Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8](Br)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:37]3[CH:38]=[C:39]([CH2:42][OH:43])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of (4S,5R)-3-[(6-Azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 35) (943 mg, 1.752 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (EXAMPLE 258, Step A) (555 mg, 2.102 mmol), potassium carbonate (1M aqueous) (4 ml, 4.00 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (114 mg, 0.175 mmol) in THF (12 ml) was stirred at 60° C. with microwaves for 1 hour. 125 mg of [4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol were added and the heating continued for another 30 minutes. The reaction mixture was filtered through a silica plug washing with EtOAc and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes. A second purification using RP HPLC afforded the pure title compound. Mass spectrum (ESI) 596.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 7.96 (s, 1H); 7.88 (s, 2H); 7.32 (d, J=8.2 Hz, 2H); 7.16 (s, 1H); 7.01 (d, J=8.2 Hz, 1H); 6.35 (d, J=8.3 Hz, 1H); 5.72 (m, 1H); 4.65 (d, J=16.3 Hz, 1H); 4.55 (s, 2H); 4.23 (s, 1H); 4.05 (t, J=7.3 Hz, 4H); 3.90 (br s, 1H); 3.77 (s, 2H); 2.43-2.36 (m, 2H); 0.60 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=O)[CH:15](O)O)=[N:6]1.S([O:27][C:28]1[NH:32][N:31]=[C:30]([NH2:33])[C:29]=1[NH2:34])(O)(=O)=O>C(O)(=O)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[N:34][C:29]3[C:30](=[N:31][NH:32][C:28]=3[OH:27])[N:33]=2)=[N:6]1
Reactant: O=C(c1nn(Cc2ccccc2F)c2ncccc12)C(O)O
Reactant: Nc1n[nH]c(OS(=O)(=O)O)c1N
Solvent: CC(=O)O
Product: Oc1[nH]nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
500 mg (1.291 mmol) of the compound from example 68A were admixed with 7 ml of acetic acid and 273 mg (1.291 mmol) of 3,4-diamino-1H-pyrazol-5-ol sulfate. The mixture was stirred at RT for 16 h and then concentrated on a rotary evaporator. Water and ethyl acetate were added, and the mixture was stirred. The organic phase was removed and extracted once with a 1N sodium hydroxide solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, ratio 80:15:5). 142 mg of the title compound were obtained (29% of theory).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 104.5 %

Procedure:
A 200-mL round bottomed flask equipped with a magnetic stir bar was charged with 1-fluoro-2-nitrobenzene (8.25 g, 58.5 mmol), DMSO (29 mL), potassium carbonate (8.89 g, 64.3 mmol), and (S)-2-aminopropane-1-ol (4.83 g, 64.3 mmol). The mixture was heated to 60° C. for 6 h and then cooled to room temperature. The reaction mixture was diluted with water (60 mL). The mixture was stirred for several minutes, then extracted with ethyl acetate (ca. 200-250 mL). The ethyl acetate extract was washed thrice with 5 wt % aqueous sodium chloride (3×50 mL) and concentrated under reduced pressure to afford crude (S)-2-(2-nitrophenylamino)propane-1-ol (12.0 g, 105%) as a bright orange syrup. MS (ESI, pos. ion) m/z 197 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5]=2[O:4][CH2:3]1.[H-].[Na+].I[CH3:29]>CN(C)C=O>[CH3:29][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:5]=2[O:4][CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc3c2OCC(=O)N3)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2c(CC3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of tert-butyl 4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylate (0.6 g, 1.73 mmol) in anhydrous N,N-dimethylformamide (1 mL), was added dropwise to a stirred suspension of sodium hydride (60%) (0.08 g) in anhydrous N,N-dimethylformamide (12 mL) at 0° C. Stirring was continued for a further 20 mins. before iodomethane (0.5 g) in anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was allowed to stir at room temperature for 4 hours. It was quenched with saturated ammonium chloride (20 mL) and extracted with diethyl ether (100 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in hexane (10–20%) gave the title compound as a solid (0.6 g, 97%).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[CH2:10][S:9][CH2:8][N:7]1[CH2:11][C:12]([OH:14])=O>ClCCl.O1CCCC1>[O:5]=[C:6]1[CH2:10][S:9][CH2:8][N:7]1[CH2:11][C:12]([Cl:3])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1CSCC1=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cl)CN1CSCC1=O
Reaction time: 5 h

Procedure:
Thionyl chloride (2.00 ml) was added dropwise to a solution of 4-oxo-3-thiazolidinylacetic acid (1.60 g) in a mixture of dichloromethane (20 ml) and tetrahydrofuran (5.0 ml) at room temperature. After the mixture was stirred for 5 hours at the same temperature, the solvent was evaporated in vacuo to give 4-oxo-3-thiazolidinylacetyl chloride (1.78 g) as brown semisolid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]([NH:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])=[O:8].[OH-].[K+]>CC(O)C>[NH2:13][C:12]1[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[C:7](=[O:8])[NH:9][C:10](=[O:14])[CH:11]=1
Reactant: N#CCC(=O)NC(=O)NCc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1cccc(Cl)c1
Yield: 89.2 %

