Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][CH:14]1[CH2:19][NH:18][CH2:17][CH:16]([CH3:20])[NH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([N:18]2[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]2)[CH:7]=1
Reactant: CC1CNCC(C)N1
Reactant: FC(F)(F)c1cnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cc(Cl)c(C(F)(F)F)cn2)C[C@H](C)N1
Temperature: 140 °C

Procedure:
2,4-dichloro-5-(trifluoromethyl)pyridine (800 mg, 3.70 mmol), 2,6-dimethylpiperazine (800 mg, 7.14 mmol), and K2CO3 (1.0 g, 7.25 mmol) were added to dimethylformamide (15 mL). The resulting solution was heated for 2 h at 140° C. The reaction mixture was then quenched by the adding 50 mL of ice-water and extracted with EtOAc (50 mL). The organic layers were combined and dried over MgSO4. The solvent was concentrated and the residue was purified using silica gel column chromatography to 0.2 g (18%) of 1-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-cis-3,5-dimethylpiperazine.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[N:21]=[C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])[CH:19]=[CH:18][CH:17]=1)[CH3:14].[NH3:27]>>[NH2:27][C:3]1[C:7]([NH:26][CH2:25][CH2:24][S:23][CH2:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[N:21]=2)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: N
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1cccc(CSCCN)n1
Product: CN(C)Cc1cccc(CSCCNC2=NS(=O)(=O)N=C2N)n1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared in Example 136, Step C] and excess ammonia, the title compound is thereby produced.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([Br:16])[C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)Cc1ccc(OC(C)C)c(Br)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 100 mg (0.369 mmol) of 1-(3-bromo-4-isopropoxyphenyl)acetone (from Example 228, Step C) in toluene (0.26 mL) was added bromine (0.019 mL, 0.369 mmol) dropwise via syringe. After stirring 30 min. At RT, a solution of sodium sulfite (676 mg) in water (1.5 mL)) was added and the mixture was extracted with 3×15 mL of ethyl ether. The combined organic layers were washed 20 mL of saturated sodium bicarbonate followed by 20 mL of brine. Drying over sodium sulfate and evaporation gave 119 mg of product as a red oil. Mass spectrum (NH3/CI): m/z=349 (M+1)
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:11]([F:23])[CH:10]=2)[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3]1.C(O)(=O)C.[CH:33](N)=[NH:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[NH2:8][C:7]1[C:6]2=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:11]([F:23])[CH:10]=3)[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3][N:2]2[N:1]=[CH:33][N:34]=1
Reactant: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Reactant: N=CN
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A mixture of ethyl 1-amino-4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate (18.06 g, 46.5 mmol), formamidine acetate (48.41 g, 464.9 mmol) and finely ground potassium phosphate (19.74 g, 93.0 mmol) in ethanol (350 mL) was heated at 80° C. overnight. After 16 h, the reaction mixture was cooled to rt and diluted with 1.8 L water. The resulting precipitate was filtered thru a glass frit and washed with water. Drying in a vacuum oven provided the title compound as a gray solid (15.6 g, 80.8%) 1H-NMR (DMSO-d6) δ 9.11 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=8 Hz, 1H), 7.26 (dd, J=12, 2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.07 (q, J=7 Hz, 2H), 1.47 (s, 9H), 1.09 (t, J=7 Hz, 3H); MS [M+H]+ 415.8=;. LCMS RT=3.05.
