Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].F[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 2-methylimidazole (256 mg, 3.13 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 180 mg, 4.50 mmol) and the resultant solution was stirred at room temperature for 30 min under argon. To the solution was added a solution of 3-fluoropyridine (88 μL, 1.01 mmol) in DMF (1 mL), the resultant solution was heated to 100° C. and stirred overnight. The solution was cooled to rt, poured into aqueous saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.12) to afford the title compound 62 (48 mg, 30% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.69 (m, 1H), 8.63 (m, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 2.38 (s, 3H); LRMS (ESI) m/z calcd for C9H10N3 [M+H]+ 160. found 160; HRMS (ESI) m/z calcd for C9H10N3 [M+H]+ 160.0875. found 160.0866; HPLC>99% (tR=7.75 min, 55 (A):45 (B): 0.032 (C); tR=5.45 min, 55 (A):45 (B): 0.01 (C)).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COCCOC(=O)Cl
Agent: Cl
Product: COCCOC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminobenzimdazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoro-methyl)phenyl)urea hydrochloride and methoxyethyl chloroformate by the same method as in Example 41.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[F:6][CH:7]([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH:7]([F:14])[C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: CCCCC(=O)C(F)F
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CCCC)C(F)F

Procedure:
To a stirred suspension of 3.6 g. of magnesium and 30 mg. of mercuric chloride in 0.33 ml. of ether is added 1.5 ml. of propargyl bromide. The mixture is stirred vigorously for several minutes to initiate reaction, then a solution of 15.5 g. of 1,1-difluoro-2-hexanone and 12.1 ml. of propargyl bromide in 33 ml. of ether is added slowly (dropwise) over a 1.5 hour period, so that the mixture remains gently refluxing (25°-30° C.). After addition, the mixture is stirred at room temperature for 30 minutes, then cooled in an ice bath to 0°-5° C. and quenched by adding 35 ml. of saturated ammonium chloride solution dropwise and then stirred for 30 minutes. The mixture is filtered through Celite and washed with ether. The filtrate is concentrated in vacuo giving a yellow oil. This oil is vacuum distilled at 71° C., 12 mm giving the product as 10.54 g. of colorless oil which becomes pale yellow on standing at room temperature.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:14]CCC.CI>C1COCC1>[C:1]([NH:5][S:6]([C:9]1([CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-tert-butyl-(3-chloro)propylsulfonamide (4.3 g, 20 mmol) was dissolved in dry THF (100 mL) and cooled to −78° C. To this solution was added n-BuLi (17.6 mL, 44 mmol, 2.5 M in hexane) slowly. The dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over a period of 1.5 hours. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 mL, 2.5 M in hexane) was added. The reaction mixture was warmed to room temperature, recooled to −78° C. over a period of 2 hours and a neat solution of methyl iodide (5.68 g, 40 mmol) added. The reaction mixture was allowed to warm to room temperature overnight, quenched with saturated NH4Cl (100 mL) at room temperature. It was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a yellow oil which was crystallized from hexane to provide the product as a slightly yellow solid (3.1 g, 81%): 1H NMR (CDCl3) δ 0.79 (m, 2H), 1.36 (s, 9H), 1.52 (m, 2H), 1.62 (s, 3H), 4.10 (br s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[NH:10][N:9]=[C:8]2/[CH:15]=[CH:16]/[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8](/[CH:15]=[CH:16]/[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:9][NH:10]2)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(/C=C/c3cccs3)n[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(/C=C/c3cccs3)n[nH]c2cc1F
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a mixed solution of 60 mg of 6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic acid methyl ester obtained by Example 142 in a mixture of 2 mL tetrahydrofuran/0.5 mL methanol was added 0.5 mL of 5N sodium hydroxide aqueous solution, and stirred at 50° C.-55° C. for 6 hours. The reaction solution was made acidic with 1N hydrochloric acid, and extracted with 15 mL of ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 53 mg of the title compound as bright yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:25][NH:26][C:27]([NH2:29])=[S:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[N:25][NH:26][C:27]([NH2:29])=[S:28])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Yield: 51.5 %

