Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO.O>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(N)n1
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
To a solution of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml) was dropwise added a solution of diphenyldiazomethane in ethyl acetate (1 m mol/ml, 200 ml) at ambient temperature and the mixture was stirred for an hour. The resultant mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.3 g). To the solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.0 g) in methanol (500 ml) was added conc. hydrochloric acid (41.6 g) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 l) and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with ether to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (72.3 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:52])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:31](=[O:51])[C@@H:32]2[CH2:36][C@@H:35]([NH:37][C:38](=[O:43])[CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][N:33]2C(OC(C)(C)C)=O)[CH:2]=1.[ClH:53]>O1CCOCC1>[ClH:53].[ClH:53].[ClH:53].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:52])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:31](=[O:51])[C@@H:32]2[CH2:36][C@@H:35]([NH:37][C:38](=[O:43])[CH2:39][N:40]([CH3:41])[CH3:42])[CH2:34][NH:33]2)[CH:2]=1
Reactant: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CC(=O)N[C@H]1CN[C@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Reaction time: 0.08 h

Procedure:
N-tert-Butoxycarbonyl-trans-4-(N,N-dimethylglycylamino)-L-prolyl-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (C, 76 mg) was dissolved in 4 N hydrogen chloride in 1,4-dioxane (10 mL) at 0° C., and stirred at 0†° C. for 5 min and at room temperature for 3 hr. The solution was evaporated in vacuo, and the residue was purified by HPLC (Shiseido, Capeell Pak C18 UG120, 3 cm×25 cm, 0.02 N hydrochloric acid:methanol=55:45, v/v) and freeze-dried from water to afford the title compound (28 mg) as a pale yellow powder: 1H NMR (400 MHz, D2O) δ 1.83-2.07 (m, 2H), 2.22-2.47 (m, 3H), 2.47-2.68 (m, 3H), 2.81 (s, 6H), 3.26-3.39 (m, 1H), 3.52-3.70 (m, 2H), 3.80-3.98 (m, 3H), 4.00-4.08 (m, 1), 4.31-4.52 (m, 2H), 4.68-4.84 (m, 2H), 7.07-7.29 (m, 5H), 7.73-7.81 (m, 1H),7.86-7.95 (m, 1H), 7.99-8.12 (m, 2H), 8.87 (s, 1H), and 9.21 (s, 1H); IR (KBr) 3367, 3025, 2952, 1654, 1648, 1610, 1571, 1554, and 1454 cm−1; mass spectrum (FAB+) m/e 616 (M+1); high-resolution mass (FAB) m/e Calcd for C33H41 N7O5: 616.3247. Found: 616.3237.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11]1>N1C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:13][CH2:14][N:10]([CH2:9][CH2:8][NH:7][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:11]2)=[CH:23][CH:24]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Reactant: Brc1nccs1
Solvent: c1ccncc1
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)C3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of 12.8 parts of 2-bromothiazole, 22 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2 -amine and 250 parts of pyridine was stirred and refluxed for 6 hours. After cooling, 12.8 parts of 2-bromothiazole were added and stirring was continued overnight at reflux temperature. The mixture was cooled and evaporated. The residue was taken up three times in methylbenzene and the latter was evaporated each time. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane, methanol and ammonium hydroxide (45:45:10:1 by volume) as eluent. The pure and the less pure fractions were collected and the eluent was evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (96:3:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 2.0 parts (7.3%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl]-3-pyrrolidinyl]-1H-benzimidazol-2-amine; mp. 127.1° C. (compound 168).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1cccs1
Yield: 39.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(thien-2-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 117, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(thien-2-yl)acetyl)pyrrolidine-2-carboxamide (12.3 mg, 39.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.34 (s, 1H), 7.55-7.60 (m, 2H), 7.37-7.39 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.03 (m, 6H), 4.48-4.51 (m, 1H), 3.90 (d, 2H), 3.75-3.80 (m 1H), 3.56 (m, 1H), 2.63-2.73 (m, 3H), 1.88-1.97 (m, 2H). MS (EI) for C30H27FN2O3S. found 515.6 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([N:12]2[CH2:15][CH:14]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:13]2)[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([N:16]([CH2:17][CH2:18][CH3:19])[CH:14]2[CH2:15][N:12]([C:5]3[S:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:3]([CH2:1][CH3:2])[N:4]=3)[CH2:13]2)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCCNC1CN(c2nc(CC)c(C(=O)OC)s2)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(CC)c(C(=O)OC)s2)C1
Yield: 65.6 %

