Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]#[N:10])[CH:2]=1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9](=[N:12][OH:13])[NH2:10])[CH:2]=1
Reactant: NO
Reactant: N#CCCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(CCc1cccnc1)=NO
Yield: 61 %

Procedure:
20.1 g (0.15 mol) of 3-(3-pyridyl)propionitrile is dissolved in a mixture of 61 ml of ethanol, and 15 ml of water and 9.5 g (0.14 mol) of hydroxylamine hydrochloride and 21 g (0.15 mol) of K2CO3 are added. After 24 hours at reflux, the solvent is removed in a vacuum, and the residue is extracted twice with ethanol. The extracts are concentrated by evaporation and recrystallized in hot ethanol. 14.1 g (56%) of product is obtained. Melting point 119-121° C.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1/[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[CH:9]/1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(F)nc1
Temperature: 78 °C
Yield: 38.1 %

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (150 mg, 0.44 mmol), 6-fluoropyridin-3-ylboronic acid (74 mg, 0.53 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 2M Na2CO3 aqueous solution (0.6 mL, 1.2 mmol). The mixture was heated at 78° C. under N2 for 3 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-3% MeOH/CHCl3 gave (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid (yield: 60 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:18][C:19]([F:20])([F:21])[F:22])=[C:11]([Cl:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-trifluoromethoxyaniline gave 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.61 (dd, 1H, J=2.1 and 8.7 Hz), 7.35 (dd, 1H, J=1.2 and 8.7 Hz), 6.98 (bs, 1H); LCMS: purity: 97%; MS (m/e): 342 (M+2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH:40](O)[CH3:41])[N:36]=2)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[Br:8][CH:40]([C:37]1[N:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[O:39][N:38]=1)[CH3:41]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Yield: 31.6 %

Procedure:
A solution of NBS (396 mg, 2.22 mmol) in THF (2 ml) was added dropwise to a solution of triphenylphosphine (583 mg, 2.22 mmol) in THF (2 ml) at 0° C. After stirring for 20 min 1-[5-(3-chloro-phenyl)-1,2,4-oxadiazol-3-yl]-ethanol (416 mg, 1.85 mmol) in THF (2 ml) was added. Stirring was continued o.n. at r.t. before the solvent was removed under reduced pressure. Flash chromatography (hep/EA 6:1) afforded 168 mg (32%) of the title compound. 1H NMR: 2.12 (d, 3 H) 5.21 (q, 1 H) 7.47 (t, 1 H) 7.57 (m, 1 H) 8.03 (d, 1 H) 8.15 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:17]=[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][N:10]3[N:9]=2)[CH2:4]1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:46])[C:27]=1[C:28](=[O:45])NC1C=CC2N(N=C(N3CCOCC3)N=2)C=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:46])[C:27]=1[C:28](=[O:45])[NH:16][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]3)[N:17]=2)[CH:15]=1)=[O:22])[CH3:19]
Reactant: COC1CCN(c2nc3ccc(N)cn3n2)C1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCC(OC)C3)nn2c1

Procedure:
Using 2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine, this compound was prepared following the same method as for the synthesis of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester. Off white solid (1.2 g, 59%). MS: m/z=414 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9](O)[C:10]=1[OH:11])=[O:5])[CH3:2]>OS(O)(=O)=O.[Rh]>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([OH:11])[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C(=O)OCC)c(O)c1O
Agent: [Rh]
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CC(O)C(C(=O)OCC)N1
Reaction time: 8 h

