Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:21])([CH3:20])[C:9]([NH:11][NH:12]C(OC(C)(C)C)=O)=[O:10])=[CH:4][C:3]=1[O:22][CH3:23].Cl>CCOC(C)=O.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:21])([CH3:20])[C:9]([NH:11][NH2:12])=[O:10])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C(C)(C)C(=O)NNC(=O)OC(C)(C)C)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(C(C)(C)C(=O)NN)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.2 %

Procedure:
To a solution of tert-butyl 2-(2-(4-chloro-3-methoxyphenyl)-2-methylpropanoyl)hydrazine carboxylate (12.63 g, 0.04 mol) in EtOAc (100 mL) at 0° C. was added 2M HCl in Et2O (92 mL). The resulting solution was stirred at room temperature 18 h and concentrated in vacuo. The residue was triturated with Et2O, collected by filtration and dried to give 2-(4-chloro-3-methoxyphenyl)-2-methylpropanehydrazide hydrochloride (6.88 g, 67%) as a white solid. 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 7.41-7.39 (d, 1H), 7.01 (s, 1H), 6.92-6.89 (d, 1H), 3.91 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:22])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)n(Cc2ccccc2F)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)n(Cc2ccccc2F)n1

Procedure:
21.58 g of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate 1-1-2 (81.66 mmol, 1.0 eq) were dissolved in dry acetone. Then 10.17 mL of iodomethane (163.3 mmol, 2.0 eq) and 40.63 g of potassium carbonate (294 mmol, 3.6 eq) were added. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was separated and extracted with DCM twice. The combined organic layers were dried over magnesium sulfate, filtered off and concentrated in vacuo to give 14.74 g (52.96 mmol, 65%) of the crude target compound that was used for the next transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:25]=[C:26]([NH:30]C(=O)C(F)(F)F)[CH:27]=[CH:28][CH:29]=4)=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:37][CH2:38][CH2:39]Cl.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[NH2:30][C:26]1[CH:25]=[C:24]([C:16]2[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH2:38][CH2:39][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH:4]=4)[N:14]=3)=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C1CCNC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCCl)c3)n2)c1)C(F)(F)F
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Yield: 50 %

Procedure:
The compound was synthesized from N-(3-{3-[2-({4-chloro-3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide and pyrrolidine using procedure outlined in Example 10, Step D, to afford a solid in 50% yield. ES-LC/MS m/z 526-[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]([NH2:17])[CH2:7]1)=[O:5])[CH3:2].[N+]([C:21]1C=CC=CC=1CN(CC#N)C(=O)OCC)([O-])=O>>[NH2:17][C:8]1[CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:12]([CH3:21])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: CCOC(=O)N1CC(N)=Nc2ccccc2C1
Reactant: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Product: CCOC(=O)N1CC(N)=Nc2ccccc2C1C
Yield: 13 %

Procedure:
This compound was prepared in a similar manner to (E)-ethyl-2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate (3), substituting ethyl cyanomethyl(1-(2-nitrophenyl)ethyl)carbamate (8) for ethyl-2-nitrobenzyl-(cyanomethyl)carbamate (2), to provide 2.6 mg (0.011 mmol, 13% yield), of the desired product. 1H NMR (400 MHz, CDCl3) δ 1.26 (br s, 3H), 1.40 (d, 3H), 3.45-3.58 (br s, 1H), 4.15-4.29 (m, 2H), 4.44 (br s, 1H), 4.97 (br s, 1H), 7.03-7.06 (m, 2H), 7.18-7.31 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH3:11].O1CCOCC1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:11])(=[O:9])=[O:8])[CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of pyridine-3-sulphonyl chloride (1 g, 5.6 mmol, 1 eq, commercially available from Davos) in THF (5 mL) is added ammonia in dioxane (23.9 mL, 2 M, 47.9 mmol, 8.5 eq). The resulting suspension is stirred at room temperature for 1 h. The solvent is removed and the residue is taken up in DCM. The organic phase is washed with a saturated aqueous solution of NH4Cl then brine and the DCM is removed under reduced pressure to afford, after drying under vacuum at 40° C., 637 mg (71%) of the title compound as a yellowish powder. 1H NMR (DMSO-d6) δ 9.20-8.90 (m, 1H), 8.85-8.75 (m, 1H), 8.40-8.05 (m, 1H), 7.80-7.40 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1C=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1O.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:15]=2[N:14]=[CH:13]1.C(OC(OCC)OCC)(=O)C.O1C2C=C(C(N3CC=CCC3)=O)C=CC=2N=C1.N1CC=CCC1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([N:1]3[CH2:2][CH:3]=[CH:4][CH2:5][CH2:9]3)=[O:23])=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=C(O)c1ccc2ocnc2c1
Agent: C1=CCNCC1
Agent: CCOC(OCC)OC(C)=O
Agent: O=C(c1ccc2ncoc2c1)N1CC=CCC1
Product: O=C(c1ccc2ocnc2c1)N1CC=CCC1

