Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1N2CN3CN(C2)CN1C3.C[C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH3:20])[CH:15]=C[C:13]=1[OH:21].Cl.F[C:24](F)(F)[C:25]([OH:27])=O>C(OCC)(=O)C>[OH:27][C:25]1[C:24]([CH3:1])=[CH:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:12]=1[CH:13]=[O:21]
Reactant: CCCc1ccc(O)c(C)c1
Reactant: O=C(O)C(F)(F)F
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1cc(C)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.2 g of hexamethylenetetramine were cautiously added to 1.5 g of 2-methyl-4-propyl-phenol in 11 ml of trifluoroacetic acid and the mixture was heated for 5 hrs. to 120° C. After the addition of 11 ml of 1N hydrochloric acid the mixture was stirred for 1 hr. at 107° C. The mixture was cooled to room temperature, diluted with ethyl acetate and washed in sequence with water, dilute sodium hydrogen carbonate solution, water and sodium chloride solution. Evaporation of the solution and chromatography on silica gel with hexane-toluene gave 2-hydroxy-3-methyl-5-propyl-benzaldehyde. MS: 178 (M)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18]([OH:20])=O)[N:16]=2)=[CH:8][CH:7]=1.ON1C2C=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=N1.Cl.CN(C)CCCN=C=NCC.N1CCCC1>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:20])[N:24]3[CH2:25][CH2:30][CH2:29][CH2:28]3)[N:16]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(Cc1coc(-c2ccc(OCCCCl)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetic acid ax63 (0.5 g, 1.69 mmol, 1 eq) in dichloromethane (50 ml) is added 1-hydroxybenzotriazole (0.025 g, 0.19 mmol, 0.11 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.357 g, 1.86 mmol, 1.1 eq). To that solution is added pyrrolidine (0.29 ml, 3.38 mmol, 2 eq) and the mixture is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum to afford 0.51 g of 2-[4-(3-chloropropoxy)phenyl]-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole ax64 as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:13]([N:15](CC)[CH2:16]C)C.CNC.CCO>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]([CH3:16])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: CCN(CC)CC
Agent: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A cooled (0° C.) solution of 5-bromo-6-chloropyridine-3-sulfonyl chloride (2.00 g; 6.87 mmol) in DCM (20 mL) was treated first with triethylamine (1.06 ml; 7.56 mmol) then with a 5.6 M solution of dimethylamine in EtOH (1.35 ml; 7.56 mmol). The reaction was stirred at 0° C. for 1.5 hours then brine was added and the phases separated. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1.C1C[O:63]CC1>>[CH:46]([OH:47])=[O:63].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:59][CH2:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: C1CCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and pyrrolidine (27 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (29 mg, 59%). LCMS (Method 5): Rt 3.72 min, m/z 732.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=8.0 Hz), 1.28 (9H, s), 1.46-1.56 (2H, m), 1.61-1.72 (6H, m), 1.75-1.98 (4H, m), 1.99-2.18 (2H, m), 2.52 (4H, m, obscured by solvent), 2.80 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.27-3.35 (1H, m, obscured by water), 4.11 (2H, t, J=8.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.97 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.05-7.14 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.14 (1H, s), 8.18 (1.3H, s).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH:24]=[N:25][N:26]([CH3:27])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:24]=[N:25][N:26]([CH3:27])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(N)(=O)=O
Reactant: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)NS(=O)(=O)N(C)C)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (54 mg, 0.13 mmol) and N,N-dimethylsulfamide (81 mg, 0.65 mmol) in DMA (2 mL), was added DMAP (80 mg, 0.65 mmol), and EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxamide (29 mg, 0.056 mmol, 43%) as a bright yellow solid. 1H NMR (500 MHz, CD3OD) δ 1.22-1.34 (m, 1H), 1.41-1.62 (m, 3H), 1.77-1.85 (m, 2H), 1.95-2.18 (m, 4H), 2.71 (s, 3H), 2.90-3.00 (m, 1H), 3.05 (s, 6H), 5.09 (d, J=15.9 Hz, 1H), 6.03 (d, =15.9 Hz, 1H), 7.67 (dd, J=8.2, 1.5 Hz, 1H), 7.79-7.87 (m, 4H), 8.00 (d, J=8.6 Hz, 1H), 8.33 (s, 1H). LCMS: m/e 519 (M+H)+, ret time 1.96 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: O=C(NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1ccccc1

Procedure:
The compound of Example 59 is reacted with phenyl isocyanate in an aprotic solvent to obtain the title compound.
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@@H:38]([OH:45])[CH2:39][C:40](OCC)=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[OH2:50].[NH2:51][NH2:52]>CN(C)C=O>[CH2:13]([O:50][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@@H:38]([OH:45])[CH2:39][C:40]([NH:51][NH2:52])=[O:41])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:8])[C:14]1[CH:23]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: CCOC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NN
Temperature: 25 °C
Reaction time: 48 h
Yield: 170.3 %