Procedure:
1,3-bis-(4-fluorobenzoyl)benzene 12 (0.347 g, 1.08 mmol) was dissolved in anhydrous methanol (50 mL). The solution was heated at reflux for 15 min, and thiosemicarbazide (0.049 g, 0.54 mmol) and a catalytic amount of p-toluenesulfonic acid were added. After 10 h at reflux, the resulting solution was concentrated under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, 70:30) afforded the desired 1,3-bis-(4-fluorobenzoyl)benzene thiosemicarbazone (0.11 g, 0.278 mmol, 52% yield) as a white solid; 1H NMR (500 MHz, CDCl3): δ 8.67 (s, 1H, NH), 7.97 (m, 1H, ArH), 7.90 (m, 1H, ArH), 7.83 (m, 1H, ArH), 7.75 (m, 1H, ArH), 7.68 (m, 1H, ArH), 7.500 (m, 2H, ArH), 7.39 (s, 1H, NH2), 7.31 (m, 2H, ArH), 7.22 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 7.16 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 7.06 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 6.36 (s, 1H, NH2); HRMS (ESI) calculated for C21H15F2N3OSH (M+H)+ 396.0970, found 394.0834; HPLC retention time 13.740, 13.966 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:29]#[N:30]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21]([C:29]#[N:30])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccc(Br)cc2)(C2CC2)N1CC(F)(F)F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1ccc(C2(C3CC3)c3cc(Cl)ccc3NC(=O)N2CC(F)(F)F)cc1
Temperature: 190 °C

Procedure:
To a solution of 0.39 g (0.85 mmol) 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 2.5 mL DMF was added 0.13 g (1.4 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 125 mL ether, washed 2×100 mL water and 1×100 mL brine, dried over dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (40 g silica gel cartridge, linear gradient 5-75% EtOAc/hexanes) followed by preperative chiral chromatography (5×50 mm Chiralcel OD, 100% MeOH) provided the first peak (−) 6-chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Optical rotation −83° (c=0.00175 g/mL in CH2Cl2, Na lamp,) 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, NH); 7.64 (br d, 2H, J=7.88 Hz); 7.39 (br d, 2H, J=6.22 Hz); 7.26 (obscured, 1H); 6.85 (br m, 1H); 6.74 (d, 1H, J=8.24 Hz); 4.34 (m, 1H); 4.23 (br m, 1H); 1.62 (m, 1H); 0.82 (m, 2H); 0.20 (m, 1H); 0.097 (m, 1H); MS (Electrospray): exact mass calculated for C20H15ClF3N3O+H 406.0925 found 406.0935 Collect 0.1 g second peak Optical rotation +100° (c=0.002 g/mL in CH2Cl2, Na lamp,).
Reaction SMILES: [CH2:1]=[C:2]1[C:15](=[CH2:16])[CH:14]2[O:17][CH:3]1[C:4]1[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([OH:18])[C:11]=3[CH2:12][C:13]=12.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:18][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:13]1[CH:14]3[O:17][CH:3]([C:4]=1[CH2:5]2)[C:2](=[CH2:1])[C:15]3=[CH2:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C1C(=C)C2OC1C1=C2Cc2c(O)cccc2C1
Reactant: BrCc1ccccc1
Product: C=C1C(=C)C2OC1C1=C2Cc2c(cccc2OCc2ccccc2)C1

Procedure:
By reacting the 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracen-5-ol with benzyl bromide in place of methyl iodide in an analogous manner, there was obtained in good yield 1,2,3,4,9,10-hexahydro-5-benzyloxy-2,3-dimethylene-1,4-epoxyanthracene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:33]=[CH:32][C:23](/[CH:24]=[CH:25]/[C:26]3[NH:30][C:29]([CH3:31])=[N:28][N:27]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:34])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]3[NH:30][C:29]([CH3:31])=[N:28][N:27]=3)=[CH:32][CH:33]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)[nH]4)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nnc(/C=C/c2ccc(Oc3c(-c4ccc(F)cc4C)sc4cc(O)ccc34)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole (15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The vial was charged with BBr3 (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min. The mixture was concentrated to 50% volume and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (7 mg, 0.015 mmol, 48% yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm=2.26 (s, 3H), 2.42 (s, 3H), 6.72-6.83 (m, 5H), 6.88 (dd, J=10.11, 2.53 Hz, 1H), 7.14 (d, J=2.02 Hz, 1H), 7.16-7.26 (m, 2H), 7.29-7.41 (m, 3H). LC/MS (m/z, MH+): 458.1.
Reaction SMILES: C([Li])CCC.Br[C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[CH3:13][C:7]([CH3:14])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
25 ml of a 1.6M solution of n-butyllithium in n-hexane were added dropwise to a solution of 5.3 ml (7 g, 36 mmol) of ethyl bromoisobutyrate in 20 ml of tetrahydrofuran at -75° to -70° C. The mixture was then warmed to -20° C., 6.42 ml (9.43 g, 54 mmol) of benzylbromide were added dropwise and the mixture was subsequently stirred at room temperature for a further 3 hours. Dilute sulfuric acid was then added to the reaction mixture and the mixture was extracted twice with ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude product (6.6 g) was purified by distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[F-:11].[K+].C1CS(=O)(=O)CC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([F:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-nitro-2-chloropyridine (2.0 g, 12.6 mmol) and anhydrous potassium fluoride (2.2 g, 38 mmol) in a combination of sulfalone (6 mL) and benzene (4 mL) was stirred at RT for 20 min. The benzene was then removed by distillation. The resulting mixture was heated at 150° C. for 12 h. The mixture was cooled to RT whereupon water (60 mL) was added. The desired product was separated from the solution via steam distillation. Extraction of the distillate with diethyl ether (2×10 mL) followed by drying (Na2SO4) and concentration gave 5-nitro-2-fluoropyridine as a water white oil (1.3 g, 73%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:2][CH3:1])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0. 14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (5 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES30) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES30) 438 [MH]+.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+:8].CC(C)=O.[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:39][S:38][C@@H:21]2[C@H:22]([NH:25][C:26](/[C:28](/[C:32]3[N:36]=[C:35]([NH2:37])[S:34][CH:33]=3)=[N:29]\[O:30][CH3:31])=[O:27])[C:23](=[O:24])[N:20]2[C:19]=1[C:40]([OH:42])=[O:41])=[O:15]>O>[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:39][S:38][C@@H:21]2[C@H:22]([NH:25][C:26](/[C:28](/[C:32]3[N:36]=[C:35]([NH2:37])[S:34][CH:33]=3)=[N:29]\[O:30][CH3:31])=[O:27])[C:23](=[O:24])[N:20]2[C:19]=1[C:40]([O-:42])=[O:41])=[O:15].[Na+:8]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h

