Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52%) as a light yellow foam: [α]23589=−27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703, found 470.0705.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.7 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), isobutyl bromide (0.64 g, 4.6 mmol) and potassium carbonate (0.57 g, 4.1 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.08 g, 19%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cn1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
The acid chloride from step 2 (0.801 g, 3.633 mmol) in DCM (10 mL) was added to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.928 g, 2.906 mmol) in DCM (20 mL). Triethylamine (1.009 mL, 7.266 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with a 0-50% ethyl acetate/petroleum ether gradient yielded the title compound as a yellow oil (1.432 g). δH (CDCl3, 400 MHz) 8.34 (1H, br.s), 7.72 (1H, br.d), 7.38 (1H, br.d), 7.18 (2H, br.m), 6.98 (2H, br.s), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, td), 2.68 (1H, d), 2.47 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.45 (9H, s), 1.19 (3H, d). MS (ES): MH+ 503/505.
Reaction SMILES: [CH2:1]([N:6]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([C:30]([N:32]([CH2:34][CH2:35][N:36](C)[C:37](OC(C)(C)C)=O)[CH3:33])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1(OC)C=CC=CC=1.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:45]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:11]([C:30]([N:32]([CH2:34][CH2:35][NH:36][CH3:37])[CH3:33])=[O:31])[CH2:10]1)=[O:8])[CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)N(C)CCN(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)N(C)CCNC)C1
Yield: 98 %

Procedure:
To a mixture of 130 mg (0.19 mmole) of 4-(N,N-di-n-pentylcarbamoyl)-1-(N,N-diphenylcarbamoyl)-2-(2-(N-methyl-N-(t-butoxycarbonyl)amino)-N-(methyl)ethylaminocarbonyl)piperazine and 0.4 mL of anisole at 0° C. was added 2 mL of trifluoroacetic acid precooled to 0° C. After 45 min the solution was concentrated in vacuo and the residue purified by flash chromatography on 16 g of silica gel eluting with 100:9 CH2Cl2 :MeOH to give 130 mg (98%) of an oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(CCN)=CC=1.C1(=O)CCCCC1.C([O:47][C:48](=[O:51])[CH2:49][CH3:50])C>>[CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:50][CH2:49][C:48]([OH:51])=[O:47])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Agent: NCCc1ccccc1
Solvent: O=C1CCCCC1
Product: O=C(O)CCSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1

Procedure:
3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-phenethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:13]=[CH:12]C(C3C=CC(B4OC(C)(C)C(C)(C)O4)=CN=3)=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=3[N:43]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C(Cl)Cl.CC(C)=O.C(Cl)Cl.C1COCC1>[C:8]1([N:7]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:1]2[CH:6]=[CH:5][C:4]([C:39]3[N:40]=[CH:41][C:36]([C:36]4[CH:41]=[N:40][C:39]([C:42]5[N:46]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[C:45]6[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=6[N:43]=5)=[CH:38][CH:37]=4)=[CH:37][CH:38]=3)=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:56]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)nc1
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: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(-c5nc6ccccc6n5-c5ccccc5)nc4)cn3)cc2)cc1
Yield: 176 %

Procedure:
Following the procedure for 3, 2 (0.758 g, 1.69 mmol), 13 (0.592 g, 1.69 mmol), tetrakis(triphenylphosphine)palladium(0) (97.6 mg, 84.5 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded 14 (0.88 g, 88%) as a yellow solid after flash chromatography (SiO2, 100% CH2Cl2 to 9:1 CH2Cl2-acetone).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([CH3:49])=[C:44]([NH2:50])[N:43]=1>C(Cl)(Cl)Cl.CO>[NH2:41][C:42]1[N:43]=[C:44]([N:50]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:45]([CH3:49])=[CH:46][C:47]=1[F:48]
Reactant: Cc1cc(F)c(N)nc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
To 1 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 280 mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added all of 2,6-diamino-3-fluoro-5-methylpyridine as described above together with 2 ml of methanol and 4 ml of chloroform. After allowing to stand at room temperature for 40 minutes, the solution was concentrated under reduced pressure. To the residue were added 600 mg of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirred at 85° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the mixture was allowed to stand overnight. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 171 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:27]([O:34][C:35]1[CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:39][CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:36]=3)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2cccc(OCc3ccccc3)c2)OC1(C)C
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C
Yield: 58.1 %

