Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[N:21]2[N:35]=[CH:36][C:37]([C:38]#[N:39])=[C:20]12)=[O:18]>>[ClH:15].[ClH:15].[C:1]1([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH2:16][C:17]([N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[N:21]4[N:35]=[CH:36][C:37]([C:38]#[N:39])=[C:20]34)=[O:18])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: Cl
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(CCc3ccccc3)CC1)CC=C2c1cccc(C(F)(F)F)c1

Procedure:
The above compound was prepared by the reaction of 4-(2-phenylethyl)piperazine with the compound of Example 1 by the methods of Examples 16 then 77, mp 235°-237° C.
Reaction SMILES: [Cl-:1].[Ca+2].[Cl-].[Cl:4][C:5]1[C:6]([F:22])=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:12]=3[CH2:11][CH:10](O)[C:9]=2[CH:21]=1.Cl>C(Cl)Cl>[Cl:4][C:5]1[C:6]([F:22])=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:12]=3[CH2:11][CH:10]([Cl:1])[C:9]=2[CH:21]=1
Reactant: OC1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: Fc1ccc2c(c1)Sc1cc(F)c(Cl)cc1C(Cl)C2
Reaction time: 8 h

Procedure:
Powdered anhydrous calcium chloride (5 g) was added to a solution of the alcohol from the preceding preparation (7.6 g) in methylene chloride (100 ml) and anhydrous hydrogen chloride introduced into the suspension for 2 hours. The mixture was then allowed to stand overnight and filtered. The filtrate was evaporated, yielding 7.5 g of the desired 8,10-dichloro-3,7-difluoro-10,11-dihydrodibenzo(b,f)thiepine which is crystallized from cyclohexane. The pure compound melts at 118.5°-119.5° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH:16]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].Cl.O1CCOCC1>CO>[NH:18]1[CH2:17][CH:16]([NH:15][C:13]([N:10]2[CH2:11][CH2:12][N:7]3[N:6]=[C:5]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9]2)=[O:14])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CNC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a stirred solution of Intermediate 339A (0.25 g, 0.50 mmol) in MeOH (5 mL) was added a 4M solution of HCl in dioxane (5 mL, 20 mmol). The resulting solution was allowed to stir at RT for 4 h. The reaction mixture was then concentrated and triturated with diethyl ether to afford Intermediate 339B (0.2 g, 55%). MS(ES): m/z=393 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (dd, J=7.03, 2.01 Hz, 1H) 7.64-7.70 (m, 1H), 7.45 (q, J=8.70 Hz, 1H), 7.18-7.39 (m, 2H), 6.61 (d, J=7.53 Hz, 1H), 5.53 (s, 1H), 4.73 (s, 2H), 4.13 (m, 1H), 3.97-4.04 (m, 2H), 3.83 (br. s., 2H) 3.05-3.16 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+]([O-])=O.CC(C)([O-])C.[K+].C(Cl)(Cl)Cl.[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][OH:26]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[O:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])cc(C)c1OCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of 3,5-dimethyl-4-nitropyridine-1-oxide (2.0 g) in 2,2,3,3,3-pentafluoropropanol (10 g), potassium t-butoxide (2 g) was added gradually at 0° C. over a period of 15 minutes, after which the solution was stirred at 60° C. for 18 hours. The resulting reaction product, after adding chloroform, was subjected to Celite filtration, after which the filtrate was applied on a silica gel (80 g) column, was eluted with ethyl acetate-hexane (1:1) and then with 20% methanol-ethyl acetate and then recrystallized from ether-hexane to give 2.6 g of 3.5-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as crystals (melting point: 89°~91° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=O.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11].[CH3:21][C:22]1[C:27](C)=[C:26](O)[CH:25]=[CH:24][C:23]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH2:6][O:8][C:9]2[CH:25]=[CH:24][C:23]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:22]([CH3:21])[C:27]=2[CH3:26])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc[nH]1
Product: CCc1ccc(-n2cccc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared by reacting methyl 1H-pyrrole-2-carboxylate with 4-ethylphenylboronic acid according to the procedures of Example 1, Steps C and D, then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:40](O)(=[O:43])[CH2:41][OH:42].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][OH:43])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CO)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Temperature: 23 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To the solution of the product of Example 345 (0.0226 g, 0.048 mmol) in N,N-dimethylformamide (0.5 mL) was added triethylamine (0.020 mL, 0.145 mmol), 4-(dimethylamino)pyridine (0.018 g, 0.145 mmol), glycolic acid (0.011 g, 0.145 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.145 mmol). The mixture was stirred at 23° C. for 15 hours and then was heated to 60° C. and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, cooled to 0° C., and hydrochloric acid (4 M in dioxane) was added (0.037 mL, 0.145 mmol). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid/water to 95% acetonitrile in 0.1% trifluoracetic acid/water to give the title compound (10.8 mg, 42%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 2 H) 4.44 (d, J=5.88 Hz, 2 H) 5.61 (bs, 2 H) 7.14 (s, 1 H) 7.29 (m, 5 H) 7.41 (t, J=7.35 Hz, 1 H) 7.52 (d, J=9.19 Hz, 1 H) 7.75 (t, 1 H) 8.21 (dd, 1 H) 8.35 (t, 1 H).
Reaction SMILES: [CH2:1]([C:6]1[CH:17]=[C:10]2[C:11]([O:13][C:14](=O)[NH:15][C:9]2=[CH:8][CH:7]=1)=O)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:18]([C:23]1[CH:31]=[C:27](C(N)=O)[C:26]([OH:32])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22].C[N:34](C=O)C>>[OH:32][C:26]1[CH:25]=[CH:24][C:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:31][C:27]=1[C:14]1[NH:34][C:11](=[O:13])[C:10]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:17]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: CCCCCc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CCCCCc1ccc(O)c(C(N)=O)c1
Product: CCCCCc1ccc(O)c(-c2nc3ccc(CCCCC)cc3c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
2.81 g compound 16 (12.1 mmole) and 2.50 g (112.1 mmole) compound 20 were heated at 150° C. in 10 ml DMF for 3.5 h. The mixture was slowly cooled down to room temperature, the formed crystals were isolated by filtration and washed with 3 ml MeOH. After drying, 2 g of compound 21 was obtained as pale green crystals (43% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To acetone (60 mL) charged with 2-amino-3-nitrophenol (32 mmol, 4.9 g) and K2CO3 (48 mmol, 6.62 g) was added MeI (32 mmol, 1.98 mL). The reaction mixture was stirred rapidly at ambient temperature for 16 h. Acetone was removed under reduced pressure and the residue was partitioned between CH2Cl2 and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure to provide the product as a brown solid. LC-MS (ESI, Method C) 2.56 min, m/z 169.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[N:17]=[C:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:49][S:50]([Cl:53])(=[O:52])=[O:51]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[N:17]=[C:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][N:35]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)[CH2:11]2)=[O:8])=[CH:38][CH:39]=1.[ClH:53]
Reactant: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4)n3)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCN(S(C)(=O)=O)CC5)cc4)n3)C2)cc1
Product: Cl