Reaction SMILES: Cl.[NH2:2][OH:3].[H-].[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:37])([CH3:36])[N:25]([CH3:35])[CH:26]([C:27]5[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1>CN(C=O)C>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:36])([CH3:37])[N:25]([CH3:35])[CH:26]([C:27]5[CH:28]=[CH:29][C:30]([C:31](=[NH:32])[NH:2][OH:3])=[CH:33][CH:34]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: NO
Reactant: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C#N)cc1)N(C)C2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C(=N)NO)cc1)N(C)C2(C)C
Temperature: 0 °C
Reaction time: 120 h
Yield: 66 %

Procedure:
841 mg (12.12 mmol) of hydroxylamine hydrochloride are suspended in 4 ml of DMF and cooled to 0° C. 303 mg (10.1 mmol) of 80% sodium hydride are added slowly. 500 mg (1.13 mmol) of (1RS,3aSR,4RS,6aSR)-4-(5-benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo-[3,4-c]pyrrol-1-yl)-benzonitrile are dissolved in DMF and added to the reaction mixture. The cooling is thereafter no longer applied. The mixture is stirred at room temperature for 5 days. Thereafter, it is filtered and the solvent is removed in a high vacuum. The mixture is purified by chromatography (RP18, gradient from water to methanol). (1RS,3aSR,4RS,6aSR)-4-(5-Benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-N-hydroxy-benzimidamide is isolated in 66% yield. Colourless solid. ISP-MS: 479.4 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([NH2:28])=[O:27])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C(N)=O)c4)nc(Cl)nc32)cc1
Yield: 33.2 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.580 mmol), 3-aminobenzamide (83 mg, 0.61 mmol) and triethylamine (0.200 mL, 1.44 mmol) in dioxane (5 mL) was stirred at 110° C. for 20 h. It was concentrated in vacuo. After the residue was acidified with HOAc (1 mL), it was purified by HPLC to give 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (85 mg).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=CC=CC=2)[N:8]2[CH:15]=N[C:17]([C:18](OCC)=O)=[C:7]2[C:6]1=[O:23])(C)(C)C.[N+:24](CC(OCC)=O)#[C-].[C:32]([N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][C:38](=O)[C:37]1=[O:47])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]2[CH:15]=[N:8][C:9]([C:14]3[N:5]=[C:6]([CH:7]4[CH2:17][CH2:18]4)[O:23][N:24]=3)=[C:38]2[C:37]1=[O:47])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)(C)n1c(=O)c(=O)[nH]c2ccccc21
Product: CC(C)(C)n1c(=O)c2c(-c3noc(C4CC4)n3)ncn2c2ccccc21

Procedure:
Ethyl 5-tert-butyl-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline-3-carboxylate, m.p. 289°-290° C. by reaction between ethyl isocyanoacetate and 1-tert-butyl-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline
Reaction SMILES: [C:1]([O:5][CH:6](Cl)[CH:7]([CH3:9])[CH3:8])(=[O:4])[CH2:2][CH3:3].[C:11]1([NH:17][C:18](=[O:54])[C@H:19]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:20][C:21](=[O:49])[CH:22]([CH2:31][P:32]([CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])([OH:34])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[I-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.C(OCC)(=O)C>[C:11]1([NH:17][C:18](=[O:54])[C@H:19]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:20][C:21](=[O:49])[CH:22]([CH2:31][P:32]([CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])([O:34][CH:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:7]([CH3:9])[CH3:8])=[O:33])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)OC(Cl)C(C)C
Reactant: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(=O)(O)CCCCN1Cc2ccccc2C1=O)C(=O)Nc1ccccc1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCC(=O)OC(OP(=O)(CCCCN1Cc2ccccc2C1=O)CC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 32 %

Procedure:
1-Chloroisobutyl propionate (0.20 mL) was added to a mixture of 4 Å molecular sieves (125 mg), tetra-n-hexylammonium iodide (40 mg, 0.083 mmol), and (2-(((4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide (50 mg, 0.081 mmol).6The mixture was warmed in an oil bath at 65°-70° C. for 7 h, then allowed to stand at room temperature overnight. The mixture was diluted into ethyl acetate (25 mL) and washed with 2N aqueous hydrochloric acid (25 mL) and saturated aqueous sodium chloride, and the organic layer was dried (sodium sulfate), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel (3 g) eluting with 20% acetone/dichloromethane to give 19 mg.(32% yield) of (2-(((4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)butyl)(2-methyl-1-(1-oxopropoxy)propoxy)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([I:13])[CH:7]=[C:8]([F:12])[C:9]=2[Cl:11])[C:4](=[O:14])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([I:13])=[C:5]2[C:10]=1[CH2:2][NH:3][C:4]2=[O:14]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(F)c(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2c(Cl)c(F)cc(I)c21