Procedure:
A suspension of 10.17 g (40.4 mM) of 1-(3-chlorobenzyl)-3-cyanoacetyl-urea in 80 ml of 2-propanol was added to a solution of 5.7 g KOH in 40 ml of 2-propanol and heated under reflux for 1 hour. After cooling the solid was collected and washed to give the crude title compound (9.07 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Cl[C:40]1[CH:45]=[CH:44][N:43]=[C:42]([NH:46][CH3:47])[N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[CH:7][C:6]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([NH:46][CH3:47])[N:41]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1/C=C/c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CNc1nccc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1nccc(-c2cnc(OC)c(/C=C/c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2)n1
Temperature: 120 °C
Yield: 90.3 %

Procedure:
To tert-butyl 4-(4-((E)-2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)vinyl)phenyl)piperazine-1-carboxylate (191 mg, 0.37 mmol) and 4-chloro-N-methylpyrimidin-2-amine (79 mg, 0.55 mmol) in toluene (4 mL) and ethanol (2 mL) under nitrogen was added 2M aqueous potassium carbonate (0.55 mL, 1.10 mmol) followed by palladium tetrakis(triphenylphosphine) (17 mg, 14.6 μmol). The reaction mixture was heated at 120° C. overnight. The reaction mixture was partitioned between EtOAc (30 mL) and water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated and the residue was purification by column chromatography (EtOAc) to give the title compound (168 mg, 91%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:8](=[O:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Product: CCCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=282.2 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and butylamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[CH3:8][C:6]1[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:2]([CH3:1])[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]=1[CH3:9]
Reactant: Cc1cc(C)c(C)c(C)c1C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C

Procedure:
In 500 ml of dichloromethane was dissolved 17.8 g of pentamethylbenzene and the solution was cooled to -5°~-10° C. A solution of 24 ml of chlorosulfonic acid in 400 ml of dichloromethane was added dropwise, and the mixture was allowed to stand at room temperature. The reaction mixture was poured into ice-5% aqueous sodium hydrogen carbonate. The organic layer was washed with water and dried over magnesium sulfate. Removal of the solvent by distillation leaves crystals which were collected by filtration and recrystallized from n-hexane. Yield 27.7 g (93.5%), m.p. 80°-81° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:14])[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>O1CCCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([OH:14])([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil, 0.3 g, 7.5 mmol) (Aldrich) was added to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (30 mL) under argon with cooling in a −25° C. bath and magnetic stirring. After 10 minutes, a solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) (Aldrich) was added dropwise at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][S:24]([O-:26])=[O:25].[Na+].CS(C)=O.[Si](C=[N+]=[N-])(C)(C)C>ClCCl.[Cu]I.CO>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([S:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])(=[O:26])=[O:25])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Reactant: COC(=O)CCS(=O)[O-]
Agent: [Cu]I
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CCS(=O)(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1
Temperature: 105 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen gas purged sealable vial of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 4-1a (3000 mg, 9.17 mmol), copper(i) iodide (6983 mg, 36.7 mmol) and sodium 3-methoxy-3-oxopropane-1-sulfinate (TYGER) (6385 mg, 36.7 mmol) was added DMSO (15 ml). The reaction mixture was heated in an oil bath at 105° C. for 18 hrs. LCMS analysis showed reaction to be a mixture of desired ester and acid. The reaction was quenched into ethyl acetate (200 ml) and water (200 ml) and the ph adjusted from 7 to 3 with 1N HCl. The reaction was filtered thru celite and sand and the filtrate layers separated. The organic which contained a mix of acid and ester was dried over sodium sulfate, filtered and concentrated to an oil. The oil was azeotroped with toluene to remove any remaining water to give a brown oil, 3.4 gms. The oil was dissolved in dichloromethane (20 ml) and methanol (20.00 ml) cooled to 0° C. and TMS-Diazomethane (4.94 ml, 9.88 mmol) slowly added dropwise. The reaction was stirred at 0° C. for 10 minutes, quenched with aq. KHSO4 and allowed to stir at room temperature for 1 hr. The reaction was concentrated to remove methanol and the product extracted into ethyl acetate (100 ml), dried over sodium sulfate and concentrated to oil. The oil was chromatographed on silica (100 g, 0-50% ethyl acetate/hexanes) to give the product 4-1b as oil, 1.46 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C)C=O.CI>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1-c1ccccc1Cl
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1.21 g (3.57 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester in 35 ml N,N-dimethylformamide 0.18 g (3.7 mmol) sodium hydride (55% dispersion in mineral oil) were added at room temperature. After 30 min 0.25 ml (3.9 mmol) methyl iodide were added and the reaction mixture was stirred for 1 h. Quenching was followed by extraction with tert-butyl methyl ether. The organic layer was washed with two portions of water, and the combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried with sodium sulfate and concentrated to give 1.26 g (100%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][NH2:13]>O1CCOCC1>[F:11][C:8]1[C:9]([F:10])=[C:2]2[C:3]([CH:4]=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(F)c1F
Reactant: NN
Solvent: C1COCCO1
Product: Fc1ccc2cn[nH]c2c1F
Temperature: 150 °C
Yield: 45.8 %

