Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[C:13](=S)=[S:14].[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[O:10][C:13]([SH:14])=[N:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc(Cc2ccc(Cl)cc2)o1
Yield: 45.3 %

Procedure:
A stirred solution of 7.0 grams (0.038 mole) of 4-chlorophenylacetic acid hydrazide, 3.0 grams (0.039 mole) of carbon disulfide and 2.8 grams (0.050 mole) of potassium hydroxide in 10 ml of water and 200 ml of ethanol was heated under reflux for four hours. The ethanol was removed under reduced pressure. The concentrate was taken up in water and the mixture washed with diethyl ether. The aqueous layer was acidified with aqueous 5% hydrochloric acid and then was extracted with diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 3.9 grams of 2-(4-chlorophenylmethyl)-5-mercapto-1,3,4-oxadiazole; m.p. 115° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>CC(O)=O.[Fe]>[F:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of 281 (288 mg, 0.94 mmol) in AcOH (25 mL) at 90° C., was added iron powder (238 mg, 4.25 mmol), and the reaction mixture was stirred vigorously at 90° C. for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 282 (248 mg, 95%) as an off-white solid. MS (m/z): 308.1(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH2:23][CH:24]([CH3:26])[CH3:25])[C:5]=2[CH:6]=1
Reactant: COC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(C)C)c2cc(C)oc2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-hydroxy-6-methoxycarbonylbenzofuran (Method 12; 412 mg, assumed 1.0 mmol) was stirred in anhydrous DMF (10 ml) and the solution treated sequentially with potassium carbonate (690 mg, 5 mmol, 5 eq) and 1-iodo-2-methylpropane (442 mg, 276 μl, 2.4 mmol, 2.4 eq). The reaction mixture was stirred at 90° C. for 3 hours, then cooled and poured into water; the resulting mixture was extracted twice with ethyl acetate, the extracts dried (MgSO4) and evaporated in vacuo to yield a brown oil. This was chromatographed (50 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound as a clear oil contaminated with ca 15% of the corresponding iso-butyl ester. NMR: 1.02 (d, 6H), 2.06 (sept, 1H), 2.45 (s, 3H), 3.84 (s, 3H), 3.91 (d, 2H), 6.66 (s, 1H), 7.24 (s, 1H), 7.66 (s, 1H); the spectrum also contained signals consistent with isobutyl ester, ca 15 mol %.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.C([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1B(O)O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:15]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cc3ccccc3[nH]2)cc1-c1nc2ccccc2s1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (25 mg, 0.080 mmol), 1-Boc-indole-2-boronic acid (40 mg, 0.20 mmol) and potassium carbonate (34 mg, 0.24 mmol) in 1,4-dioxane (1.4 mL) and H2O (0.5 mL) was degassed and refilled with argon (3×) prior to the addition of Pd(dppf)Cl2 (6 mg, 0.01 mmol). The reaction mixture was degassed and refilled with argon (2×) and left to stir at 100° C. in the microwave reactor for 30 min. Then, the mixture was passed through PL-Thiol MP SPE resin and concentrated in vacuo. The residual oil was partitioned between DCM and H2O. The combined organic layers were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting Boc-protected intermediate was left to stir in (1:1) DCM:TFA mixture (1.0 mL) at rt for 15 min. Purification via MDP afforded the title compound as a yellow solid. MS (ES+): m/z=343.08 (100) [MH+]. HPLC: tR=4.00 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>O>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: CCN1C(=O)C(N=[N+]=[N-])CCc2c1ccc([N+](=O)[O-])c2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(N)CCc2c1ccc([N+](=O)[O-])c2OC

