Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([OH:7])=O.[NH2:18][CH:19]1[C:30](=[O:31])[N:21]2[C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH3:26])[CH2:24][S:25][C@H:20]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([NH:18][CH:19]1[C:30](=[O:31])[N:21]2[C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH3:26])[CH2:24][S:25][C@H:20]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csc2cc(Cl)ccc12
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csc2cc(Cl)ccc12
Yield: 7959.2 %

Procedure:
Following the general procedure of Example 36, 2.8 g (10.39 mM) of α-methoxyimino-α-(6-chloro-3-benzothienyl)acetic acid were converted to the acid chloride and reacted with 2.33 g (10.91 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid to provide 385 g (80% yield) of 7-[α-methoxyimino-α-(6-chloro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (CDCl3): δ 2.02 and 2.21 (two s, 3H); δ 3.1-3.85 (m, 2H); δ 4.01 (s, 3H); δ 5.06 (d, 1H); δ 5.86 (dd, 1H); δ 7.2-7.8 (m, 4H); δ 8.3-8.7 (m, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])=[O:4].[CH3:14][C:15](C)=[CH:16]C(Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:15]1[CH:16]=[C:6]([C:7]([F:10])([F:9])[F:8])[O:5][C:3](=[O:4])[CH:2]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)oc(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trifluoroacetic anhydride (10.63 g, 50.61 mmol) and 3,3-dimethylacryloyl chloride (5.0 g, 42 mmol) in chloroform (85 mL) at 0° C. was added triethylamine (12.91 mL, 92.60 mmol). The resulting reaction mixture was stirred at same temperature for 1 h, then allowed to warm to room temperature overnight. The reaction solution was washed with water (2×), saturated sodium bicarbonate, water, and brine, and then dried over Na2SO4, filtered and concentrated. The crude residue was used in next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:12]1[CH:30]=[CH:29][C:15]([CH:16]=[CH:17][C:18]([NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[C:22]=2[OH:28])=[O:19])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:31][O:32][C:33](=[O:38])[CH:34]=[CH:35][CH2:36]Br.O>CC(C)=O>[CH3:31][O:32][C:33](=[O:38])[CH2:34][CH:35]1[O:28][C:22]2[C:21]([NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:30][CH:29]=3)=[CH:27][CH:26]=[CH:25][C:23]=2[O:24][CH2:36]1
Reactant: COC(=O)C=CCBr
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc(O)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1

Procedure:
Potassium carbonate (509 mg) was added to a solution of 3- (p-pentylcinnamoyl) aminopyrocatechol (300 rag; synthesized by the same procedure as reference example 1) and 4-bromo-2-butenoic acid methyl ester in acetone (10 ml), and the mixture was refluxed for 10 min. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was purified by column chromatography on silica gel (hexane: ethyl acetate=5:1) to give the title compound (341 mg).
Reaction SMILES: [O:1]=[C:2]([N:5]1[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])[CH2:3][CH3:4].CCN(C(C)C)C(C)C.[CH:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:10]([C@@H:9]1[CH2:8][O:7][C:6](=[O:17])[N:5]1[C:2](=[O:1])[C@H:3]([CH3:4])[C@H:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[OH:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of (R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone (Aldrich, 2.0 g, 8.6 mmol) in DCM (60 mL) at −40° C., a solution of TiCl4 in DCM (1.0 M, 10.0 mL, 10.0 mmol) was added. The mixture was stirred at −40° C. for 10 min., then DIPEA (3.7 mL, 21 mmol) was added. The reaction mixture was allowed to warm to 0° C. and stirred for 20 min. A solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Aldrich, 2.0 g, 8.7 mmol) in DCM (20 mL) was then added dropwise and the resulting mixture was stirred for 1.5 h. The reaction was quenched by the addition of a saturated aq. NH4Cl and the mixture was extracted with EtOAc. The separated organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-40% EtOAc in hexanes) to give the sub-title compound as the major product (5:2) in 87% yield (3.44 g). LCMS calc. for C24H34N2NaO7 (M+Na)+: m/z=485.2. found 485.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:40])[CH3:39]>>[CH2:42]([N:41]([CH:38]([CH3:40])[CH3:39])[C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)NCc1ccccc1
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)N(Cc1ccccc1)C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-isopropyl-N-benzylamine, mp 168°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](F)=[O:8].[OH-:14].[Na+]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:14])=[O:8]
Reactant: [OH-]
Reactant: O=C(F)c1cc(Cl)c(F)c(F)c1F
Agent: [Na+]
Product: O=C(O)c1cc(Cl)c(F)c(F)c1F