Procedure:
4-Amino-3-hydroxybenzoic acid is converted into 1,3-benzoxazol-5-carboxylic acid by treating with diethoxymethyl acetate as described for the preparation of Invention Compound IX. EMIS m/z=163 (parent), 146 (base), 118, 90, and 63. Coupling of the acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of isomeric Invention Compound IX. 1H NMR δ 2.1-2.4 (br, 4), 3.4-4.3 (br m, 4), 5.5-5.95 (br m, 2), 7.45 (dd, 1, J=8.17, 1.41 Hz), 7.70 (d, 1, J=0.96 Hz), 7.83 (d, 1, J=8.16 Hz), and 8.18 ppm (s, 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40][CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:44].C(OO)(C)(C)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40]([CH3:41])=[O:44])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:35]=[CH:34][CH:33]=[CH:32][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC(C)(C)OO
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 133.3 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (291 mg, 0.49 mmol) was dissolved in chloroform (2.5 mL). Camphorsulfonic acid (20 mg, 0.09 mmol) was added, followed by t-butyl hydroperoxide solution (0.1 mL, 1.00 mmol). The reaction was stirred overnight and then loaded directly onto a column for flash column chromatographic purification (about 30 g silica, 10% EtOAc/CH2Cl2 through 100% EtOAc). The pure material (75 mg, 0.12 mmol, 25%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:23][CH2:24][CH2:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:23][CH2:24][CH2:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC3=NCCS3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1CSC1=NCCS1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.77 g, 1.9 mmol) in anhydrous DCM (41 mL) at room temperature add trifluoroacetic acid (37.7 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (10 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (linear gradient: 100:0 to 90:10 DCM/2M ammonia in methanol over 30 min; 35 mL/min) to afford 7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.58 g, 100%). MS (ES+) m/z: 313.1 (M+H)+.
Reaction SMILES: C(Cl)(=[O:3])C.[C:5]1([CH:11]2[NH:15][CH2:14][CH:13]([CH2:16][Cl:17])[O:12]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:15][CH2:14][CH:13]([OH:12])[CH2:16][Cl:17])(=[O:3])[CH3:5]
Reactant: ClCC1CNC(c2ccccc2)O1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCC(O)CCl
Temperature: 25 °C
Yield: 65 %

Procedure:
15.7 g of acetylchloride are added dropwise to a solution of 39.5 g of 2-phenyl-5-chloromethyloxazolidine in a mixture of 150 ml of chloroform and 16 ml of pyridine at a temperature of -40° C. under agitation. The solution is allowed to warm up to room temperature. After a reaction period of 14 hours, 100 ml of concentrated hydrochloric acid are added. After thoroughly mixing, the aqueous phase is separated and diluted with water to twice its volume and then is saturated with sodium chloride. By extracting the aqueous phase with methylene chloride, drying the methylene-chloride-extract and evaporating the solvent, 19.7 g of N-acetyl-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be used in the following reaction without any purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Brc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
2-bromopyridine (75.0 g, 475 mmol), 3-bromophenylboronic acid (104.8 g, 520 mmol), palladium acetate (2.6 g, 2.5 mol %), triphenylphosphine (5.37 g, 5 mol %) and potassium carbonate (196.0 g, 1425 mmol) was placed in a 2 L 3-neck round bottom flask. 500 mL of dimethoxyethane and 500 mL of H2O was added to the flask. Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for 8 h in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was washed with ethylacetate and the organic fractions were combined and dried over magnesium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 84.0 g of a clear oil (76% yield).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]3[N:19]([C:24]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[F:36])=[O:28])=[CH:25][N:26]=3)[N:20]=[C:21](Cl)[CH:22]=2)=[N:12]1)(C(C)(C)C)(C)C.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:21]2[CH:22]=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][OH:8])[N:12]=3)[C:18]3[N:19]([C:24]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[F:36])=[O:28])=[CH:25][N:26]=3)[N:20]=2)[CH2:38][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccn(CCO)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 110 °C