Procedure:
Combined (+/−)-3-Azido-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (280 mg), Triphenylphosphine Resin (1.0 mmol/g loading; 1.83 g,), Tetrahydrofuran (25 mL) and Water (0.25 mL) and stir at rt overnight. Filter and concentrate. Strip down from benzene to remove water. (+/−)-3-Amino-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an orangish oil isolated (251 mgs). 1H-NMR (CDCl3, 400 MHz): 7.84 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.36-4.28 (m, 1H), 3.97 (s, 3H), 3.71-3.62 (m, 1H), 3.36-3.31 (m, 1H), 3.23-3.18 (m, 1H), 2.52-2.39 (m, 2H), 2.03-1.99 (m, 1H), 1.66 (broad s, 2H), 1.21 (t, J=7.3 Hz, 3H). LC/MS: (M+H)+ found 280.18.
Reaction SMILES: O=CC1C=CC(O)=C(OC)C=1.[H-].[Na+].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=1[O:26][CH3:27].OC1C=CC(CCC(O)=O)=CC=1OC.[Cl:42][C:43]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:44]=1[CH2:45]Cl.S(=O)(=O)(O)O>CN(C)C=O>[Cl:42][C:43]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:44]=1[CH2:45][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=1[O:26][CH3:27]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: COc1cc(C=O)ccc1O
Agent: COc1cc(CCC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COc1cc(CCC(=O)O)ccc1OCc1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
16.6 g. of vanillin, 22.4 g. of triethylphosphonoacetate, and 5.75 g. of sodium hydride - oil suspension (80%) in 100 ml. of dimethylformamide are reacted analogously to Example 75. Reaction time: 6 hours at 100°. 21 g. of the thus-obtained ethyl ester of 3-(4-hydroxy-3-methoxyphenyl)-acrylic acid is hydrogenated as described in Example 75. 10 g. of the thus-formed ethyl ester of 3-(4-hydroxy-3-methoxyphenyl)-propionic acid is combined in 100 ml. of dimethylformamide with 1.34 g. of sodium hydride - oil suspension (80%), and after 15 minutes at room temperature, 8.8 g. of 2,4-dichlorobenzyl chloride is added thereto. After 2 hours at room temperature, the mixture is poured on 1N sulfuric acid and extracted with ethyl acetate. After drying and evaporation, 17 g. of the ethyl ester of 3-[4-(2,4-dichlorobenzyloxy)-3-methoxyphenyl]-propionic acid is obtained and slowly combined in 200 ml. ether with 7.1 g. Br in 10 ml. of carbon tetrachloride. After the bromine coloring has disappeared, the mixture is extracted with water and potassium bicarbonate solution, and the ether phase is dried and evaporated. After recrystallization from ethanol, 13.9 g. of the ethyl ester of 3-[2-bromo-4-(2,4-dichlorobenzyloxy)-5-methoxyphenyl]-propionic acid is obtained, m.p. 102°-106° By lithium aluminum hydride reduction of 10 g. of this compound in tetrahydrofuran, 7.5 g. of 3-[2-bromo-4-(2,4-dichlorobenzyloxy)-5-methoxyphenyl] -1-propanol is obtained, m.p. 102°-103°. This product is reacted analogously to Example 75 with thionyl chloride and then with sodium imidazole to obtain the final product. Yield: 2.72 g.; m.p. 142°-144° (from acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 49 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (39 mg, 49%) which was obtained as a white solid. MS: m/e=398.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][Br:23])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccccc2)CC1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Temperature: -1.7999999523162842 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of (4-phenylcyclohexyl)-acetic acid ethyl ester (10.0 g, 40.6 mmol) (patent WO2004 047755) in DCM (100 mL) at 0° C. is added AlCl3 (9.94 g, 74 mmol) portionwise. After it is stirred at −1.8° C. for 10 min, bromoacetyl bromide (3.59 mL, 40.6 mmol) is added dropwise over 2 min. The reaction mixture is allowed to stir at −1.8° C. for 2 h. It is then poured slowly to water/ice mixture (200 mL) and stirred for 30 min. The mixture is extracted with DCM (2×50 mL). The organic phase is separated and washed with NaHCO3 (3×100 mL), and brine (3×100 mL), dried with Na2SO4, concentrated and dried under high vacuum to give the title compound (12.8 g) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.17 (m, 2 H) 1.20 (t, J=8.00 Hz, 3 H) 1.39-1.51 (m, 2 H) 1.56-1.68 (m, 1 H) 1.76-1.87 (m, 4 H) 2.18 (d, J=4.29 Hz, 2 H) 2.48 (td, J=12.32, 2.65 Hz, 1 H) 4.08 (q, J=7.24 Hz, 2 H) 4.35 (s, 2 H) 7.25 (d, J=8.34 Hz, 2 H) 7.85(d, J=8.59 Hz, 2 H).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:18][C:19](=[O:21])[CH3:20])[CH2:10][O:11]C1CCCCO1)([O-:3])=[O:2]>Cl.O1CCOCC1>[N+:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:18][C:19](=[O:21])[CH3:20])[CH2:10][OH:11])([O-:3])=[O:2]
Reactant: CC(=O)N[C@@H](COC1CCCCO1)C(=O)NCCO[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](CO)C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
In 5 ml of 4N-hydrogen chloride/dioxane solution was dissolved 0.42 g of (2S)-N-(2-nitrooxyethyl)-2-acetylamino-3-(tetrahydropyran-2-yl)oxypropanamide, and the resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was neutralized with aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography through silica gel using ethyl acetate as an eluent and recrystallized from ethyl acetate to give 48 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].Cl[C:10]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[C:11]([C:12]#[N:13])=[CH:14][CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[N:17]=1
Reactant: CN(C)CCO
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1nc(C(F)(F)F)ccc1C#N
Temperature: 65 °C
Yield: 92 %

