Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[I:11]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1I
Temperature: 65 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a 500 mL round-bottomed flask was added 5-fluoro-2-iodo-benzoic acid (23 g, 86.5 mmol) in methanol (230 mL). To the resulting solution was added conc. sulfuric acid (2.3 mL, 43.2 mmol). The reaction mixture was warmed to 65° C. and stirred for 15 h. The resulting mixture was concentrated under reduced pressure to give crude product which was then was partitioned between EtOAc (250 mL) and a half sat. Na2CO3(aq) solution (250 mL). The layers were thoroughly mixed and then separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil (23 g, 95% yield). 1H NMR (400 MHz, CDCl3): 7.94 (dd, J=8.7, 5.4 Hz, 1H), 7.54 (dd, J=9.0, 3.1 Hz, 1H), 6.93 (m, 1H), 3.94 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH2:22][CH3:23])(=O)=O)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:27]([O:26][C:25](=[O:29])[NH:24][CH:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][CH2:17][S:18][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[CH:6]1[CH2:5][C:4]1[CH:3]=[CH:2][CH:32]=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCCS(=O)(=O)CCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCSCCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OCC)CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
Ethyl 1-(3-chlorobenzyl)-7-(2-(propylsulfonyl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (27.1 mg, 0.057 mmol) and ammonium formate (71.5 mg, 1.134 mmol) were dissolved in 5 ml MeOH. Pd/C (0.845 mg, 7.94 μmol) was added and stirred at 80° C. for 4 h. The mixture was filtered, the solvent evaporated, the residue re-dissolved in ethyl acetate, which was subsequently washed with water, NaHCO3 and brine, dried, filtered. Solvent was evaporated to obtain white solid which was purified by chromatography affording 12.7 mg of product as a white solid.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[C:3]2[C:6]3[C:12](=[CH:13][C:2]=12)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:14][C:15]1C=CC=C2C(=CC3C2=CSC=3)[CH:16]=1.C1SC=C2C3C(=CC=12)C=CC=CC=3>>[CH:15]([C:8]1[CH:7]=[C:6]2[C:12]([CH:11]=[CH:10][CH:9]=1)=[C:13]1[C:4]([S:5][CH:1]=[CH:2]1)=[CH:3]2)([CH3:16])[CH3:14]
Reactant: c1ccc2cc3cscc3c-2cc1
Reactant: Cc1cccc2c3cscc3cc-2c1
Product: CC(C)c1cccc2c3ccsc3cc-2c1

Procedure:
The position numbering system of the following azuleno[1,2-c]thiophene derivatives is ##STR12## Azuleno[1,2-c]thiophene 7-Methylazuleno[1,2-c]thiophene
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].Cl.[OH:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:2][C:1](=[N:25][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:4]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Yield: 110.1 %

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (1.67 g) obtained in Example 2 was dissolved in ethanol (10 mL), and hydroxyamine hydrochloride (1.17 g) and potassium carbonate (3.11 g) were added thereto, heated under reflux for 2 hours, and the solvent was evaporated away, the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away to obtain 2.04 g of the entitled compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35].N1C=CC=CC=1>C(Cl)Cl>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34]([O:1][C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[C:18]3[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=3)=[C:9](\[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)/[CH2:10][CH3:11])=[CH:4][CH:3]=2)=[O:35])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of compound 12 (0.5 g, 1.17 mmol, ˜9:1 Z/E ratio by 1HNMR) in CH2Cl2 (10 mL) was added p-nitrophenyl chloroformate (0.35 g, 1.76 mmol) and pyridine (0.29 mL, 0.28 g, 3.58 mmol). The reaction mixture was stirred at ambient temperature for 18 h and then concentrated. The residue was purified by chromatography (silica gel, hexanes/EtOAc, 8:1) to provide 38 (0.63 g, 91%, ˜9:1 Z/E mixture) as a cream-colored solid foam. 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, J=7.4 Hz, 3H), 1.42 (s, 9H), 2.39 (q, J=7.4 Hz, 2H), 6.50 (d, J=16 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 7.1-7.8 (m, 14H), 8.3-8.4 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[CH:12][C:13]=2[Cl:14])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=2[Cl:14])[CH2:15][Br:18])=[O:7])=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cc(CBr)ccc1Cl
Yield: 50.5 %