Procedure:
When 5-chloro-2,3,4-trifluorobenzoyl fluoride is briefly treated with aqueous sodium hydroxide solution then, after acidification and drying, crystals of 5-chloro-2,3,4-trifluorobenzoic acid are obtained, melting point: 123°-4° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.CCCCCC.[Sn:18](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22]>CCOCC>[CH3:1][C:2]1[O:6][C:5]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cnco1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ncc(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
A solution of 5-methyloxazole (5.0 g, 60.2 mmol) in Et2O (100 mL) was cooled to −78° C. under N2 and treated with a 1.6 M solution of BuLi in hexane (41.4 mL, 66.2 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and a solution of Bu3SnCl (16.31 mL, 60.2 mmol) in Et2O (50 mL) was then added dropwise. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT. The reaction mixture was filtered on celite, and the filtrate concentrated in vacuo. Purification by distillation (0.1 Torr, 128-130° C.) afforded the title compound (3.5 g) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (m, 12 H) 1.14-1.22 (m, 6 H) 1.27-1.38 (m, 6 H) 1.52-1.61 (m, 6 H) 2.17-2.21 (m, 3 H) 7.49-7.54 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:6]=2[CH:17]=1
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 71 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.208 g, 0.6 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.13 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.68-6.63 (m, 1H), 4.57 (q, J=14.8 Hz, J=40.0 Hz, 1H), 4.11-3.94 (m, 2H), 3.14-3.04 (m, 2H), 2.30 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.20-2.09 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 3H), 1.71-1.52 (m, 3H), 1.40-1.34 (m, 2H), 1.32-1.19 (m, 8H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.6 Hz), 130.0 (d, J=10.8 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.4 Hz), 103.8 (d, J=28.9 Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4, 28.4, 28.2, 27.2, 22.8, 7.0, 14.2.
Reaction SMILES: [NH:1]1[C:18](=[O:19])[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H](C(N[C@H](C(O)=O)CC1C=CC=CC=1)=[O:27])CC(C)C>>[NH2:9][C@H:10]([C:18]([NH:1][C@H:2]([C:7]([OH:27])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@@H]1NC(=O)[C@H](Cc2ccccc2)NC1=O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
As a result, it was confirmed that 6.8 mg/l cyclo(L-Leu-L-Phe), 28.7 mg/l L-Leu-L-Phe and 18.5 mg/l L-Phe-L-Leu were formed. No cyclopeptide or straight-chain peptide was detected in the reaction mixture without ATP incubated in the same manner.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A suspension of 2,5-difluorobenzaldehyde (291.5 mg, 2.05 mmol), 2-methyl-2-nitropropane (427.3 mg, 4.14 mmol) and zinc (407.3 mg, 6.23 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature, stirred for 2 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (393 mg; 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[BH4-].[Na+].[C:29]([OH:32])(=[O:31])[CH3:30]>C(O)C>[C:29]([OH:32])(=[O:31])[CH3:30].[C:29]([OH:32])(=[O:31])[CH3:30].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[OH:21])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CNc1ccnc2cc(Cl)ccc12)NCc1ccccc1O
Yield: 40 %