Procedure:
To N,N-dimethylaminoethanol (25 mL) at 0° C. was added in small portion NaH 60% (4 mol eq, 0.465 g, 11.62 mmol) and after 10 min 2-chloro-6-trifluoromethyl-nicotinonitrile (0.6 g, 2.90 mmol) was slowly added. The mixture was heated at 65° C. for 4 h. Then the solvent was removed at reduced pressure, water was added and the aqueous phase was extracted with EtOAc (3×30 mL). The recombined organic phases were washed with brine, anhydrified over Na2SO4 and evaporated at reduced pressure to obtain a pale yellow oil (0.69 g, 2.66 mmol, 92% Yield) used for the next step of reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.Cl.[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([NH2:45])[CH2:41][CH2:42][CH2:43][CH3:44]>N1C=CC=CC=1.CCOC(C)=O>[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([NH:45][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[NH2:1])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC[C@H](NC(=O)c1ccc(OC)cc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 2-amino-4-methoxy-benzoic acid (1.0 g, 5.98 mmol) and 1,1′-carbonyldiimidazole (980 mg, 6.04 mmol) in pyridine (5 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL, 6.02 mmol). The mixture is stirred at room temperature for 2 hours follows by the addition of (S)-2-amino-hexanoic acid methyl ester hydrochloride (1.1 g, 6.06 mmol). The reaction mixture is stirred at room temperature for 16 hours and diluted with EtOAc (100 mL), the solution is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, and is concentrated. The resulting residue is purified by flash chromatography with 60% EtOAc in hexanes as the eluent to afford (S)-2-(2-amino-4-methoxy-benzoylamino)-hexanoic acid methyl ester (1.03 g, 59%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[N:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[N:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nn2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nn2)CC1
Yield: 40.3 %

Procedure:
The title compound (0.22 g, 40%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.30 g, 1.46 mmol), 1,1-dimethylethyl 4-{[(6-chloro-3-pyridazinyl)oxy]methyl}-1-piperidinecarboxylate (0.40 g, 1.22 mmol), 2M Na2CO3 (7 mL) and Pd(PPh3)4 (15 mg, 0.01 mmol) in DME (7 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.25 (d, 2H, J=8.3 Hz), 8.16 (d, 1H, J=8.3 Hz), 8.09 (d, 2H, J=8.3 Hz), 7.30 (d, 1H, J=8.3 Hz), 4.42 (d, 2H, J=6.3 Hz), 4.15-4.05 (m, 2H), 3.17 (s, 3H), 2.90-2.75 (m, 2H), 2.20-2.05 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [Na].[OH:2][CH:3]1[CH2:7][CH2:6][C:5](=[N:8]O)[C:4]1([CH3:11])[CH3:10]>C(O)CC.[Cl-].[Na+].O>[NH2:8][CH:5]1[CH2:6][CH2:7][CH:3]([OH:2])[C:4]1([CH3:11])[CH3:10]
Reactant: CC1(C)C(=NO)CCC1O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC1(C)C(N)CCC1O
Temperature: 25 °C
Yield: 95.6 %