Procedure:
2,5-Bis-ethoxycarbonyl-3,4-dihydroxypyrrole (1.0 g, 4.1 mmol) was dissolved in 3% ethanolic H2SO4 (50 ml). Rhodium on carbon (5%) (1.0 g) was added and the reduction reaction was allowed to run under hydrogen (9.4 bar) at 80° C. overnight. The catalyst was filtered off and the solvent evaporated. The reaction mixture was dissolved in water, the pH was adjsusted with Na2CO3, and extracted with dichloromethane. The crude mixture was chromatographed on silica and the title product was isolated. Yield: 0.2 g (21%), FAB-MS: 232 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CC(C)=O.O>[Cl:16][C:15]1[C:7]([Cl:6])=[CH:8][C:9]2[N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[N:11][C:10]=2[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)n1cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methanesulphonyl chloride (60 parts) in acetone (800 parts) was added dropwise to a suspension of 5,6-dichloro-benzimidazole (94 parts) in acetone (240 parts) containing triethylamine (50 parts). A precipitate of triethylamine hydrochloride was observed and the temperature rose to 40° C. The mixture was heated under reflux for 10 minutes and then stirred at room temperature for 20 hours. On pouring into cold water (4000 parts) a solid product precipitated out, which was filtered off, washed with water, dried and recrystallised from acetone (charcoal) to give 5,6-dichloro-1-(methylsulphonyl)-benzimidazole (61 parts) as pale yellow needles, melting point 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH:6]=[CH:7][CH:8]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Li].[Cl-].[NH4+]>O1CCCC1>[OH:21][C:12]1([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Reactant: [Li]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.3 g (1.07 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide was dissolved in 10 ml of absolute tetrahydrofuran and, at 0° C., admixed dropwise with a 1 M solution of 0.14 g (1.6 mmol) of 2-thienyllithium. The reaction mixture was allowed to warm to room temperature, after which stirring was continued for 2 h, and the mixture was then admixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted three times with diethyl ether and the combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. The oily crude product was purified by chromatography. Elution was carried out using a dichloromethanelmethanol gradient (0 to 1% methanol). Yield: 0.2 g of an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[IH:17]>>[I:17][C:10]1[CH:15]=[C:14]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:12][N:11]=1
Reactant: OB(O)c1ccco1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Ic1cc(-c2ccco2)ncn1

Procedure:
The compound was prepared according to Example 1 using furan-2-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)C>Cl.CC(C)=O>[CH:4]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)=[O:3]
Reactant: CCOC(=O)c1csc(C(OCC)OCC)n1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C=O)n1
Yield: 97.6 %