Procedure:
A refluxing solution of 3-(4-chlorobenzoyl)-4-chlorotoluene (5.3 g, 20. mmol) and dibenzoylperoxide (200 mg, 0.83 mmol) in benzene (200 ml) was treated in portions with N-bromosuccinimide (4.4 g, 25. mmol) over 20 minutes. The mixture was refluxed 15 hours, cooled and filtered. The filtrate was evaporated under vacuum, triturated with diethyl ether (150 ml), filtered, and evaporated under vacuum. The residue was chromatographed on silica gel (500 g) eluted with 97:3 (v/v) n-hexane-ethyl acetate using a preparative high-performance liquid chromatograph to provide 3.47 g (50%) of 3-(4-chlorobenzoyl)-4-chlorobenzyl bromide, m.p. 81°-83° C.
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](=O)C1C=CC(CCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([OH:31])=O>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[C:29]([N:3]([O:2][CH3:1])[CH3:4])=[O:31]
Reactant: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide but substituting 3-Chloro4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. (M+H m/z=356.9).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: Cc1cc(Cl)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-chloro-2-methylphenylboronic acid (CAS RN 209919-30-2). Off-white solid (27%). MS (ESI): m/z=472.8 [M+H]+.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.O[C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:42]=[C:39]1[NH:38][C:37]2[CH:43]=[C:33]([C:31]([NH:30][CH:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:17]4[CH:16]=[N:15][C:14]5[C:19]([N:18]=4)=[CH:20][C:11]([O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:12][CH:13]=5)[CH2:29][CH2:28]3)=[O:32])[CH:34]=[CH:35][C:36]=2[S:41][CH2:40]1
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (519 mg, 2.92 mmol, 20.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (610.4 μL, 4.38 mmol, 30.0 eq). After 30 minutes stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford methanesulfonic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as an off-white powder (25 mg, 26% yield).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH2:12][CH3:13])[CH2:10][SH:11].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:11][CH2:10][CH:9]([CH3:8])[CH2:12][CH3:13])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCC(C)CS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 2-methylbutane-1-thiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 4.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (80 mg, yield 32%).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3-Hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) was obtained as a yellow crystalline solid; mp 215-216° C., lit [25] 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:8]1[S:13][CH:12]=[C:11]2[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH3:17])[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCOc1nc2ccsc2c(=O)n1CCC
Solvent: c1ccncc1
Product: CCCOc1nc2c(Cl)scc2c(=O)n1CCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
In a sulfonation flask, 2.02 g (0.008 mol) of 2-propoxy-3-propylthieno[3.2-d]pyrimidin-4-one are added, with stirring, to 10 ml of absolute pyridine. The internal temperature is then raised to 70° C. and then 1.60 g (0.012 mol) of N-chlorosuccinimide (NCS) are added over about 5 min in smallish portions. After stirring for 1 hour at 70-75° C., the pyridine is removed in a water-jet vacuum and the residue is taken up in ethyl acetate. The mixture is washed repeatedly with dilute aqueous hydrochloric acid, dried over sodium sulfate and then the solvent is removed in the water-jet vacuum. The crude product so obtained is purified by column chromatography over silica gel (eluant: n-hexane/ethyl acetate=9:1), giving 2.2 g of 7-chloro-2-propoxy-3-propylthieno[3.4-d]pyrimidin-4-one in the form of a green powder having a melting point of 93-95° C.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:11](=[O:12])[C:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:9][S:8][CH2:7]1)([O:3]C)=[O:2].O1CCCC1.Cl>O>[C:1]([CH2:5][N:6]1[C:11](=[O:12])[C:10]([N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])=[CH:9][S:8][CH2:7]1)([OH:3])=[O:2]
Reactant: COC(=O)CN1CSC=C(N2C(=O)c3ccccc3C2=O)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CSC=C(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
A 24 mg. (0.07 mmole) sample of the methyl ester product obtained in Step A. above, in a solution of 1.5 ml. of tetrahydrofuran, 0.5 ml. of water, and 0.25 ml. of concentrated hydrochloric acid, was refluxed under nitrogen for 3.5 hrs. The solution was cooled and diluted with 5 ml. of water and then extracted four times with a total of 15 ml. of dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was triturated with dichloromethane and crystals formed, which were washed with dichloromethane and dried to give 10.1 mg. of product having a m.p. of 227°-228° C. The mother liquor on concentration in vacuo also crystallized to give 13.3 mg. of product.
Reaction SMILES: [Cl:1][CH:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:5])=[O:4].[Cl:21]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]([Cl:21])([C:13]1[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=1[F:19])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CC(S(=O)(=O)C(Cl)c2c(F)cccc2F)=NO1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(Cl)(Cl)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2 lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.38 ml, 0.77 mmol) was added dropwise at 0° C. to a solution of 3-[chloro-(2,6-difluoro-phenyl)methanesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (prepared according to Example P3) (0.2 g, 0.64 mmol) in THF (5 ml). The solution was stirred for 10 minutes at room temperature. N-chlorosuccinimide (NCS) (0.10 g, 0.77 mmol) was added and the mixture was stirred for 1 hour at room temperature. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was recrystallised from ethanol to give the product (Compound No. 1.26 of Table 27) as a white solid (110 mg, 48% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].C1COCC1>CO.[Ni]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Br)c1O