Procedure:
Sodium (2.312 g, 101 mmol) was added in small portions over 30 min to a solution of 3-hydroxy-2,2-dimethylcyclopentanone oxime (3.60 g, 25.1 mmol, from Step 2) in n-propanol (50 mL) at 80° C. The resultant mixture was heated to 100° C. for 2 h, cooled to room temperature, poured into brine (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give crude 3-amino-2,2-dimethylcyclopentanol (3.10 g), which was used in the next reaction without purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:21][C:22]([CH2:24][O:25][N:26]=[C:27]([C:61]1[N:62]=[C:63]([NH2:66])[S:64][CH:65]=1)[C:28]([NH:30][CH:31]1[C:59](=[O:60])[N:33]2[C:34]([C:43]([O:45]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:44])=[C:35]([CH:39]=[C:40]([F:42])[F:41])[CH2:36][S:37](=[O:38])[C@H:32]12)=[O:29])=[O:23])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl>[C:22]([CH2:24][O:25][N:26]=[C:27]([C:61]1[N:62]=[C:63]([NH2:66])[S:64][CH:65]=1)[C:28]([NH:30][CH:31]1[C:59](=[O:60])[N:33]2[C:34]([C:43]([OH:45])=[O:44])=[C:35]([CH:39]=[C:40]([F:41])[F:42])[CH2:36][S:37](=[O:38])[C@H:32]12)=[O:29])([OH:23])=[O:21]
Reactant: Nc1nc(C(=NOCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=C(F)F)CS(=O)[C@H]23)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(C=C(F)F)CS(=O)[C@H]23)cs1
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Trifluoroacetic acid (0.805 g) was added to a suspension of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(2,2-difluorovinyl)-3-cephem-4-carboxylate-1-oxide (syn isomer) (0.3 g) in methylene chloride (0.6 ml) and anisole (0.382 g) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was dropwise added to diisopropylether (10 ml) and the precipitates were collected by filtration. The precipitates were added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(2,2-difluorovinyl)-3-cephem-4-carboxylic acid-1-oxide (syn isomer) (0.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl-].[NH4+]>>[Cl:14][C:15]1[N:20]=[C:19]([NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCCNC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
2-Amino-N-propyl-benzamide (0.360 g, 0.00202 mol), 2,4,5-Trichloro-pyrimidine (0.370 g, 0.00202 mol) and Potassium carbonate (0.837 g, 0.00606 mol) were dissolved in N,N-Dimethylformamide (10.0 mL, 0.129 mol) and the reaction was heated at 90° C. and was allowed to stir overnight. The reaction mixture was then cooled was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 420 mg (64%) of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-propyl-benzamide. LC/MS (ESI): 325.12. 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-butyl-benzamide was made in an analogous fashion replacing 1-aminopropane with 1-aminobutane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2.CCN(C(C)C)C(C)C.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([S:34][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2ccc(SCc3ccccc3)cc2C1
Temperature: 90 °C
Yield: 92.1 %

Procedure:
To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (2 g, 6.71 mmol) in 1,4-dioxane (17.1 mL) in a round bottom flask was added Pd2(dba)3 (0.154 g, 0.168 mmol), xantphos (0.194 g, 0.335 mmol), DIPEA (2.343 mL, 13.41 mmol) and benzyl mercaptan (0.873 mL, 7.38 mmol) and the resulting mixture was stirred and heated at 90° C. under nitrogen for overnight. The reaction mixture was filtered through celite, rinsed with ethyl acetate and the filtrate concentrated in vacuo. The residue was purified on silica gel, eluting with ethyl acetate in cyclohexane (0-20%) to afford the title compound (2.11 g). LCMS (A): m/z [(M-tBu)+H]+ 286, C20H23NO2S requires 341 (acidic).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH:2]([CH3:4])[CH3:3].Cl[CH:10]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:6]1[O:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([C:18]([F:19])([F:21])[F:20])[N:8]=1
Reactant: CC(C)CNC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCOC(=O)c1oc(NCC(C)C)nc1C(F)(F)F
Yield: 33.7 %

Procedure:
By the procedure of Example 4, 7.0 g (60 mmol) of isobutyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 4.72 g of a yellow powder product (m.p.=43°-44° C.) identified in Table I.