Procedure:
6 g of sodium acetate trihydrate are dissolved in 20 ml of water. 40 ml of acetone and 20 g of cefotaxime in free acid form are added to the stirred solution. The mixture is cooled to 0°. A solution is obtained within 2 to 5 minutes. The solution is filtered through a filter bed and subsequently through a sterile filter. The filters are washed with a chilled mixture of 3 ml of water and 15 ml of acetone. The filtrate is seeded with 0.2 g of seed crystals (Claforan®) and warmed to 20°. The mixture is stirred for 60 minutes. The sodium salt of cefotaxime partially crystallises. In order to compete crystallisation, 300 ml of acetone are added dropwise within 3 hours, and stirring is effected for a further 30 minutes at 20°. The sodium salt of cefotaxime is separated off by filtration, washed with acetone and dried overnight in a vacuum drying chamber at 40° and for 1.5 hours in a stream of dry nitrogen gas at 70°. Crystalline sodium cefotaxime substantially in form of needles is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28]I.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][N:21]2[CH3:28])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CC(=O)NC(=O)N1c1cc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2)c(Cl)c1
Reaction time: 3 h

Procedure:
1 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione in 10 ml of N-methylpyrrolidone was heated at 140° to 160° C. with 10 ml of methyl iodide for four hours and, after addition of a further 10 ml of methyl iodide, for a further three hours. After the mixture had been cooled, water was added and an oil separated out, which slowly became solid and was recrystallized from methanol with the addition of active charcoal. Melting point 223° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.Cl.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:27])[C:25]=1Cl.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:27])[C:25]=1[N:15]1[CH2:16][CH2:17][CH:12]([C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[O:11])[CH2:13][CH2:14]1
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Reactant: Fc1cncc(Br)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3Br)CC2)CC1
Temperature: 150 °C

Procedure:
A mixture of (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (50.65 g, 178.2 mmol), 3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (40 g, 162 mmol) and dipotassium carbonate (94.04 g, 680.4 mmol) in NMP (400 mL) was heated at 150° C. overnight. The mixture was cooled to room temperature then filtered to remove inorganic salts and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (800 mL), washed with brine (100 mL×4), dried (MgSO4), filtered and concentrated in vacuo to afford a brown viscous oil. This residue was purified by silica gel column (approx 800 g of silica), product loaded onto silica in DCM, then eluting with 3% methanol (containing 10% ammonium hydroxide)/DCM to afford the desired product as a brown oil which crystallised on standing (27.44 g, 44%). MS (ES+) 387.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:31]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Agent: Cl
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1cccnc1

Procedure:
The title compound of Step A was prepared from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester, prepared in Step A of Example 11c, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method of Example 1, Step B. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, 1H), 8.80 (m, 1H), 8.09 (m, 1H), 7.91 (d, 2H), 7.86 (m, 1H), 7.46 (m, 1H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 (t, 2H), 1,48 (m, 2H), 1.37 (m, 2H), 1.14 (m, 4H); MS 474 (M+1)
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:55])[C:36]([CH3:54])([O:47]C1C=CC=CC=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([O:45][CH3:46])[CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:44][C:41]3[CH:42]=[CH:43][C:38]([CH2:37][C:36]([CH3:54])([O:47][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:35]([OH:34])=[O:55])=[CH:39][C:40]=3[O:45][CH3:46])[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 7, Part D) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a steam of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to provide analytically pure material. MS (EI) 564.4 (M+H)+.