Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4](=[O:13])[CH2:3]1.[OH-].[CH2:15]([N+:22](C)(C)C)[C:16]1C=CC=C[CH:17]=1.C(#N)C=C.Cl>O.N1C=CC=CC=1>[C:15]([CH2:16][CH2:17][N:5]1[C:4](=[O:13])[CH2:3][CH:2]([CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6]1)#[N:22]
Reactant: CC1CC(=O)NCc2ccccc21
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C=CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC1CC(=O)N(CCC#N)Cc2ccccc21
Temperature: 80 °C

Procedure:
To a mixture of 6 g. (0.034 moles) of 5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one and 4 drops of Triton B (benzyltrimethylammonium hydroxide) in 10 ml. of pyridine, are added dropwise 2 g. (0.038 moles) of acrylonitrile dissolved in 2.5 ml. of pyridine. The reaction mixture is heated to 80° C. for 2 hours and then poured into iced water. It is acidified with hydrochloric acid to pH 4 and extracted with chloroform. The organic phase is washed neutral with water and then dried over anhydrous sodium sulfate. It is filtered and the solvent is evaporated off in vacuo. 8 g. (almost theoretical yield) of syrupy 2-(2-cyanoethyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[N:13]=[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[N+:31]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.C1COCC1.[Zn]>[NH2:31][C:11]1[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:13][C:14]([NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])=[N:15][C:10]=1[NH:9][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[NH:8][N:7]=1
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of (S)-ethyl 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitropyrimidine-4-carboxylate (Method 10; 0.7 g, 1.5 mmol) and zinc dust (0.5 g, 7.7 mmol) in EtOH:THF (1:1, 20 ml) was slowly added saturated aqueous NH4Cl solution (3 ml). After 1 hour, the reaction mixture was cooled to 0° C., to which was added saturated NH4OAc solution (10 ml). The resulting mixture was allowed to stir for 10 minutes at 0° C. and then filtered through a plug of celite with EtOAc (100 ml). The resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give the title compound (0.60 g, 92%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[NH:10][C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6].[CH2:27]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH3:27])[C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6]
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Yield: 78 %

Procedure:
(3R)-4-(2,4-Dimethoxybenzoyl)-3-ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 18) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-4-(2,4-dimethoxybenzoyl)-3-ethyl-6-fluoro-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (78%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 72 h
Yield: 98.3 %

Procedure:
(60 g (0.3 mol) of 4-hydroxybenzophenone, 42 g of benzyl chloride, 45.6 g of potassium carbonate, 0.5 g of potassium iodide and 1 litre of dimethylformamide are introduced into a flask. Stirring is carried out at room temperature for 72 hours. The mixture is filtered and concentrated to dryness without exceeding 30° C. The residue is taken up in methylene chloride and washed with a 10% sodium carbonate solution and then with a saturated lithium chloride solution. The mixture is dried over sodium sulphate and concentrated to dryness. There are obtained 85 g of 4-benzyloxybenzophenone. Yield: 99%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:32]([CH2:39][C@:40]([OH:44])([CH3:43])[CH2:41][OH:42])[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:42][CH2:41][C@@:40]([OH:44])([CH3:43])[CH2:39][N:32]3[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=[C:31]3[Cl:30])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@](O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 8.5 h
Yield: 90.7 %

