1.5 g, yield: 46%). 1H NMR (400 MHz, DMSO-d6): δ 12.34 (s, 1H), 12.19 (s, 1H), 5.67 (s, 1H), 2.66 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). LCMS (ESI) m/z: 171.0 [M+H+].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-:12].[Na+].O(CCCC[O:25][C:26]1C=CC=CC=1)C1C=CC=CC=1>>[OH:11][C:2]1[C:3]([C:26]([OH:25])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: c1ccc(OCCCCOc2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 260 °C
Yield: 77 %

Procedure:
A stirred autoclave is charged with 1220 parts of β-naphthol, 620 parts of caustic soda solution of 50% by weight strength and 360 parts of 1,4-diphenoxybutane. As described in Example 4 the autoclave is heated to an internal temperature of 260° C. while stirring and kept at this temperature for ten minutes. Residual moisture is removed from the autoclave for five minutes at a pressure of 40 mm. Dehydration is practically complete. Carbon dioxide is then passed into the autoclave at the internal temperature of 260° C. up to a pressure of 7 atmospheres. Carboxylation followed by processing are carried out analogously to Example 4. The mixture of organic phase and aqueous phase is acidified to pH about 5 at a temperature of 95° C. with vigorous stirring so that the β-naphthol liberated is taken up by the solvent. The organic phase is separated from the aqueous layer. The clear aqueous phase is heated to 85° to 90° C., acidified with hydrochloric acid to pH about 3 and stirred for another 10 minutes. After cooling to 50° C. the yellowish crystals of 2-hydroxynaphthalene-3-carboxylic acid are suction filtered and dried in vacuo at 70° C. 560 parts of 2-hydroxynaphthalene-3-carboxylic acid (77% of theory based on β-naphthol reacted) is obtained with a melting point of 214° to 217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5].[CH2:16]([NH2:20])[CH2:17]CC.FC1C=[CH:24][C:25]2[NH:30]C(=O)OC(=O)C=2C=1>>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:2]=1[NH:1][CH2:24][C:25]1[NH:30][CH2:17][CH2:16][N:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNC(=O)c1cc(F)ccc1N
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CCCCN
Product: CCCCNC(=O)c1cc(F)ccc1NCC1=NCCN1

Procedure:
2-Amino-N-butyl-5-fluorobenzamide (prepared from butylamine and 6-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-butyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-5-fluorobenzamide, isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-piperidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 98-100° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (bs, 6 H), 2.06 (s, 2 H), 2.33 (s, 4 H), 2.55-2.94 (m, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.20-6.35 (bd, 1 H), 6.95 (s, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.61 (m, 3H), 7.81-7.83 (m, 1 H), 8.00 (d, J=8.4 Hz, 1 H), 8.23 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[C:20]2[C:27]([CH3:28])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1>C(O)(C)C>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:19]1[C:20]2[C:27]([CH3:28])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3C[C@@H](C)NC[C@@H]3C)c12
Temperature: 150 °C
Yield: 13.9 %

Procedure:
Trans-2,5-dimethylpiperazine (1 g, 8.8 mmol), N,N-diisopropylethylamine (1 ml) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 11.9 mmol) were added to isopropanol (10 ml). The solution was heated in a microwave at 150° C. for 6 hours, then concentrated under vacuum. The material was purified by prep HPLC (Sunfire C18 30×250 mm column. 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min.) to give 4-(trans-2,5-dimethylpiperazin-1-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 14%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]([CH:82]3[CH2:84][CH2:83]3)[C:69]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=3)=[O:70])[CH2:63]2)=[O:61])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]([CH:82]5[CH2:83][CH2:84]5)[C:69]([O:71][CH2:72][C:73]5[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=5)=[O:70])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C2CC2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C5CC5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 369 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.66 g) in anhydrous acetonitrile (7 ml), N,N-diisopropylethylamine (0.19 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(N-cyclopropyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.14 g) in anhydrous acetonitrile (8 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=95/5), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(N-cyclopropyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.80 g) was obtained.
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=O)[O:4][CH3:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[S:29])[O:4][CH3:5])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CCP(=S)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by preparative thin-layer chromatography (on silica gel, eluting with 20% ethyl acetate/hexane) to give O-methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: C(OC([O:6][C:7]1[CH:30]=[CH:29][C:10]([CH:11]=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=O)C.N1CCCC1>C(Cl)(Cl)Cl>[OH:6][C:7]1[CH:30]=[CH:29][C:10]([CH:11]=[CH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCNC1
Product: O=C(C=Cc1ccc(O)cc1)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
The piperazine compound was dissolved in 150 ml of chloroform, and to the solution was added 2.30 g of pyrrolidine. The resultant mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and the residue was subjected to chromatography using a silica gel column and purified with a mixed solvent of chloroform and methanol (10:1), thereby obtaining 11.1 g (a stoichiometric amount) of 1-(4-hydroxycinnamoyl)-4-(pyrrolidinocarbonylmethyl)piperazine as a colorless oily substance.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([NH:20][C@@H:21]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:25][N:24]=2)[CH3:22])(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16].O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([N:20]([C@@H:21]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[N:25][N:24]=2)[CH3:22])[CH3:1])(=[O:18])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](C)N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
K2CO3 (78 mg) and MeI (0.022 ml) were added at room temperature to a solution of Compound 12 (150 mg) of Example 1 in dimethylformamide (2.0 ml), and the mixture was stirred at room temperature for three hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform=1/4). The resulting organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and evaporated under reduced pressure to remove the solvent. After eluting the residue with a mixed solvent of ethyl acetate and hexane, the resulting elute was purified by column chromatography (acidic OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-10%) and then recrystallized (ethyl acetate-hexane) to give 111 mg of the titled compound as a colorless powdered compound.