Procedure:
The same operation as in Example (221c) was performed using methyl 4-ethyl-2-[3-(n-propylamino)azetidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (228b) (74 mg, 0.26 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (46 mg, 0.26 mmol), WSC hydrochloride (150 mg, 0.78 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N-methylmorpholine (0.06 mL, 0.52 mmol), to obtain 75 mg of the title compound as a colorless oily substance (65%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[N:11]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCc2c(cccc2C2OCCO2)N1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCc2c(C3OCCO3)cccc2N1c1ccccc1
Yield: 93.8 %

Procedure:
5-(1,3-Dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (2.30 g, 10.5 mmol), iodobenzene (3.5 ml, 31.5 mmol), copper(I) iodide (400 mg, 2.10 mmol), trans-1,2-diaminocyclohexane (0.129 ml, 1.05 mmol) and cesium carbonate (6.84 g, 21.0 mmol) were stirred in 30 ml of 1,4-dioxane under reflux for three days. After cooling, the insoluble matter was filtered off through a Celite pad. Ethyl acetate and water were added to the filtrate, and the resulting mixture was washed (twice with water and once with a saturated sodium chloride solution), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3→1:1) to thereby obtain 2.91 g (yield: 92%) of 5-(1,3-dioxolan-2-yl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one as a white solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:30])[N:11]3[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:32]1[CH:36]=[N:35][N:34]2[CH2:37][CH2:38][N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]=12.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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].ClCCl.C(OCC)(=O)C.O>[CH:1]1([O:5][C:6]2[C:15]([C:32]3[CH:36]=[N:35][N:34]4[CH2:37][CH2:38][N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]=34)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:30])[N:11]3[C:25]([CH:27]2[CH2:28][CH2:29]2)=[O:26])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2OC2CCC2)N1C(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCn2ncc(Br)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(-c3cnn4c3N(C(=O)OC(C)(C)C)CC4)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
An 8-mL resealable tube was charged with (2S)-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (60 mg, 0.15 mmol), tert-butyl 7-bromo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carboxylate (45 mg, 0.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (11 mg, 0.02 mmol), sodium carbonate (30 mg, 0.28 mmol), 1,4-dioxane (1.5 mL) and water (0.5 mL). The resulting mixture stirred overnight at 80° C. After cooling to room temperature, the reaction mixture was poured into 20 mL of ethyl acetate. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 40% ethyl acetate-petroleum ether) to afford tert-butyl 7-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2,3-dihydroimidazo[1,2-b]pyrazole-1-carboxylate (50 mg, 69%) of as a black solid. MS (ESI, pos. ion) m/z 493 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2ccoc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCC2
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of methyl benzofuran-6-carboxylate (17.8 g, 100 mmol) and 10% Pd/C (10.5 g) in MeOH was stirred under hydrogen atmosphere at 50 psi for 2 h. The catalyst was removed by filtration. The solvent was removed under reduced pressure to afford the desired methyl 2,3-dihydrobenzofuran-6-carboxylate (17.8 g, 98.5% yield). 1H NMR (400 MHz, CDCl3) δ: 7.57 (d, J=7.6, 1H), 7.40 (s, 1H), 7.23 (d, J=7.6, 1H), 4.61 (t, J=8.8, 2H), 3.89 (s, 3H), 3.25 (t, J=8.8, 2H).
Reaction SMILES: C([O-])(=O)C.[NH4+].[N+:6]([CH3:9])([O-:8])=[O:7].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:9]/[N+:6]([O-:8])=[O:7])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOCCOc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
Ammonium acetate (4.16 g, 53.9 mmol) and nitromethane (6.1 mL, 113 mmol) were added to a solution of 3-(benzyloxy)-4-(2-ethoxyethoxy)benzaldehyde described in Production Example 24-2 (13.5 g, 45.0 mmol) in acetic acid (36 mL) under nitrogen atmosphere at room temperature. The liquid mixture was heated and stirred under reflux at 130° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature. The precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.[OH-].[Na+]>C(O)C>[Cl:10][C:8]1[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[N:5]=[C:4]([C:3]([OH:22])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
4-chloro-6-[3-(trifluoromethyl)phenoxy] picolinic acid methyl ester (3.1 g, 0.0093 mol) was dissolved in 40 ml of ethanol. 4 ml of an aqueous solution of sodium hydroxide (0.41 g, 0.0093×1.1 mol) was added to the obtained solution. The resultant mixture was heated and stirred at 60° C. for 20 minutes. Thereafter, the obtained reaction solution was cooled and distilled under reduced pressure to remove ethanol therefrom. The obtained residual solution was treated with concentrated hydrochloric acid so as to adjust the pH thereof to 3. The precipitated solids were filtered out from the above residual solution, washed with water and then dried, thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.[OH-:30].[NH4+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19]([CH3:20])=[O:30])[N:14]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A solution of K2S2O8 (0.20 g, 0.73 mmol) in water (5 mL) was added to 4-(4-fluorophenyl)-5-[2-(methylthio)-4pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole (0.20 g, 0.48 mmol) in glacial acetic acid (10 mL). After stirring at ambient temperature for 72 h, the reaction mixture was poured into water, neutralized with concentrated aqueous ammonium hydroxide and extracted four times with dichloromethane. The organic phases were combined and evaporated. The residue was purified by flash chromatography eluting successively with 1%, 2%, 4% and 10% methanol in dichloromethane to afford the title compound as a clear oil (0.15 g, 73%). 1H NMR (CDCl3) δ8.57(d, J=7 Hz, 1H), 7.77(s,1H), 7.47 (dd, 2H), 7.18(d, J=5 Hz, 1H)7.09(t, J=9 Hz, 2H), 4.56(m, 2H), 3.72(t, J=5 Hz, 4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2.33(t, J=8 Hz, 2H), 1.94(m, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[NH2:4][CH:5]1[CH:8]2[S:9][CH2:10][C:11]3[CH:15](O)[O:14][C:13](=[O:17])[C:12]=3[N:7]2[C:6]1=[O:18].C(=O)([O-])O.[Na+]>O>[NH2:4][CH:5]1[C:6](=[O:18])[N:7]2[C:12]([C:13]([OH:14])=[O:17])=[C:11]([CH:15]=[N:2][OH:3])[CH2:10][S:9][C@H:8]12
Reactant: NO
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(C=NO)CS[C@H]12
Reaction time: 8 h