Procedure:
Compound 163 (32 mg, 0.056 mmol) was dissolved in 3 mL NMP. To it were added DIEA (60 μL, 0.34 mmol) and then methanesulfonyl chloride (13 μL, 0.17 mmol). The reaction was quenched in 20 m using TFA (0.1 mL). The mixture was directly subjected to reverse phase preparative HPLC to isolate (R)-5-(3-(4-methoxybenzamido)piperidin-1-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)pyrazine-2-carboxamide (173) as HCl salt. MS found for C30H37N7O5S as (M+H)+ 608.2, (M−H)− 606.3. UV: λ=304, 335, 372 nm.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]#[N:7])[C:4]#[N:5].[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].S(OC)(OC)(=O)=O.C(N(CC)CC)C.Cl.[C:35]([NH:39][NH2:40])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[NH2:5][C:4]1[N:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:40]=[C:15]([C:14]2[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[C:3]=1[C:6]#[N:7]
Reactant: N#CCC#N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(-c2ccc([N+](=O)[O-])cc2)c(C#N)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (4.80 g, 0.2 mol, 2 eq, 60% dispersion in mineral oil) in tetrahydrofuran (100 mL) was slowly added malonodinitrile (6.61 g, 0.1 mol). 4-Nitrobenzoyl chloride (18.8 g, 0.1 mol, 1 eq) was then added in portions while keeping the reaction temperature below 10° C. The reaction mixture was stirred for 1 hour at room temperature. Dimethyl sulfate (15.1 g, 0.12 mol, 1.2 eq) was then added and the reaction mixture was refluxed for 2 hours. Triethylamine (25.3 g, 0.25 mol, 2.5 eq), followed by tert-butyl hydrazine hydrochloride (12.4 g, 10 mmol), was added and the reaction mixture was heated under reflux for an additional hour. The solvent was then evaporated and 50 mL of ethanol were added. The reaction mixture was heated under reflux, and water (250 mL) was added while keeping the temperature above 50° C. The reaction mixture was then cooled to 10° C. and 5-amino-1-tert-butyl-3-(4-nitro-phenyl)-1H-pyrazole-4-carbonitrile was isolated by filtration. 1H-NMR (DMSO-d6): ppm 1.59 (s, 9H), 6.55 (br s, 2H), 8.05 (d, 2H, J=7.2 Hz), 8.33 (d, 2H, J=7.2 Hz). LC MS (m/e)=285.8 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:5][CH:6]=1
Reactant: C1CCNC1
Reactant: O=Cc1cc(Br)co1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1coc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and pyrrolidine (0.47 mL, 5.74 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (400 mg, 61%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4ccccn4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4ccccn4)CS[C@H]23)cs1
Temperature: -40 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(2-pyridylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (722 mg: 0.70 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) cooling at -40° C. is added a solution of aluminum chloride (744 mg; 5.59 mMol. ) in anisole (2 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (6 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the organic solvents, and passed through a styrene-divinylbenzene copolymer column. The adsorbed material is eluted with methanol-water (4:1). The eluate is concentrated. The residue is washed with ethyl acetate and dried to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(2-pyridylthiomethylthio)-3-cephem-4-carboxylic acid (289 mg). Yield: 79%.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[Cu][C:28]#[N:29].CN(C)C=O.Cl>O>[C:28]([C:2]1[C:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1)#[N:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(C#N)c3c2OC(C)(C)O3)c1=O
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
In a flask are placed 2.20 g (0.005 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil, 0.62 g (0.0069 mole) of copper(I) cyanide and 60 mL of N,N-dimethylformamide. The resulting mixture is heated at reflux for 5 hours. This mixture is then cooled and poured into a solution of 2.5 g of hydrated ferric chloride, 0.62 mL of concentrated hydrochloric acid, and 3.8 mL of water. The resulting mixture is maintained at 60-70 ° C at which it is stirred for 20 minutes. After being cooled the mixture is extracted with methylene chloride, and the extract is washed with dilute hydrochloric acid. The extract is then dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated under reduced pressure, leaving a residue. This residue is passed through a column of silica gel, eluting with ethyl acetate/heptane (1:1 ). The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, leaving 3-(7-cyano-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil (Compound 15) as a residue.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([NH2:16])=O.S(Cl)([Cl:19])=O>CN(C)C=O>[C:14]([C:2]1[CH:1]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([C:11]([Cl:19])=[O:12])[CH:8]=[CH:9]2)#[N:16]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
2.8 g of naphthalene-2,6-dicarboxylic acid monoamide, 10 ml of thionylchloride and 1 drop of dimethylformamide are refluxed for 5 hours. The clear yellow solution is evaporated down in vacuo and the solid evaporation residue is mixed with 20 ml of diethylether and 20 ml of petroleum ether, then stirred and suction filtered. The filter cake is washed with petroleum ether and diethylether and dried in vacuo.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][S:9][CH3:10]>CC(C)=O>[Br-:1].[C:3]([CH2:2][S+:9]([CH3:10])[CH3:8])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CSC
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)C[S+](C)C
Product: [Br-]
Reaction time: 72 h