Procedure:
A solution of ethyl 2-[bis(ethyloxy)methyl]-1,3-thiazole-4-carboxylate (455 mg) in 10% 1M hydrochloric acid in acetone (50 ml) was heated at reflux for 1 h. The mixture was concentrated in vacuo, taken up in DCM (20 ml) and washed with saturated sodium bicarbonate solution (10 ml). The organic layer was separated using a hydrophobic frit and evaporated to give the title compound (317 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20](=O)[CH2:21]Br)[C:5]([NH:7][CH:8]1[C:18](=[O:19])[N:10]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6].[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].C(OC(C)C)(C)C>CO>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:4](=[N:3][O:2][CH3:1])[C:5]([NH:7][CH:8]2[C:18](=[O:19])[N:10]3[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH2:13][S:14][C@H:9]23)=[O:6])[N:24]=1
Reactant: NC(N)=S
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 5 h
Yield: 118.7 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 10 g.) was added to a solution of thiourea (2.81 g.) and sodium acetate (2.22 g.) in methanol (50 ml) and stirred at 30° C. for 5 hours. To the resultant solution was added diisopropyl ether (200 ml.) and stirred at 30 minutes. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 11.2 g.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.[N-:47]=[N+:48]=[N-:49].[Na+]>C(Cl)(Cl)(Cl)Cl>[N:47]([CH2:19][C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:8]=1)=[N+:48]=[N-:49]
Reactant: Cc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
In a 50 mL round bottom flask, 7-fluoro-1-(2-fluoro-phenyl)-3-methyl-1H-quinolin-4-one (1.20 g, 4.42 mmol), N-bromosuccinimide (0.787 g, 4.42 mmol) and V65 [2,2′-azobis(2,4-dimethylvaleronitrile)](0.33 g, 1.33 mmol) were combined with carbon tetrachloride (35.0 mL). The reaction mixture was heated to reflux for 5 hr. The reaction was concentrated to dryness and the crude (containing 3-bromomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one) was redissolved in DMF (10.0 mL). To this reaction mixture was added sodium azide (1.44 g, 22.1 mmol) and the reaction was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was evaporated to dryness and purified by flash chromatography using 40% ethyl acetate-hexanes to afford 3-azidomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one (740 mg, 53.6%).
Reaction SMILES: [CH:1]([C:24]1[CH:29]=[C:28](CC2C=CC=CC=2)[C:27](O)=[C:26]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=1)([C:3]1[CH:8]=[C:7](CC2C=CC=CC=2)[C:6](O)=[C:5](CC2C=CC=CC=2)[CH:4]=1)C.[CH2:45]=[O:46].[OH-:47].[K+]>C(O)C>[CH2:38]([C:26]1[CH:27]=[C:28]([CH2:45][OH:46])[CH:29]=[C:24]([CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:25]=1[OH:47])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=O
Reactant: [OH-]
Reactant: CC(c1cc(Cc2ccccc2)c(O)c(Cc2ccccc2)c1)c1cc(Cc2ccccc2)c(O)c(Cc2ccccc2)c1
Agent: [K+]
Solvent: CCO
Product: OCc1cc(Cc2ccccc2)c(O)c(Cc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
The desired alcohol was prepared by reaction of 2,6-dibenzylphenol with an equivalent of 37% aqueous solution of formaldehyde in ethanol. A solution of 6.85 grams of 2,6-dibenzylphenol in 5 mL ethanol was added to a solution of 1.65 grams 85% KOH in 5 mL ethanol and stirred for 30 minutes. About 1.91 mL of a 37% formalin solution was added dropwise at 25° C. and stirred overnight. The ethanol was removed from the purple solution by rotary evaporation and the residue was dissolved in methylene chloride, washed with saturated ammonium chloride solution and brine, and dried over sodium sulfate. Solvent removal provided 6.6 grams of a crude orange solid which was analyzed by gas chromatography as 4.1 grams starting material 2,6-dibenzylphenol and 2.2 grams 2,6-dibenzyl-4-hydroxymethylphenol (m.p. 116° C.).
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:37][Zn+]>C1COCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15]([CH3:37])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Zn+]
Reactant: COC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CC1CCn2c1c(C)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.923 g, 1.54 mmol) was mostly dissolved in anhydrous THF (15.4 mL) to give a turbid suspension which was degassed with N2 for about 15 min. Bis(tri-t-butylphosphine)Pd(0) (0.071 g, 0.139 mmol) and 2.0 M methylzinc chloride in THF (2.318 mL, 4.64 mmol) were added at 25° C. The reaction mixture was sealed and heated at 70° C. to give a dark suspension. After 2 h at 70° C., the reaction mixture was cooled to 25° C., quenched with NaHCO3 (4 mL), stirred for 5 min, and filtered through a celite pad. The filtrate was diluted with MTBE, washed with H2O (twice), brine, and dried over MgSO4. The solvent was evaporated in vacuo to give a solid. The solid was dissolved in DCM/hexanes (1:1) and purified by silica gel column chromatography to give the titled compound (0.582 g) as a white solid. LCMS m/z=486.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.66 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.05-2.14 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.51 (dd, J=15.92, 10.11 Hz, 1H), 2.82-2.90 (m, 1H), 2.94 (dd, J=15.79, 4.67 Hz, 1H), 3.32-3.43 (m, 1H), 3.73 (s, 3H), 3.75-3.80 (m, 1H), 3.92-4.01 (m, 1H), 4.02-4.10 (m, 1H), 5.09 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H), 7.04 (d, J=2.27 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.61 (d, J=8.08 Hz, 1H), 7.71 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 2-aminopyridine (50.0 g, 531 mmol) in methylene chloride (500 mL) were added triethylamine (81.4 mL, 584 mmol) and pivaloyl chloride (71.9 mL, 584 mmol) at 0° C., which was stirred for 4 hours and 30 minutes at room temperature. The reaction solution was partitioned into water and methylene chloride. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. To a solution of the resulting residue in methanol (300 mL) was added potassium carbonate (73.4 g, 531 mmol) at 0° C., which was stirred for 90 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. Heptane (300 mL) was added to the residue, and the precipitated solids were filtered to obtain the title compound (80.2 g, 85%). The filtrate was then concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (12.2 g, 13%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:21][CH2:20]3)[CH2:13]2)[CH2:9]1.[CH3:36][C:37](OC(C)=O)=[O:38]>C(Cl)Cl>[C:37]([N:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:23][CH2:24]3)[CH2:13]2)[CH2:11]1)(=[O:38])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CN(C3CNC3)CCO2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(N2CCO[C@@H](CN3CCN(C(=O)Nc4ccc(Cl)c(Cl)c4)CC3)C2)C1
Reaction time: 3 h