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.54 g of salicylaldehyde were stirred under reflux overnight in the presence of 1.25 g of molecular sieve (E. Merck, 3 Å). Thereafter, the mixture was filtered and the solvent was evaporated. From a small amount of diethyl ether and ethyl acetate there was obtained a crystalline product which was again taken up in 20 ml of ethanol. After the addition of 0.19 g of sodium borohydride the mixture was left to react overnight, thereafter 5 ml of glacial acetic acid were added thereto and the mixture was evaporated to dryness. After the addition of 10 ml of methanol the mixture was again evaporated. Addition of methanol and evaporation were repeated twice. The residue was then crystallized from 10 ml of ethanol. 0.9 g (40%) of colourless crystalline product of m.p. 150° C. was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35](Cl)=[O:36]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:35](=[O:36])[C:34]3[CH:33]=[C:32]([Cl:31])[CH:40]=[C:39]([Cl:41])[CH:38]=3)[CH2:17]2)=[O:15])=[N:2]1
Reactant: O=C(NCCNc1nsc2ccccc12)C1CCCNC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)C1CCCN(C(=O)c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
N-(2-(Benzo[d]isothiazol-3-ylamino)ethyl)piperidine-3-carboxamide (75 mg, 0.24 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (38 μL, 0.27 mmol). The solution was cooled on an ice-water bath and then a solution of 3,5-dichlorobenzoyl chloride (57 mg, 0.27 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir overnight while warming to room temperature. The solution was washed with saturated sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-1-(3,5-dichlorobenzoyl)piperidine-3-carboxamide (23 mg). 1H NMR (300 MHz, CDCl3): 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.1 (m, 1H), 6.3 (m, 1H), 3.7 (m, 4H), 3.3 (m, 2H), 2.5 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H) 1.1 ppm (m, 1H). MW=477 confirmed by LC-MS, tr=3.93 min (Method Y) MH+=478.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[Cl:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1>>[Cl:12][C:13]1[O:14][C:15]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:16][CH:17]=1
Reactant: Clc1ccco1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Phosphorus pentachloride (40.53 g, 0.1947 mol) was added portionwise (caution, foaming) over 5 min at 25° C. to chlorosulfonic acid (56.8 g, 32.4 mL, 0.487 mol) and the resulting solution was stirred at 25° C. for 10 min. Then, 2-chlorofuran (20.0 g, 20 0.1947 mol) was added in one portion and the resulting dark suspension was heated to 55° C. for 1.0 h during which time foaming occurred and subsided. The reaction mixture was then poured onto ice and the resulting suspension was extracted with CH2Cl2 (250 mL). The organic was filtered through a pad of celite, washed with brine (70 mL) and dried over MgSO4. The solvent was removed in vacuo to provide 5-chlorofuran-2-sulfonyl chloride as a black oil (14.1 g, 36.02%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.05 (d, 1H); 6.35 (d, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].Br[CH:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=O>CCO.CCOC(C)=O>[Br:10][C:6]1[CH:7]=[CH:8][N:9]2[C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CC(Br)CC(F)(F)F
Reactant: N#Cc1c(Br)ccnc1N
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)ccn2c(CC(F)(F)F)cnc12
Temperature: 150 °C
Yield: 48.8 %

Procedure:
A mixture of compounds D8 (2 g, 10.1 mmol) and D4 (2.898 g, 14.14 mmol) in EtOH (10 ml) was subjected to microwave heating at 150° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was diluted with EtOAc and washed with water. The organic layer was separated and washed with water, then with 1M HCl (aqueous solution), dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was triturated with diethylether to yield compound D9 (1.5 g, 48.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:9][CH:8]=[N:7][C:6]=2[N:29]=1>C(O)(=O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([S:21][C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[C:12]([NH:11][C:10]2[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[N:29][C:6]=3[N:7]=[CH:8][N:9]=2)[CH:17]=1
Reactant: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(N)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.3 %

Procedure:
A slurry of 4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-nitro-phenylsulfanyl]-phenol (0.19 g, 0.469 mmol) and 10% Pd/C (0.025 g) in acetic acid (3 ml) was placed under a hydrogen atmosphere with stirring for 2 hr at room temperature. The slurry was filtered and the solvent removed under vacuum leaving a brown solid as an acetate salt of 4-[4-Amino-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenol (0.21 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:22]([C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
A solution containing 80 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanol and 64 μl of triethylsilane in 2 ml of trifluoroacetic acid was stirred at rt for 15 h. The mixture was concentrated, diluted with 10 ml of saturated sodium hydrogen carbonate solution and extracted twice with 10 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°-60° C. (1:10) for the elution to give 60 mg of 4-benzyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (El) m/z 424 [M]+. 1H NMR (DMSO-d6) 2.26 (s, 3H), 3.88 (s, 2H), 6.77 (d, 2H), 7.13 (m, 3H), 7.20 (m, 2H), 7.32 (t, 1H), 7.35-7.48 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=3)([CH3:13])[C:11](=[O:34])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[Na].O>CO>[N:29]1([CH2:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C@H:15]3[CH2:14][C@@:12]4([CH3:13])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[OH:34])[C@H:7]4[C@H:16]3[C:17]3[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][C:4]=3[CH2:5][CH2:6]4)=[CH:21][CH:22]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@]12C[C@H](c3ccc(CCCN4CCCC4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(CCCN4CCCC4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 69.7 %