Procedure:
134 mg (0.2 mmole) of ethyl 4(S)-[N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl]amino-3(S)-hydroxy-6-methylheptanoate (prepared as described in Example 1) were dissolved in 2 ml of dimethylformamide, and 100 mg (2 mmole) of hydrazine hydrate were added to the resulting solution, which was then stirred at room temperature for 2 days. The solvent was then removed by distillation under reduced pressure, and water was added to the resulting residue to form a precipitate, which was filtered off. The resulting precipitate was washed thoroughly with water and then dissolved in methanol. The solvent was removed by distillation under reduced pressure. A 1:1 by volume mixture of diethyl acetate and diethyl ether was added to the resulting solid residue, which was then finely pulverized and filtered. There were obtained 112 mg of the title compound as a white powdery solid, melting at 120°-127° C., [α]24 -58.6°. (C=0.5, dimethylformamide).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>N1C=CC=CC=1.C(OCC)C>[CH2:27]([O:26][C:24]([C:23]1[N:21]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1)=[O:25])[CH3:28]
Reactant: Nc1cccc[n+]1N
Reactant: CCOC(=O)C(=O)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2ccccn2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a light red solution of 1,2-diaminopyridinium 2,4,6-trimethylbenzenesulfonate (10.9 g, 35.2 mmol) in pyridine (50 mL) was added ethyl 2-chloro-2-oxoacetate (9.62 g, 7.84 mL, 70.5 mmol) at RT (exotherm reaction!). The light red solution turned into a dark red solution. The mixture was heated to 100° C. and stirred overnight. The reaction mixture was evaporated and the black residue was triturated for 30 min with Na2CO3 (saturated aqueous solution, 300 mL). The reaction mixture was extracted with dichloromethane (4×250 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 6.64 g of crude product. The crude product was suspended in diethyl ether (30 mL), filtered and washed with diethyl ether. The obtained precipitate was dried in vacuo to give the product as light brown solid (6.1 g, 31.9 mmol, 90.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccc(F)cc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-(p-fluorophenyl)-2-butanone (174.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2S,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-(p-fluorophenyl)butane (160.1 mg; yield: 91.0%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 18.3:1. The results of elementary analysis were as follows.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]12.[CH2:16](N(CC)CC)C.[NH2:23][C:24]1[S:25][CH:26]=[C:27](/[C:29](=[N:43]/[O:44]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:30](O[C:33]2[C:38]3N=C(S)S[C:37]=3[CH:36]=[CH:35][CH:34]=2)=[O:31])[N:28]=1>O1CCCC1.O>[CH:5]1([NH:4][CH2:14][CH2:2][NH:1][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:6][CH2:9][CH2:10][CH2:16][CH2:11]1.[NH2:23][C:24]1[S:25][CH:26]=[C:27](/[C:29](=[N:43]/[OH:44])/[C:30]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]23)=[O:31])[N:28]=1
Reactant: CCN(CC)CC
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)Oc2cccc3sc(S)nc23)cs1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: O
Solvent: C1CCOC1
Product: C1CCC(NCCNC2CCCCC2)CC1
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 32 °C
Reaction time: 5 h

Procedure:
To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (50 gm) in a mixture of tetrahydrofuran (250 ml) and water (31.5 ml), triethylamine (45 gm) was added drop-wise at 20±2° C. over 30-45 minutes. 2-mercaptobenzothiazolyl (Z)-(2-aminothiazol-4-yl)-2-(trityloxyimino)acetate (130 gm) was added to the clear solution and the resulting mixture was stirred at 32±2° C. for 4-6 hours. The reaction was monitored by HPLC. After the completion of reaction, THF was completely removed under vacuum at 28-30° C. To the concentrated mass, acetone (300 mL) was added and stirred at 30° C., 1:1 Hydrochloric acid (200 mL) was added and the temperature was raised to 63-64° C. At this temperature, it was refluxed for about 35 min and then cold acetone of 1.8 Liter dumped to the reaction mass to bring down the temperature to 30° C., EDTA (0.5 g) was added and stirred for 10 min at 30-35° C., pH of the solution was adjusted to 2.5 using Triethyl amine (100 mL) at 30-35° C. To the reaction mixture hot solution of N,N′-Dicyclohexylethylenediamine (DDA) 40.0 g in Isopropyl alcohol (100 mL) was added slowly to adjust the pH of the solution 5.5 and stirred for 1.0 hour at 30-35° C. The precipitated material was filtered, washed with acetone and dried under vacuum at ˜40° C. to get N,N′-Dicyclohexylethylenediamine salt of 7β-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid. Step-ii
Reaction SMILES: S([C:5]1[CH:11]=C[C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[SH2:12].[Na].[SH2:14].Cl.C([OH:18])C>O>[SH:12][C:6]1[C:7](=[O:18])[CH:8]([CH3:9])[S:14][C:5]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCO
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC1=C(S)C(=O)C(C)S1
Reaction time: 1 h