Procedure:
Triethylamine (61 uL) was added to a stirring solution of 4-{[(25)-4-azetidin-3-ylmorpholin-2-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (125 mg) in DCM (5 ml) followed by Ac2O (30 uL) and the reaction was stirred for 3 h. The reaction was then quenched by addition of 1M NaOH (aq.) (10 ml) and DCM (15 ml). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography 5-10% MeOH:DCM afforded the title compound (31 mg) as a white foam.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27](OC)=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].Cl.[NH2:41][OH:42]>CO.C[O-].[Na+]>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:41][OH:42])=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCOc3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 34 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(3,4-dihydro-2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 34f (0.095 g, 0.22 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 34%) as a white solid. MS found: (M+H)+=435.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]([CH:9]([N:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[Br:32]Br.C(OCC)(=O)C>O1CCOCC1>[CH3:5][O:6][C:7]([CH:9]([N:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Br:32])[CH:15]=1)=[O:8]
Reactant: COC(=O)C(c1ccc(O)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccc(O)c(Br)c1)N1CC(NC(=O)Cc2ccccc2)C1=O
Yield: 8.1 %

Procedure:
Chloroform (1.5 ml.) was added to a solution of 1-(α-methoxycarbonyl-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (184 mg.) dissolved in dioxane (2 ml.), and a chloroform (0.5 ml.) solution containing bromine (184 mg.) was added dropwise to said mixture in 5 minutes under ice-cooling. After addition of ethyl acetate (80 ml.) to said reaction mixture, the ethyl acetate layer was separated out, washed with water and dried over anhydrous magnesium sulfate. This solution was concentrated, and the residue was dissolved in a small amount of acetone. The solution was subjected to preparative thin layer chromatography using silica.gel [developing solvent; a mixture of chloroform and methanol (5:0.3)] for isolation and purification. The product thus obtained was recrystallized from a mixture of ethyl acetate and acetone to give 1-(α-methoxycarbonyl-3-bromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (18 mg.). Mp 151° to 153° C. (dec.).
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=O>C(O)C.O>[CH3:17][C:18]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-:29])=[O:28])[C:19]=1[CH:20]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium (0.41 g, 0.018 g atom) was dissolved in ethanol (40 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (4.21 g, 18 mmol) added. After 5 minutes, 2,3-dimethyl-6-nitrobenzaldehyde (2.66 g, 15 mmol) was added in one portion and the mixture stirred at room temperature for 90 minutes. The mixture was diluted with water, filtered and the solid washed with water and air dried gave 5-[(2,3-dimethyl-6-nitrophenyl)methylene]-2,4-imidazolidinedione as a single geometrical isomer (3.35 g, 86%). Analytical sample prepared by crystallization from methanol had m.p. 293°-295° C.