Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1C(OC(C)(C)C)=O)[C@@H:4]([CH3:25])[C:5]([NH:7][C@@:8]1([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:1][O:2][C@@H:3]([C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C@@H:4]([CH3:25])[C:5]([NH:7][C@@:8]1([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
617 mg (1.2 mmol) of tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidine-1-carboxylate (Intermediate 24) were taken up in 44 ml of dichloromethane, 4.4 ml of trifluoroacetic acid were added and the mixture was stirred at RT for 30 min. Subsequently, the reaction mixture was concentrated under reduced pressure and the remaining residue was lyophilized from dioxane/water. 702 mg (quant.) of the deprotected compound (2R,3R)-3-methoxy-2-methyl-N-[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]-3-[(2S)-pyrrolidin-2-yl]propanamide trifluoroacetate were obtained as a crude product, which was used in the following stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)=[N:25]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([C:26]5[N:27]=[N:28][N:24]([CH3:23])[N:25]=5)[CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cn1nnc(-c2cccc(C=O)c2)n1
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nnc(-c2cccc(C=Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)c2)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 565 mg (3.0 mmol) of 3-(2-methyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{3-(2-methyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in methanol yield 4-(3-chloro-phenylamino)-3-[3-(2-methyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.51 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=8.7; FAB-MS: (M+H)+=433.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[F:37])[CH:24]=[C:23]([C:38]([F:41])([F:40])[F:39])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[C:23]([C:38]([F:39])([F:40])[F:41])[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.39 g, 72%). MS (ISP) 542.1 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54]C(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)C(O)=O)=[O:62].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:52]([N:45]1[CH2:46][C@@H:47]([CH2:49][O:50][CH3:51])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:54])=[O:62]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnight then heated to 50° C. for 3h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N80s: 882.4; observed [M+1]+: 884.1. Diagnostic peaks in NMR ′H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH3:22])[CH3:2].[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36]Br)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:36][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH2:20][CH2:21][CH3:22])[CH:5]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)ccc1CC

Procedure:
In a manner similar to that of Example 1(o), by reacting 1.28 g (4.3 mmol) of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)-1-propanone with 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, an oil is obtained, which is used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[F:29])[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[F:29])[C:22]([O:24][CH3:25])=[O:23])=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (step 3) (1.8 g, approximately 7.47 mmol) and thionyl chloride (10 ml, 137 mmol) under N2 was heated at reflux for 1.5 hrs. The reaction mixture was concentrated in vacuo and azeotroped with toluene. Methyl 3-amino-4-fluorobenzoate (1.263 g, 7.47 mmol) (pre-dried at 45° C.) was added followed by pyridine and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with EtOAc and washed with H2O. The resulting solid was collected by filtration. The filtrate was dried (MgSO4) and concentrated in vacuo and triturated with ether to afford cream solid. The solids were combined and dried at 45° C. to afford the title compound;
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1C=CC2N(O)N=NC=2C=1.[NH:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:29]([C:31]([NH:33][C@H:34]([C:38](O)=[O:39])C(C)C)=[O:32])[CH3:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:38](=[O:39])[CH2:34][NH:33][C:31](=[O:32])[C@H:29]([CH3:30])[NH:28][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC(c1nc2ccccc2s1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
36 (0.43 g, 1.23 mmol), HOBt (0.183 g, 1.35 mmol), WSCD (0.259 g, 1.35 mmol), Boc-Ala-Val-OH (0.303 g, 1.23 mmol), TEA (0.172 ml, 1.54 mmol)
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]([CH3:14])([CH2:8][CH2:9][C:10](Cl)([CH3:12])[CH3:11])[CH3:7].O.[Cl-].[Ca+2].[Cl-].[Cl:19][C:20]([Cl:22])=[CH2:21]>>[Cl:19][C:20]([Cl:1])([Cl:22])[CH2:21][C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:6]([Cl:5])([CH3:14])[CH3:7]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: C=C(Cl)Cl
Reactant: [Cl-]
Agent: [Al+3]
Agent: [Ca+2]
Solvent: O
Product: CC(C)(Cl)CCC(C)(C)CC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
At 0° C. under agitation, 3.75 g of aluminum chloride is added in portions within 45 minutes to a thoroughly stirred suspension of 54.9 g of 2,5-dichloro-2,5-dimethylhexane in 135 ml of 1,1-dichloroethylene. The reaction mixture is then stirred for another 100 minutes at 0° C. and combined with 10 ml of water and 20 g of anhydrous calcium chloride. The mixture is then filtered and the excess 1,1-dichloroethylene removed under vacuum. Yield: 88.4 g of a viscous oil from which, by solid-matter distillation, 17.5 g of 2,5-dichloro-2,5-dimethylhexane is recovered. The residue is distilled, thus obtaining 34.3 g of 1,1,1,6-tetrachloro-3,3,6-trimethylheptane as a slightly yellow oil, boiling point 79°-80° C. under 0.5 mbar.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20].O>CO>[F:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]([C:15]([F:17])([F:16])[F:18])[C:5]=1[CH2:19][OH:20]
Reactant: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
To a solution of 1.6 g (41.0 mmoles) of sodium borohydride dissolved in 300 ml of methanol was added, with ice-cooling, a solution of 26.5 g (102.5 mmoles) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol. The resulting mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 28.5 g (yield: 100%) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[O:31]1.[I-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32](=[O:33])[O:31]4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: O=C1OC(Br)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OC2OC(=O)c3ccccc32)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(2.16 g) in N,N-dimethylformamide (20 ml) were added 3-bromophthalide (1.3 g) and sodium iodide (1.35 g), and the mixture was stirred at ambient temperature for 40 minutes. Thereto were added ethyl acetate (100 ml) and water (50 ml), and the separated ethyl acetate layer was washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After removal of the solvent, the residue (2.6 g) was chromatographed on silica gel (50 g) using a mixture of benzene and ethyl acetate as an eluent. The freactions containing the desired compound were collected and evaporated to give phthalid-3-yl 7-[2(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(1.4 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]([O:13][CH3:14])[O:4]1.[H][H]>CO.[Ni]>[CH3:1][O:2][CH:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:5]([O:13][CH3:14])[O:4]1
Reactant: CCOC(=O)C1=CC(OC)OC1OC
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)C1CC(OC)OC1OC
Yield: 90.7 %