Procedure:
A mixture of 50A (40 mg, 0.075 mmol) and trans-cyclohexane-1,4-diamine (86 mg, 0.753 mmol) in NMP (0.5 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and purified by reversed-phase preparative HPLC. The desired fractions were concentrated and dried to give 50B (19.3 mg, 51%) as a beige solid. HPLC Rt=2.037 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=495.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:28]([OH:29])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: CCC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 0.72 mL, 1.44 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (435 mg, 1.02 mmol, 78%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Br:39])=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22](=[O:30])[NH:23]C(=O)C(Cl)(Cl)Cl)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+]>CO>[CH:1]([NH:3][C:4]1[S:5][C:6]([Br:39])=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22](=[O:30])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nc(NC=O)sc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.9 g.) was added to an aqueous solution (80 ml.) of sodium bicarbonate (225 mg.), and adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. Methanol (4 ml.) was added to the solution and stirred at room temperature for 2.5 hrs. The reaction mixture was adjusted to pH 7.5 and washed with ethyl acetate. The aqueous solution was adjusted to pH 2.0 with 6N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 0.95 g.).
Reaction SMILES: S1(CCCC1)(=O)=O.[F-:8].[K+].[F-].[Cs+].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=1>[Br-].C([P+](CCCCCCCC)(CCCCCCCC)CCCCCCCC)CCCCCCC>[Cl:25][C:24]1[C:19]([F:8])=[N:20][CH:21]=[C:22]([Cl:26])[CH:23]=1
Reactant: [F-]
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: CCCCCCCC[P+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: Fc1ncc(Cl)cc1Cl
Temperature: 215 °C
Yield: 0.5 %

Procedure:
850 g of sulfolane, 204.3 g (3.3 mol) of potassium fluoride/cesium fluoride (9:1), 7.5 g of potassium carbonate and 20.4 g of tetra-n-octylphosphonium bromide as the phase transfer catalyst were azeotropically dried by removal of about 100 g of sulfolane by distillation (170° C.). 273.5 g (1.5 mol) of 2,3,5-trichloropyridine were then added at 190° C. and the reaction mixture was heated to 215° C. After about 2 h reflux commenced. This was maintained for 20 h, and all the substance which boiled below 3 mm Hg/140° C. was then removed from the reaction mixture by distillation. A first fraction (15.8 g) which contained 14.2 g of 5-chloro-2,3-difluoropyridine and 1.3 g of 3,5-dichloro-2-fluoropyridine (determined by GC by means of internal standard) was obtained. The second fraction (168.0 g) contained 89.4 g of 5-chloro-2,3-difluoropyridine and 64.5 g of 3,5-dichloro-2-fluoropyridine and the third fraction (b.p.>130° C./4 mm Hg) contained 98.5 g (GC) of sulfolane. The fractions were purified by fractionation. The yield was 46% for 5-chloro-2,3-difluoropyridine and 27% for 3,5-dichloro-2-fluoropyridine (total 73%, isolated). The yield of 5-chloro-2,3-difluoropyridine was 63%, relative to reacted material. The amount of 3-chloro-2,5-difluoropyridine, which additionally was about 5% of the quantity of 5-chloro-2,3difluoropyridine, was not taken into account here. (Space yield with respect to 5-chloro-2,3-difluoropyridine: 4.7 g/l·h; selectivity: 82%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[N:7]([NH2:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:20](N)=[NH:21].C(OC(O)C)C.C(Cl)(Cl)Cl>CO>[C:1]([C:5]1[CH:9]=[C:8]2[N:7]([CH:6]=1)[N:15]=[CH:20][N:21]=[C:10]2[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)cn1N
Reactant: N=CN
Agent: CCOC(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(O)ncnn2c1
Yield: 25.6 %