Procedure:
A solution of 5.3 g (22.7 mmol) 2-bromo-6-nitro-phenol in 100 ml MeOH:THF=1:1 is hydrogenated in the presence of 0.2 g Ra—Ni (in EtOH, Degussa B113W). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)([Cl:19])(=O)=O>CC(O)=O>[NH2:1][C:2]1[C:10]([Cl:19])=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 2-amino-5-trifluoromethoxybenzoic acid (49.0 g, 0.22 mol; see step (ii) above) in HOAc (1200 mL) was slowly added sulfuryl chloride (41.8 g, 0.31 mol). Gas evolution was observed. The resulting heterogeneous mixture was stirred at room temperature for 1 h. Additional HOAc (300 mL) was added to aid stirring, followed by sulfuryl chloride in 5 mL portions until the starting material was consumed based on TLC analysis. The reaction was concentrated in vacuo to give solids that were flushed on a rotary evaporator with EtOAc (2×) followed by Et2O (1×) to remove the HOAc. The resulting solids were further dried to give the HCl salt of the crude sub-title compound (60.5 g, 94%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[C:23]1([C:29]#[C:30][CH2:31]O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C@H:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCC#Cc1ccccc1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Yield: 55.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl}2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.159 g (1.2 mmol) of 3-phenyl-2-propyn-1-ol provided 0.254 g (55%) of methyl (3S)-2,2-dimethyl4-({4-[(3-phenyl-2-propynyl)-oxy]phenyl)sulfonyl)-3- thiomorpholine carboxylate as a pale yellow solid. Electrospray Mass Spec: 460.1(M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[C:28](=[O:31])[NH:29][N:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]([CH2:32][C@H:33]([OH:38])[C:34]([F:36])([F:37])[F:35])[C:28](=[O:31])[N:29]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:18])([F:17])[F:16])[N:4]=3)[N:30]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccccc1-c1nccc(CBr)n1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3ccccc3C(F)(F)F)n2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 96 h

Procedure:
303 mg (0.19 mmol) of the compound from Example 80A (purity about 20%) were dissolved in 2 ml of acetonitrile, and 65 mg (0.21 mmol) of the compound from Example 5A and 93 mg (0.29 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2.5 h and at RT for a further 96 h. The solid was then filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. This gave 19 mg of the target compound, which were subjected to a further chromatographic purification on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3, then 1:1). This gave 8 mg (7% of theory) of the target compound.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18]Cl)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[I-:46].[Na+].[C:48]([NH2:56])(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1.C(OC(C)C)(C)C>CN(C)C=O>[I-:46].[CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18][N+:52]4[CH:53]=[CH:54][C:49]([C:48](=[O:55])[NH2:56])=[CH:50][CH:51]=4)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccncc1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: NC(=O)c1cc[n+](CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate 1-oxide (syn isomer) (2.5 g) and sodium iodide (3.4 g) in N,N-dimethylformamide (20 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added isonicotinamide (0.91 g) under ice-cooling and the mixture was stirred for 2 hours at the same temperature. The mixture was poured into diisopropyl ether to give an oil. The oil was separated by decantation and triturated with water. The solid was dissolved in tetrahydrofuran, dried over magnesium sulfate, concentrated under reduced pressue, and triturated in diisopropyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer) as a solid.