Procedure:
Ethyl 2,5-dimethoxy-2,5-dihydrofuran-3-carboxylate (615 mg, 3.044 mmol) was dissolved in methanol (10 mL) and treated with hydrogen (10 bar) over Raney nickel at 40° C. for 2 h. The reaction mixture was evaporated to dryness to give ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate (564 mg, 91%) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.Cl.[CH3:15][O:16][NH:17][CH3:18].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11](=[O:13])[N:17]([O:16][CH3:15])[CH3:18])[N:10]=2)[CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1cn2cc(Br)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
850 mg of 6-bromo-2-hydroxycarbonyl-imidazo[1,2-a]pyridine, 519 mg of N-methoxy-N-methyl-amine hydrochloride, and 1.12 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in 10 ml of pyridine, and the mixture was stirred at room temperature for 2 days. Water was added to the obtained solution, and the products were extracted with ethyl acetate. Organic layer was washed with saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate. Then, the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (ethyl acetate) to obtain 362 mg of the above compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C:31]5[O:30][N:29]=[C:28]([CH3:27])[CH:32]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (107 mg, 95%), MS (ISP) m/z=452.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.B([O-])O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C(CO)=CC=CC=1.O>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: [O-]BOc1ccccc1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccccc3)c2)cc1
Yield: 93.4 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (0.60 g, 1.7 mmol), phenyl boronate (0.25 g, 2.1 mmol) and sodium carbonate (0.55 g, 5.2 mmol) were dissolved in toluene-methanol-water (5:1:1, 35 mL), the mixture was purged with argon, and then tetrakistriphenylphosphine palladium (99 mg, 0.086 mmol) was added thereto. The reaction solution was heated under reflux overnight under argon atmosphere. The reaction solution was cooled, and then water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water, dried and then concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.55 g, yield 92%) as white powders.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].O.Cl.N[CH:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14].C(=O)([O-])[O-:19].[K+].[K+].O>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:8][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: N#CCc1cccs1
Reactant: NC(CS)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Cc1cccs1)NC(CS)C(=O)O

Procedure:
24.6 g (0.2 mole) thiophene-2-acetonitrile, 35.2 g (0.2 mole) D,L-cysteine hydrochloride monohydrate and 27.6 g (0.2 mole) potassium carbonate were heated in 500 ml methanol and 250 ml water for 6 hours at the boiling point. Then the solvent was removed under reduced pressure, the residue taken up in 200 ml water and adjusted with concentrated hydrochloric acid to pH 4. 40.8 g (83% of theory) colorless product with a melting point of 138°-140° C. precipitated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[SH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](F)=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([S:19][C:10]2[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22]
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(S)c1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Sc2cc(C(F)(F)F)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and the product from example 7 step (ii), yield 0.43 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][N:19]=1>N1C=CC=CC=1>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CSc1ncc(CC2CCCCC2)c(=O)[nH]1
Reactant: CCCN(CCCCN)c1ccccn1
Solvent: c1ccncc1
Product: CCCN(CCCCNc1ncc(CC2CCCCC2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (1.17 g) and 2-methylthio-5-cyclohexylmethylpyrimid-4-one (0.9 g) were heated together under reflux in pyridine (2.5 ml) for 28 hrs. After stripping, the residue was chromatographed (silica gel, dichloromethane/methanol 40:1) crystallized from ethanol/water and recrystallized from acetone/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-cyclohexylmethyl pyrimid-4-one 1.4 H2O, 0.62 g (38%) m.p. 62°-64° C.