Procedure:
Ethyl 3-tert-Butyl-1-aminopyrrole-5-carboxylate (1.00 g, 4.76 mmol, 1 eq), formamidine acetate (1.46 g, 14.3 mmol, 3 eq.) and ethoxyethanol (10 mL) were mixed and refluxed for 3 hours. The solvent was stripped and then restripped from chloroform (3×) to yield a solid. This solid was stirred in 5 mL MeOH, filtered, and the collected solids rinsed with Et2O and dried to yield 233 mg of a white solid as product. LCMS found: (M+H)++=191.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:11])([CH2:7][CH2:8][CH2:9]C)[CH3:6])(=[O:3])[CH3:2].CC(O)(CCC)C.CC(CCC)CO.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:4][C:5]([CH3:11])([CH2:7][CH2:8][CH3:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)OC(C)=O
Agent: CCCC(C)(C)O
Agent: CCCC(C)CO
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC(C)(C)OC(C)=O
Temperature: 70 °C

Procedure:
Prepared in a manner similar to 2-methylhexan-2-yl acetate, except using 2-methylpentan-2-ol. A 500 mL round bottom flask was charged with pyridine (30 mL), 2-methylpentanol (30 mL, 208 mmol) and was added followed by DMAP (1.213 g, 9.93 mmol). Acetic anhydride (46 mL, 417 mmol) was added slowly and the mixture heated at 70° C. for 20 hours. The reaction was quenched by pouring into a 10° C. Et2O bath on ice. 200 mL of water was added and the mixture was extracted with saturated CuSO4 (4×50 mL). The mixture was then washed with water (2×200 mL), saturated NaHCO3 (1×50 mL) and brine (1×50 mL). Mixture was dried with sodium sulfate, filtered and concentrated in vacuo. Distillation of the concentrate at 90° C. at reduced pressure (100 mtorr) resulted in 95% pure 2-methylpentan-2-yl acetate. 1H-NMR: 400 MHz, (CDCl3): 1.91 (s, 3H); 1.69-1.5 (m, 2H); 1.37 (s, 6H); 1.31-1.25 (m, 2H); 0.87 (t J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[N:45]1([CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
5.0 g. (14.6 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c][1]benzopyran, prepared according to the method of Example 50, 3.14 g. (15.2 mmoles) of dicyclohexylcarbodiimide and 3.15 g. (15.2 mmoles) of γ-piperidinobutyric acid hydrochloride (m.p. 190°-192° ), Cruickshank & Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), are combined with 250 ml. of methylene chloride and stirred for a total of 40 hours at room temperature. The insoluble by-product of dicyclohexylurea is separated by filtration and the methylene chloride is removed using a rotary evaporator. The brown residue is treated with approximately 75 ml. of benzene, and filtered to remove a small amount of insoluble material. The benzene is evaporated and the viscous residue is triturated with about 200 ml. of ether to give the crude product. Recrystallization from benzene yields the desired product.
Reaction SMILES: C([C@@H]1C(OC)=[N:8][C@@H:7]([CH2:12][CH2:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([F:18])([F:17])[F:16])[C:6]([O:25][CH3:26])=N1)(C)C.O.FC(F)(F)C(O)=[O:31].[Cl-].[NH4+]>C(#N)C>[CH3:26][O:25][C:6](=[O:31])[C@@H:7]([NH2:8])[CH2:12][CH2:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCC(c1ccccc1)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H](N)CCC(c1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3-phenyl-butyl)-2,5-dihydro-pyrazine (1.86 g) in acetonitrile (18 ml) were added water (7 ml) and trifluoroacetic acid (3.8 ml). The mixture was stirred overnight at 40° C. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane three times. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=98:2 to yield a light yellow solid, (0.98 g, 71%); MS (ISP): 276.1 ((M+H)+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:31]5[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3C(=O)CCC3C)cn2)CC1
Yield: 26.8 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 5-methylpyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (42 mg) was obtained.