Procedure:
To a solution of 310 mg of the product obtained in example 2 in 3 ml of methanol, 54 mg of sodium borohydrure at 97% is added at 0-5° C., stirred for 1 hour at this temperature, salt water is added, it is drawn off, washed, dried and evaporated under reduced pressure until 320 mg of raw product is obtained that is purified by chromatography by eluting with the compound CH2Cl2/MeOH/NH4OH 90/10/1. 217 mg of pure expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH2:12]([O:11][C:7]1[C:8]([CH3:10])=[CH:9][C:2]([N:17]2[CH:16]=[C:15]([CH3:14])[CH:19]=[N:18]2)=[C:3]([CH:6]=1)[CH:4]=[O:5])[CH3:13]
Reactant: Cc1cn[nH]c1
Reactant: CCOc1cc(C=O)c(Br)cc1C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c(-n2cc(C)cn2)cc1C
Yield: 20 %

Procedure:
A solution of 2-bromo-5-ethoxy-4-methylbenzaldehyde (100 mg, 0.41 mmol), 4-methyl-1H-pyrazole (40.5 mg, 0.49 mmol), K2CO3 (114 mg, 0.82 mmol), CuI (78 mg, 0.41 mmol) in DMF (2 mL) was stirred at 110° C. for 3 hours. The reaction mixture then was filtered concentrated and the residue was purified on a silica gel column eluting with 30% EtOAc in hexanes and then with 5% MeOH in DCM to provide the title intermediate (20 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:29]C)C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:29][CH:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccco3)[C@H]2SC1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccco3)[C@H]2SC1
Yield: 57.3 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2'-[fur-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (463mg, 1.365 mmole) was treated with anisole and trifluoroacetic acid in the manner described previously [see Example 10 (b)] to give (6R,7R,2'R and S)-7-[2'-hydroxy-2'-(fur-2-yl)acetamido]-3-methylceph-3-em-4-carboxylic acid as a foam (368mg, 1.09 mmole, 57.3%). The title compound was obtained from the acid (368mg, 1.1 mole) by treatment with sodium 2-ethylhexanoate in acetone and ether, as a pale-brown solid containing 21/2mole-equivalents of water (i.r. and microanalysis), (221mg, 0.545 mmole, 50%); λmax (pH6 buffer) 220 and 258nm (ε10,780 and 8,000 respectively); νmax (Nujol) 3370 (OH,NH, and H2O), 1755 (azetidin-2-one), 1675 and 1518 (CONH), and 1590 cm-1 (CO2-); τ(Me2SO-D6) 1.57 and 1.63 (total 1H,2d, J9Hz, NH), 2.37 (1H,s) and 3.59 (2H,m) (furyl protons), 4.44 (1H,m, C7 -H), 4.81 and 4.83 (total 1H, 2s, -CHOH), 4.97 (1H,d,J5Hz, C6 -H), 6.47 and 6.86 (2H,ABq, J18Hz, C2 -H2), 8.00 (3H,s, C3 -CH3). (Found: C, 41.2, 41.5; H,3.4, 3.6; N,6.4, 6.5; S,7.8; Na,5.9. C14H13N2NaO6S.2.5 H2O (405.3) requires: C, 41.6; H,4.5; N,6.9; S,7.9; Na,5.7%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH:11]([OH:13])[CH3:12].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH:11]([O:13][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:12])[CH3:10]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ncccc1C#N
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
A mixture of 2-chloronicotinonitrile (1.0 g, 7.2 mmol), 2-propanol (0.87 g, 14.4 mmol), KOH (0.81 g, 14.4 mmol) and 18-crown-6 (1.8 g, 2.89 mmol) in toluene (30 mL) was stirred at 60° C. for 16 h. The reaction mixture was quenched with water and the organic phase was separated and then washed with water (×5). The organic phase was dried over Na2SO4 and concentrated to yield crude 2-isopropoxy-nicotinonitrile (1.1 g, 94%) which was used without further purification.