Procedure:
4-(4-Trifluoromethoxyphenyl)piperazine-1-carbonylchloride (1.25 g, 4.2 mmol), N,N-diisopropylethylamine (0.96 ml, 5.6 mmol) and 4-dimethylaminopyridine (67 mg, 0.56 mmol) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (0.65 g, 2.8 mmol) in toluene (13 ml) followed by stirring at 100° C. for 8.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=19/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (1.29 g, yield 92%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:23][CH3:24])[N:15]=[CH:14][N:13]=[C:12]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1cc2ncnc(Cl)c2cc1Cl
Reactant: Clc1ccc2c(c1)NCC2
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1Cl
Yield: 17 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 17% yield from 6-chloro-indoline and 4,6-dichloro-7-methoxy-quinazoline. (M.P. 226° C.; LC-MS: 346 (MH+)).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[N:3]=1.O.NN>[Ni].C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CC#N)cn2)c(C)c1-c1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2ccc(CCN)cn2)c(C)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of [6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]acetonitrile (step 3, 633 mg, 2.20 mmol), Raney Ni (W2, 0.5 g), hydrazine monohydrate (1.1 mL, 22.0 mmol), and ethanol (20 mL) was stirred at 60° C. for 6 h. After cooling to room temperature, the mixture was filtered through a bed of celite. The filtrate was evaporated to afford 642 mg (quant.) of title compound: MS (ESI) m/z 293 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)[C:9]([C:24]#[N:25])=[C:8]([S:26]C2C=CC=CC=2)[N:7]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)[C:9]([C:24]#[N:25])=[C:8]([SH:26])[N:7]=1
Reactant: N#Cc1c(NOCCO)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: N#Cc1c(S)nc(NOCCO)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.30 g (0.70 mmol) of the compound from Example 31A is dissolved in 2 ml of DMF, and 0.19 g (2.43 mmol) of sodium sulphide is added. The mixture is stirred at 80° C. for 2 h and then at RT for 12 h. 1N hydrochloric acid (10 ml) is then added, and the precipitate is filtered off.
Reaction SMILES: [O:1]=[C:2]1[C:6](=O)[CH2:5][C:4](=[O:8])[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[H][H]>[Pd].C(O)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:8])[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCCCCCC1C(=O)CC(=O)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCC1C(=O)CCC1=O

Procedure:
A mixture containing 45.7 parts of 2,3,5-trioxocyclopentaneheptanoic acid, 13 parts of 5% palladium-on-carbon catalyst, 453 parts of glacial acetic acid and 63.3 parts of concentrated sulfuric acid is shaken with hydrogen at a pressure of 3 atmospheres until 2 molecular equivalents of hydrogen are absorbed. The reaction mixture is then filtered and the resulting filtrate is mixed with 100 parts of solid sodium acetate. Evaporation of the mixture to dryness affords a solid residue which is extracted with water. The resulting extract is filtered and the filter cake is washed with water, dried, then recrystallized from acetone to afford white crystals of 2,5-dioxocyclopentaneheptanoic acid, melting at about 160°-161.5°.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:12](Cl)[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]>>[C:1]1([CH:12]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)CC[Si](Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 36.0 ml (405 mmol) of benzene and 0.53 g (4.0 mmol) of aluminum chloride were alkylated with 10.08 g (41.0 mmol) of (3,3-dichloropropyl)trichlorosilane. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 6.76 g of (3,3-diphenylpropyl)trichlorosilane (bp; 124-125° C./0.5 torr, yield; 50%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:8]=1)#[N:2].[CH2:21]=[O:22].O>C(O)=O>[C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([N:9]([CH2:21][OH:22])[C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:8]=1)#[N:2]
Reactant: N#Cc1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Reactant: C=O
Solvent: O=CO
Solvent: O
Product: N#Cc1cn(N(CO)c2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
Two grams of 5-cyano-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione is added to 1.6 ml of 35% formaldehyde in enough 95% formic acid to effect stirring. The mixture is heated to reflux and 95% formic acid is added dropwise until the solid is dissolved. The mixture is refluxed overnight, after which 3.2 ml of aqueous formaldehyde is added and refluxing is continued for another 8 hours. The reaction mixture is poured into water and the precipitate is filtered to yield the compound 5-cyano-1-(N-hydroxymethyl-2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.>300°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=O)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[CH2:26]([N:28]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:29]1=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCOCC1
Reactant: CCN=C=O
Product: CCn1c(=O)c2cnc3c(OC)cccc3c2n(CC2CCOCC2)c1=O
Yield: 51.4 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (265 mg, 1.0 mmol) was treated with C-(tetrahydro-pyran-4-yl)-methylamine (1.5 mmol) following general procedure B to afford 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (324 mg). 3-Ethyl-7-methoxy-1-(tetrahydro-pyran-4-ylmethyl)-1 H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 370 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[CH:19][C:20]3[S:24][N:23]=[CH:22][C:21]=3[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:8][S:7][C:4]1[S:3][C:2]([C:18]2[CH:17]=[CH:25][C:21]3[CH:22]=[N:23][S:24][C:20]=3[CH:19]=2)=[N:6][N:5]=1
Reactant: CSc1nnc(Br)s1
Reactant: CC1(C)OB(c2ccc3sncc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CSc1nnc(-c2ccc3cnsc3c2)s1
Temperature: 140 °C
Yield: 87.4 %