Yield: 84.6 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-4-chloro-5-fluoro-7-iodo-2(1-methyl-1-phenylethyl)isoindolinone (806 mg, 1.81 mmol) was dissolved in nitromethane (32 mL), and the solution was treated with trifluoroacetic acid (1.40 mL, 18.1 mmol) and triethylsilane (0.578 mL, 3.62 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-fluoro-7-iodoisoindolinone (477 mg, yield 85%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.15 g) is reacted with aniline following the procedure outlined in example 10 and reduced with lithium aluminum hydride (0.15 g) in THF at room temperature. Aqueous work-up and. crystallization from methanol gives 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-phenylamino-5α-chola-8,14-dien (106 mg). 1H-NMR (CDCl3, 300 MHz)): δ=7.17 (2H, t); 6.69 (1H, t); 6.6 (2H, d); 5.35 (1H, s); 3.6 (1H, s); 3.2 (1H, m); 3.09 (2H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[OH:13].[Br:14][CH2:15][CH:16](OC)OC.C1COCC1.OS(O)(=O)=O>O.CCOC(C)=O>[Br:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: CS(=O)(=O)c1ccc(CO)c(O)c1
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Yield: 179.8 %

Procedure:
2-(hydroxymethyl)-5-(methylsulfonyl)phenol (3.3 g, 16.3 mmol), 2-bromo-1,1-dimethoxyethane (19.0 ml, 163 mmol), dry THF (30 ml) and concentrated H2SO4 (5 ml) were heated at 55° C. for 1 h. The reaction mixture was brought to ambient temperature and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give an oil (9.0 g). The oil was crystallizing upon cooling. The product was washed with EtOAc, EtOH and DEE and afforded the pure title compound (4.0 g, 80%). MS m/z (rel. intensity, 70 eV) 308 (M+, 11), 306 (M+, 10), 213 (45), 184 (bp), 77 (35).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[OH-:16].[K+].[CH3:18]O>CS(C)=O>[CH3:18][O:16][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (4.61 g, 19.2 mmol) and KOH (2.78 g, 42.2 mmol) in MeOH (20 mL) and DMSO (40 mL) according to the general procedure E. Obtained as a yellow solid (4.18 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:44])[C@@H:4]2[CH:19]([NH:20][C:21](=[O:42])[CH:22]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[C:28](=[O:34])[C:27]3=[O:35])=[O:25])[C:18](=[O:43])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].S1[C@@H]2CC(=O)N2C=CC1.O1CCCC1.C(O)(=O)C>[Zn].CCOCC>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])=[O:8])[N:5]2[C:18](=[O:43])[CH:19]([NH:20][C:21](=[O:42])[CH:22]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[C:28](=[O:34])[C:27]3=[O:35])=[O:25])[C@H:4]2[C:3]1=[O:44]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCOC(=O)C(C)(C)C)=C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Agent: O=C1C[C@H]2SCC=CN12
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pivaloyloxymethyl 2-methyl-1-oxo-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapen-2-em-3-carboxylate [freshly prepared according to Example 28 from 127 mg. (0.19 mmole) of the ceph-3-em precursor] was taken up in a minimum of tetrahydrofuran and added to a slurry of activated zinc powder (1.27 g.) in a mixture of 26 ml. of acetic acid and 12 ml. of tetrahydrofuran at 0° C. Stirring at 0° C. was continued for 1 hour. Product was isolated according to procedures detailed in Example 2, followed by trituration with ether, yielding pivaloyloxymethyl 2-methyl-1-oxo-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate [30 mg.; Rf 0.91 (ethyl acetate)]. An additional 13 mg. of less pure product was obtained by evaporation of the ether triturate to dryness.