Procedure:
A solution of ethyl bromoacetate (265 g) and dimethyl sulfide (114 g) in acetone (500 mL) was stirred at room temperature. After three days, the title compound was isolated by filtration of the reaction mixture. Melting point 88-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1Br)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1)[CH3:25]
Reactant: CCc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-ethylbromobenzene. MS (ESI): mass calcd. for C18H16FN3, 293.13; m/z found, 294.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (d, J=1.3, 1H), 7.92 (m, 1H), 7.36 (d, J=3.9, 2H), 7.32-7.19 (m, 4H), 6.71 (s, 2H), 2.60 (q, J=7.5, 2H), 1.06 (t, J=7.5, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:17]=2)=[CH:3]1.[NH2:35][C:36]([NH2:38])=[S:37]>C(O)C>[CH3:32][S:29]([OH:31])(=[O:30])=[O:28].[C:36]([S:37][CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:33])[NH:13][C:12](=[O:34])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1)(=[NH:38])[NH2:35]
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: NC(N)=S
Solvent: CCO
Product: CS(=O)(=O)O
Product: Cn1cc(C2=C(c3cn(CCCSC(=N)N)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 78.8 %

Procedure:
1.455 g of the product of Example 58 in 45 ml of ethanol were treated with 364 mg of thiourea and the mixture was heated at reflux for 18 hours. After cooling the precipitate was filtered off and washed with ethanol and with diethyl ether. The solid was dried to give 1.33 g of 3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesulphonate, m.p. 236°-238° C. (decomposition).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([CH2:10][C:11](=O)[CH3:12])[C:7]([CH3:9])=O.C([O-])(=O)C.[K+]>C(O)(=O)C.O>[Br:2][CH2:3][CH2:4][N:5]1[C:11]([CH3:12])=[CH:10][CH:6]=[C:7]1[CH3:9]
Reactant: NCCBr
Reactant: CC(=O)CCC(C)=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)n1CCBr
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-bromoethylamine hydrobromide (20.5 g, 0.1 mol) and acetonylacetone (12.5 ml, 0.1 mol) in acetic acid (10 ml) was added potassium acetate (10 g, 0.1 mol), and the mixture was stirred for 1 h at 20° C. and for 2 h at 80° C. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether (150 ml). The extract was washed with brine and concentrated in vacuo to afford an oily residue. The residue was distilled at 60-64° C./0.5 mm of mercury to afford the title compound as a colourless oil (9.45 g, 47%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:18]=1[CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][C:25]1[C:17]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:18]([CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:19]([O:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[C:20]2[C:24]=1[CH2:23][O:22][C:21]2=[O:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Trifluoromethanesulfonic anhydride (10.57 g) was added to a solution of methyl (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate in methylene chloride (500 ml) amd pyridine (5 ml) at 0° C. After 6 hours the reaction was added to excess aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[CH:9]=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 46.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 1-(3,5-dimethylpyridin-2-yl)piperazine (256 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (257 mg) was obtained.