Procedure:
A solution of 1.26 g of the hydrochloride of hydroxylamine in 7.5 ml of water is treated under stirring at 0° with 4.74 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin and stirred for ca. 8 hours at 0° under nitrogen. The pH of the reaction mixture is adjusted to 3.5 using solid sodium hydrogen carbonate. 7-Amino-3-[(hydroxy-imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with ca. 5 ml of cold water and 5 ml of acetone and dried. b) A suspension of 0.79 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin in 10 ml of dichloromethane is treated under stirring at 4° with 2.67 g of N,O-bis-(trimethylsilyl)acetamide. A clear solution is obtained within 10 minutes. 0.21 g of the hydrochloride of hydroxylamine are added. The reaction mixture is stirred for ca. 2 hours under nitrogen at 4° and the solvent is evaporated off. The residue is treated with 10 ml of isopropylalkohol, precooled to 1°. 7-Amino-3-[(hydroxy-imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost colourless crystals which are filtered off, washed with 5 ml of acetone and dried.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH2:32][OH:33])=[N:28][O:29][C:30]=2[CH3:31])[OH:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH:32]=[O:33])=[N:28][O:29][C:30]=2[CH3:31])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1onc(CO)c1-c1ccccc1C(O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1onc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 98.3 %

Procedure:
To a round bottomed flask was added CH2Cl2 and oxalyl chloride (1.21 mL, 13.8 mmol) before the solution was cooled to −78° C. To this solution was added DMSO (1.47 mL, 20.65 mmol) and the solution stirred for 15 min before addition of (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanol (1.14 g, 3.44 mmol) dissolved in CH2Cl2. The reaction was stirred for 15 min at −78° C. before addition of Et3N (3.84 mL, 27.5 mmol) and warming the reaction to room temperature overnight. This reaction was diluted with water and the layers separated. The aqueous was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (1.10 g, 3.38 mmol). LC/MS m/z 326 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)cnn2C1CCCCO1
Reactant: COc1cc(OC)c(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(F)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (333 mg, 1.40 mmol), 2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400.0 mg, 1.333 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (21.0 mg, 0.0266 mmol), and potassium phosphate (566 mg, 2.66 mmol) in tetrahydrofuran (3 mL) and water (5.5 mL) in a reaction vial was degassed and sealed. The mixture was stirred at r.t. for 30 min. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.38 g, 76%). LCMS (M+H)+=376.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:3]1
Reactant: NC1CC1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(NC1CC1)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94°-96° C.