Procedure:
12.8 grams (0.1 m) of 4 hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one were dissolved in 70 ml of dry pyridine. The solution was stirred and cooled to -10° C in an ice-salt bath. With stirring a cold solution of 22.9 grams (0.12 m) of p-toluene sulfonylchloride in 50 ml of dry dichloromethane was added dropwise (temp. below -5° C). After completion of the addition (1 hour), stirring at 0° C was continued for 3 hours, and water (10 ml) was added in portions at intervals of 5 min., with stirring and cooling, so that the temperature did not rise above 5° C. The solution was then poured into 250 ml of ice-water. The mixture was extracted four times with dichloromethane, the combined extracts were successively washed with portions of ice-cold dilute sulphuric acid, water, sodium hydrogen carbonate solution and water. The dichloromethane solution is then dried with anhydrous solution sulphate and evaporated to dryness. Crystallization from ethanol yielded 21.3 grams = 75.5% of the pure 4-p-toluene-sulfonyloxy-2,5-dimethyl-2,3-dihydrofuran-3-one with m.p. 70°-72° C. 3.5 grams (12.4 mmol) of the tosylate thus otained were dissolved in a mixture of 15 ml of ethanol and 5 ml of water at 40° C. To this solution was added a solution of 1.68 grams (30 mmol) of sodium hydrogensulphide in 20 ml of ethanol, while a gentle stream of hydrogen sulphide was passed through the reaction mixture. AFter completion of the addition, which took one hour, stirring and passing of H2S into the solution were continued for 6 hours at 40° C and the reaction mixture was diluted with 200 ml of water, acidified with aqueous dilute hydrochloric acid (pH 5.5) and continuously extracted with ether for 18 hours. The extract was dried over anhydrous sodium sulphate and evaporated to dryness. From the residue the title compound was isolated in a quantity of 3 grams by preparative gaschromatography, using a column of 600 × 0.4 cm, a support of Diatoport S (a silanated silicagel) ex Hewlett Packard, loaded with 1% Carbowax 20 M (a polyethylene glycol ether with a molecular weight above 20,000) ex Hewlett Packard and 10% Apiezon (a mixture of stable alkanes) ex Shell Comp. Nitrogen was used as a carrier gas at a velocity of 40 ml per minute.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:26])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:8]2([F:26])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1CC(O)(c2ncccc2Cl)CCC12OCCO2
Solvent: ClCCl
Product: CC1CC(F)(c2ncccc2Cl)CCC12OCCO2
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of Example 32E (1.30 g, 4.58 mmol) in dichloromethane (100 mL) was cooled to −78° C., treated with diethylaminosulfur trifluoride (0.730 ml, 5.96 mmol) (Aldrich), and the reaction mixture was stirred at −78° C. for 2 hours. After 2 hours the reaction was partially complete and the mixture was allowed to stir for 2 additional hours. The reaction mixture was poured into dichloromethane (200 mL) and washed with saturated Na2CO3, dried over Na2SO4, and concentrated in vacuo. The material was purified on SiO2 and eluted with hexane/ethyl acetate (20%) to give a white solid (0.625 g) in 48% yield. 1H NMR (300 MHz, CDCl3) δ ppm 8.46 (dd, J=1.6, 4.7, 1H), 7.67 (dt, J=1.2C, 8.0, 1H), 7.17-7.09 (m, 1H), 4.17-3.92 (m, 4H), 2.72 (ddd, J=5.4, 10.7, 19.5, 3H), 2.57-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.06-1.94 (m, 1H), 1.83 (dd, J=6.0, 14.1, 1H), 1.08 (dd, J=6.9, 20.9, 3H). MS (DCI+) M/Z 286 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenethylpyrrolidine (0.53 g, 1.93 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA. The solution was warmed to room temperature and stirred for 3 hours. The organic layer was concentrated under reduced pressure and redissolved in CH2Cl2. The organic layer was washed with 1 M NaOH, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (0.31 g, 91%). ES (+) MS m/e=176 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 3-methylbutyric acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(3-methyl-butyrylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(N(CC)CC)C.[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>CCOCC>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=1[N:15]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)c(F)c1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Fc1ccc(N=C=S)c(F)c1F
Temperature: 20 °C
Yield: 77.2 %

Procedure:
Reference Example 1 Thiophosgene (1.4 g) was dissolved in 25 ml of ether, 2.0 g of triethylamine was added thereto with ice cooling and stirring (at not higher than 20° C.), then a mixture of 1.4 g of 2,3,4-trifluoroaniline and 3 ml of ether was gradually dropped thereinto at the same temperature, and the mixture was stirred for one hour at the same temperature. Then it was filtered off, the filtrate was concentrated, the residue was extracted with n-hexane, insoluble matters were removed by filtration, the resulting hexane-soluble matters were subjected to a silica gel column chromatography (Wacogel C-200 in the amount of 15 g) and eluted with n-hexane to give 1.39 g of 2,3,4-trifluorophenyl isothiocyanate.