Procedure:
To a solution of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (130 mg, 0.282 mmol) in dioxane, was added 3-benzyloxyphenylboronic acid pinacol ester (105 mg, 0.338 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), 2N K2CO3 (700 μL). The reaction mixture in sealed tube was heated at 95° C. for 1.5 hs. Then the reaction was cooled down. The reaction mixture was washed by sat. NaHCO3, and extracted by EtOAc. The organic phase was filtered, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product (100 mg, 58%). LCMS-ESI+: calc'd for C32H36BrNO4S: 610.2 (M+H+); Found: 610.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23](B(O)O)([CH3:25])=[CH2:24]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[C:23]([C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:25])=[CH2:24]
Reactant: C=C(C)B(O)O
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)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: C1COCCO1
Product: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
0.56 g (0.0015 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl) -phenylamine, 0.171 g (0.00015 Mol) Pd(PPh3)4 and 0.191 g (0.0021 Mol) isopropenyl boronic acid were stirred at reflux for 18 h in a mixture of dioxane (10 ml) and 2N Na2CO3 (4 ml). Then the solvent was evaporated, the residue was taken up in ethyl acetate, washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexane 1:2 the product containing fractions were evaporated and the residue taken up in hexane. The suspension was stirred for 1 h and then filtered. The residue on the filter was washed with hexane (10 ml) and dried in a high vacuum. It was obtained 0.265 g (52%) 4-(2-isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a light yellow solid; mp.: 200-201° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCCCC1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>CN(C)C=O.O.O.O.O.O.O.[Co](Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCCCC3)CS[C@H]12
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
4.76 g (20 mmols) of cobalt(II) chloride hexahydrate are added in several portions, at 0°-5° C., to a solution of 11.7 g (20 mmols) of 7β-phenoxyacetylamino-3-piperidino-3-cephem-4-carboxylic acid benzhydryl ester in 50 ml of dimethyl formamide. The solution turns dark blue. Then 75 ml of glacial acetic acid are added dropwise at 0° C. over 30 minutes. Then 4.08 g (120 mmols) of sodium borohydride are added in 200 mg portions over 1 hour, with vigorous evolution of gas after each addition. When the addition is complete, the reaction mixture is warmed to room temperature and, after the addition of a further 50 ml of glacial acetic acid, stirred for 36 hours at room temperature. The dark red solution is filtered to remove the pink precipitate, the filter residue is washed with methylene chloride, and the filtrate is concentrated in vacuo. The dimethyl formamide is distilled off in a high vacuum. The oily residue is dissolved in methylene chloride and washed three times with 50 ml of water. The methylene chloride solution is filtered over 50 g of silica gel to remove residual cobalt salts and the eluate is concentrated, affording pure 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a white foam.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:34])[N:20]([CH2:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17](=[O:18])[N:9]([CH:8]2[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]2=[O:2])[C:10]3=[O:22])[CH3:21])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N(C)Cc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and 3,4-dimethylphenyl isocyanate (0.32 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diidopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL). The suspension was filtered, and the resulting solid cake was rinsed with CH2Cl2 (5 ml). The solid was reslurried with ether (I 5 mL) to give 3-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea as a solid (0.51 g, 59%)): mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 (99%); 1H NMR (DMSO-d6): δ 2.14 (s, 3H), 2.16 (s, 3H), 2.54-2.64 (m, 2H), 2.85-2.97 (m, 1H), 3.03 (s, 3H), 5.00 (s, 2H), 5.14-5.20 (dd, J=5.3, 12.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.89-7.81 (m, 2H), 8.34 (s, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 18.62, 15.54, 21.97, 30.91, 35.10, 47.46, 48.85, 117.61, 121.43, 121.83, 127.54, 129.12, 129.51, 131.78, 132.42, 134.95, 135.63, 137.93, 138.97, 155.79, 16696, 167.58, 169.80, 172.74. Anal Calcd for C24H24N4O5: C, 64.28; H, 5.39; N, 12.49. Found: C, 63.99; H, 5.26; N, 12.39.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OC)=O)=[CH:4][CH:3]=1.[C:13]1([NH2:20])[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>CO>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:9]1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CO
Product: Oc1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 2-(4-hydroxyphenyl)acetate (40.0 g, 241 mmol) and benzene-1,2-diamine (26.0 g, 241 mmol) in a sealed vessel was heated to 150° C. for 18 h. After cooling to room temperature, the mixture was diluted with MeOH and heated to 100 C for 1 h. The mixture was cooled to −20 C overnight, then filtered to collect 25.8 g (48%) of a lavender solid. MS (ESI, pos. ion) m/z: 225 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[C:44]([F:45])=[CH:43][C:42]3[C:46](=[O:52])[C:47]([C:49]([OH:51])=[O:50])=[CH:48][N:40]4[C:41]=3[C:36]=2[CH2:37][CH2:38][N:39]4[CH3:53])[CH2:30]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[C:44]([F:45])=[CH:43][C:42]3[C:46](=[O:52])[C:47]([C:49]([OH:51])=[O:50])=[CH:48][N:40]4[C:41]=3[C:36]=2[CH2:37][CH2:38][N:39]4[CH3:53])[CH2:30]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
350 mg (2 mmol) of N-t-butoxycarbonylglycine and 202 mg (2 mmol) of N-methylmorpholine were added to 6 ml of methylene chloride. The mixture solution was cooled on freezing mixture, and 0.26 ml (2 mmol) of isobutyl chlorocarbonate was added to the solution. After 20 minutes, 716 mg (2 mmol) of the compound (30) obtained in Example 5 (1) was added to the solution, and the solution was stirred at room temperature for 30 minutes. Then, 10 ml of water was added to the solution, and the solution was acidified with by citric acid. The organic layer was separated from the solution and was removed distillation after drying over sodium sulfate. Ethyl acetate--ether was added to the residue, then the product came out of the solution, and the solid was filtered off to obtain 776 mg of the subject compound (84) in a 75% yield. The results of the analysis of this compound were as follows:
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1.S(=O)(=O)(O)O.[C:30](=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CO>[CH3:30][O:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(CO)cc2-3)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(C)cc3)nc1-2

Procedure:
To a suspension of 0.75 g of 9-hydroxymethyl-2-(4-methylphenyl)2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in methanol was added 0.1 ml of conc. sulfuric acid at room temperature and the mixture was refluxed under heating for 3 hours. The mixture was poured into aqueous sodium hydrogen carbonate solution and extraced with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform as an eluent. The solid was recrystallized from a mixed solvent of ethanol and isopropyl ether to give 0.7 g of 9-methoxymethyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white powder, melting at 109°-110° C.