Procedure:
To a stirred mixture of 2-bromo-5-(methylthio)-1,3,4-thiadiazole (0.22 g, 1.0 mmol) (prepared as described in WO 97/30981), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazole (0.18 g 0.69 mmol), Na2CO3 (0.22 g, 2.1 mmol), and Pd(PPh3)4 (80 mg, 0.07 mmol) was added EtOH (1.0 mL), water (1.0 mL) and DME (3.0 mL). The resulting mixture was heated at 90° C. overnight and at 140° C. for 30 minutes. The mixture was cooled and passed through a short path of Celite, washing with DCM (3×10 mL). The combined organic phases were concentrated to give the crude residue. Purification by chromatography on silica gel (DCM—5% MeOH in DCM) gave the product as an off-white powder (0.16 g, 87%). LCMS (API-ES) m/z (%): 266.4 (100%, M+H+); 1H NMR (400 MHz, CDCl3): δ ppm 8.97 (s, 1 H) 8.48 (s, 1 H) 8.16 (d, J=8.53 Hz, 1 H) 8.00 (d, J=8.03 Hz, 1 H) 2.87 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[N:11]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[N:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(CC(=O)O)[C@@H](CF)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A mixture of (2R,5R)-4-benzyloxycarbonylmethyl-5-fluoromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.42 g, 1.1 mmol), methanol (20 mL) and 10% palladium on carbon (0.14 g) was hydrogenated at 20° C. and 1 bar for 18 h. Catalyst was removed by filtration and the filtrate evaporated in vacuo to give the title compound (0.289 g) as an oil. MS: [M+H]+=291.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(OC)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Phenylacetic acid (7.39 g, 54.28 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (4.74 ml, 54.28 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-methoxyanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (9.63 g, 72.37 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as yellow liquid (4.3 g, 49% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.30(s,1H), 7.42(d, J=3.0Hz, 1H), 7.33-7.21(m, 5H), 7.17(dd, J=9.0,3.1Hz, 1H), 6.92(d, J=9.0 Hz, 1H), 4.43(s, 2H), 3.74(s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[O:42])[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C2CCCCO2)[CH:16]=1)(=[O:12])=[O:11].Cl.[SiH](CC)(CC)CC.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[OH:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36](=[O:42])[N:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:30][CH:29]=1)[S:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)N3CCCC3)cc2)c(C)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(C=CC(=O)N3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
To a solution of 2,4,6-trimethyl-N-[4-(3-oxo-3-pyrrolidin-1-yl-propenyl)-phenyl]-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.021 g, 34.9 μmol) in 0.5 mL methanol was added HCl (0.19 mL of a 4.0 M solution in 1,4-dioxane, 2 mmol) and Et3SiH (0.047 ml, 0.30 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. The residue was purified by preparative TLC (eluting with 10% methanol/methylene chloride) to afford 0.012 g of N-(3-hydroxybenzyl)-2,4,6-trimethyl-N-[4-(3-oxo-3-pyrrolidin-1-yl-propenyl)-phenyl]-benzenesulfonamide. 1H NMR (acetone-d6) δ 6.16 (d, 1H, J=15.6 Hz), 6.02–5.98 (m, 2H), 5.71–5.67 (m, 3H), 5.57 (s, 2H), 5.35–5.26 (m, 4H), 3.43 (s, 2H), 2.29–2.19 (m, 4H), 1.13 (s, 6H), 0.95 (s, 3H), 0.72–0.56 (m, 4H).
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: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
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-2,3dioxopiperazine-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: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C1C=CC=CC=1>[NH:13]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc2c(Nc3ccccc3)ncnc2c1
Yield: 82.7 %

Procedure:
8.0 g of 4,7-dichloroquinazoline were dissolved in 250 ml of benzene, and then 4.0 g of aniline and 4.8 g of triethylamine were added to the solution. The resulting mixture was heated to reflux for 5 hours, with stirring. After completion of the reaction, 200 ml of water were added to the reaction mixture. The mixture was shaken and the benzene phase was separated and dried over anhydrous sodium sulphate. The benzene was distilled off and the resulting crystals were recrystallized from ethyl acetate to give 8.5 g (yield 83%) of the desired Compound No. 5 in the form of colourless granules having a melting point of 215°-217° C.