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:30])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:9]=2[N:10]=1)[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:11][C:9]=2[N:10]=1)=[O:30])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3cc(C)ccn3)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude Trifluoro-methanesulfonic acid 2-(3-ethyl-ureido)-7-(4-methyl-pyridin-2-yl)-benzothiazol-5-yl ester (44 mg, 0.096 mmol), 3-pyridineboronic acid (13 mg, 0.106 mmol), powdered potassium phosphate tribasic (25 mg, 0.115 mmol), anhydrous 1,4-dioxane (0.7 ml) and anhydrous methanol (1.2 ml) was purged with nitrogen for 15 min. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex (12 mg, 0.0144 mmol) was added and the mixture heated at 80° C. for 16 h under an atmosphere of nitrogen. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-Ethyl-3-[7-(4-methyl-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]urea.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](=[N:47][NH2:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOCC.O.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[NH:48][N:47]=[C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(NN=C(c2ccccc2)c2ccccc2)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
Put 2 g (4 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate in 10 mL of anhydrous toluene in a screw-top bottle. To the solution, under argon, add successively 938 mg (4.78 mmol) of benzophenone hydrazone, 1.95 g (6 mmol) of caesium carbonate and 65 mg (0.08 mmol) of PdCl2 (dppf). Heat the reaction mixture for 3 h at 90° C. while stirring, then distribute in 100 mL of ether/water 1:1 mixture. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/acetone gradient from 0 to 5% of acetone. After concentration under reduced pressure, we obtain 1.94 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3N)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]C1N=CN=C2C=1NC=N2.C(C1C=CC(CCl)=CC=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[Cl:26])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1ncnc2c1ncn2Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C(c1ccccc1)c1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Cn2cnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
The synthesis of 9-(4-benzoylbenzyl) -9H-adenine (20) was achieved by the following procedure (Scheme 9). A mixture of 6-chloropurine (3.09 g, 20 mmol), 4-benzoyl-benzyl chloride (6.05 g, 22 mmol)and K2CO3 (3.04 g, 22 mmol) in DMF (50 ml) was stirred overnight at rt, diluted with water (400 ml), and extracted with EtOAc (3×100 ml) (Scheme 9)52. The combined organic layers were washed with water and brine, dried over MgSO4, concentrated in vacuo, and subjected to flash-chromatography on silica gel eluting with CH2Cl2 -acetone (80:20). The fractions containing the higher Rf, the major component, were combined and concentrated in vacuo to give 2.86 g (41%) of 9-(4-benzoylbenzyl)-6-chloro-9H-purine. To a solution of this iminochloride (1.05 g, 3 mmol) in EtOH (20 ml) was added a 2M solution of NH3 in MeOH. This medium was warmed overnight at 90° C. under pressure (constant volume). It was then cooled and concentrated in vacuo. The residue was washed successively with a 1M solution of NaHCO3, water, iPrOH, and hot CH2Cl2, and then was recrystallized from butanol to give 0.53 g (54%) of 9-(4-benzoylbenzyl)-9H-adenine (20). 1H NMR (DMSO) δ 5.49 (s, 2H, CH2), 7.27-7.71 (m, 9H, H-Ar), 8.15 (s, 1H, H-2), 8.30 (s, 1H, H-8). ##STR10## Synthesis of 9-[(4-bis-phenyl)buten-4-yl]-9H-adenine (21)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:21]([N:28]1[C:32](=[O:33])[CH:31]=[CH:30][C:29]1=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C.CO>[C:10]([OH:12])(=[O:11])[CH3:2].[CH2:21]([N:28]1[C:32](=[O:33])[CH:31]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:8])=[NH:9])([C:10]([OH:12])=[O:11])[CH:30]2[C:29]1=[O:34])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCCC1(C(=O)O)NC(c2ccccc2)C2C(=O)N(Cc3ccccc3)C(=O)C21
Yield: 107.3 %

Procedure:
871 mg (5 mmol) of arginine, 530 mg (5 mmol) of benzaldehyde, 1.122 g (6 mmol) of N-benzylmaleimide and 25 drops of acetic acid were heated under reflux in 25 ml of methanol for 60 hours. After cooling the colourless precipitate was filtered off under suction and washed with ether. 1.367 g of (1RS,3SR,3aRS,6aSR)-5-benzyl-1-(3-guanidino-propyl)-4,6-dioxo-octahydro-3-phenyl-pyrrolo[3,4-c]-pyrrole-1-carboxylic acid acetate (54%) were isolated as a colourless powder. M.p.: from 195° C. decomposition. ISP-MS: 450.4 ([M+H]+, 100).