Procedure:
In a microwave vial 2,3,4-trifluorobenzaldehyde (1.5 g, 9.4 mmol) was dissolved in 1,4-dioxane (6 mL) and hydrazine (6 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 664 mg (46%) of 6,7-difluoro-1H-indazole as a light brown powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.10 (d, J=3.4 Hz, 1H), 7.47 (dd, J=8.9, 4.0 Hz, 1H), 7.05 (ddd, J=10.6, 8.9, 6.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Se](=O)=[O:12]>O1CCOCC1>[CH:1]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 116.1 %

Procedure:
A solution of 2-methyl-3-nitropyridine (10.155 g, 72.46 mmol) prepared in Step 1 of Preparation 1 and selenium dioxide (8.84 g, 79.71 mmol) in 1,4-dioxane (80 ml) was refluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/2, v/v) to give 12.8 g of the titled compound as red oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>CO.CS(C)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:17]([C:13]4[CH:12]=[C:11]([C:8]5[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=5)[CH:16]=[CH:15][CH:14]=4)[CH2:18][C:19](=[O:35])[NH:20][C:21]=3[CH:27]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C1CC(c2cccc(-c3nc(C(=O)O)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (49 mg, 0.1 mmol) in a mixture of MeOH (1 mL) and DMSO (1.5 mL) was added 2N KOH (1 mL, 2 mmol). The mixture was stirred at 23° C. for 0.5 h and then partitioned between ethyl acetate and H2O. The pH of the aqueous phase was set to 3 by the addition of 3N HCl and then stirred in the ice-bath for 0.5 h. The precipitate was collected by filtration, triturated with EtOH/Et2O (1/1) and dried, to give the title compound as light yellow solid (25 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([CH2:24][C:25](OCC)=[O:26])(=O)[C:19]([CH3:22])([CH3:21])[CH3:20]>O>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:25]([OH:26])=[CH:24][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Solvent: O
Product: CSc1nn2c(O)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Yield: 48 %

Procedure:
2 g (7.4 mmol) of 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 2.91 ml (18.3 mmol) of ethyl pivaloylacetate were added to 27 g of polyphosphoric acid and heated to 120° for 5 hrs. After cooling 100 ml of water were slowly added thereto and the mixture was extracted three times with CH2Cl2. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/EtOAc) yielded 1.34 g (48%) of 3-benzenesulphonyl-5-tert-butyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a colorless foam.
Reaction SMILES: S([O-])(O)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:35][O:36][CH:37]2[CH2:39][CH2:38]2)[C:13]([NH:15][C@@H:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:11]=1.[BH4-].[Na+].Cl>O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:35][O:36][CH:37]2[CH2:39][CH2:38]2)[C:13]([NH:15][C@@H:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N:24]4[CH2:25][CH:26]=[CH:27][CH2:28][CH2:29]4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:11]=1
Reactant: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C[n+]4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CN4CC=CCC4)CS[C@H]23)cs1
Reaction time: 2.5 h
Yield: 13.8 %

Procedure:
To a solution of 7β-[2-(2-aminothiazol-4-yl)-2(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylic acid hydrogen sulfate (syn isomer) (3 g) in water (100 ml) was portionwise added sodium borohydride (1.9 g) under ice-cooling, keeping the pH of the reaction mixture at 6.5-7.0 with 1N hydrochloric acid. The mixture was stirred at the same condition for 2.5 hours. The mixture was adjusted to pH 2.5 with 6N hydrochloric acid and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (90 ml). After the column was washed with water (630 ml), the elution was carried out with 20% methanol. The fractions containing the object compound were combined, concentrated in vacuo to about 100 ml, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2(cyclopropyloxyimino)acetamido]-3-(1,2,3,6-tetrahydropyridin-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) (0.35 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C[Si]([N:29]=[C:30]=[O:31])(C)C>C1COCC1>[C:30]([NH:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:31])[NH2:29]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNC(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (125 mg) in THF (1.5 mL) was added trimethylsilyl isocyanate (57.7 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (160 mg).