Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[C:12]([C:14]1[CH:15]=[C:16]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1)#[N:13]>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([C:16]3[CH:15]=[C:14]([C:12]4[NH:13][N:11]=[N:10][N:9]=4)[CH:19]=[C:18]([F:20])[CH:17]=3)[O:25][N:24]=2)=[N:27][CH:28]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4nnn[nH]4)c3)n2)nc1
Temperature: 80 °C
Yield: 36 %

Procedure:
To a mixture of 2 M trimethylaluminum (0.45 mL, 0.9 mmole, toluene) with toluene (1 mL) at 10° C., trimethylsilyl azide (0.11 g mL, 0.9 mmole) was added, followed by the addition of 5-(3-cyano-5-fluorophenyl)-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. The reaction was heated at 80° C. for 2 hours and then quenched with 6 N hydrochloride (2 mL) and solid was collected by filtration. The product was recrystallized with dimethylformamide to give 59 mg (36%) of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1H-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (DMSO-d6), δ (ppm): 8.83 (d, 1H), 8.70 (s, 1H), 8.31 (m, 1H), 8.10 (m, 0.2H), 8.04 (dt, 1H).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1>O>[OH:3][C:4]1[C:12]([Br:1])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc(O)nc1
Solvent: O
Product: O=C(O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Bromine (4.2 mL, 81.4 mmol) was added dropwise to the suspension of 6-hydroxynicotinic acid Compound 116a (8.00 g, 57.6 mmol) in water (30 mL) at 4° C. After the completion of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. Saturated Na2SO5 was added slowly to the stirred mixture until the brown mixture became white. The solid was collected through filtration, washed with water, and dried under vacuum overnight to give 12.17 g (97%) of 6-hydroxy-5-bromonicotinic acid as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ12.95 (brs, 1H), 12.55 (brs, 1H), 8.16 (s, 1H), 8.04 (s, 1H). Quinoline (1.0 mL, 8.47 mmol) was slowly added to the solution of POCl3 (2.0 mL, 21.5 mmol), followed by 6-hydroxy-5-bromonicotinic acid (3.92 g, 18.0 mmol) at room temperature. After heating at 120° C. for 2 h, the reaction was quenched by addition of water dropwise at 10° C. After the mixture was cooled at 4° C. for a few hours, the solid was collected through filtration, washed with water, and dried under vacuum overnight to give 3.68 g (87%) of Compound 116b as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ8.86 (s, 1H), 8.55 (s, 1H); MS (ES) m/z: 236 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]C(N(C)C)=O.CI>O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[N:12]2[CH3:33])=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1cc(OC[C@H]3COC(C)(C)O3)ccc1C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To the mixture of 3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4 mg, 2.3 eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.) were added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with MTBE to obtain the title compound (white solid, 31.2 mg, 91%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Yield: 103.9 %

Procedure:
L-Serine methyl ester hydrochloride (5 g, 32.13 mmol) dissolved in methylene chloride (200 ml) was added with TEA (2 equiv., 8.95 ml) and in one portion 5-chlorothiophene-2-sulfonyl chloride (1.0 equiv., 6.97 g). The reaction was refluxed for 4 hours. The solvent was evaporated and the crude was dissolved in AcOEt (100 ml) and washed with water (1×80 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from diethyl ether and petroleum ether afforded 10 g of the white product. Yield=93% 1HNMR (DMSO, 200 MHz) δ 2.81 (2H, q, J=7.2 Hz), 3.52 (3H, s), 3.92 (1H, t), 5.06 (1H, bs), 7.24 (1H, dd, J=4.2 Hz), 7.45 (1H, dd, J=4 Hz), 8.92 (1H, bs)
Reaction SMILES: C[C:2]1(C)[O:6][C@H:5]([CH2:7][NH:8]C(=O)OCC2C=CC=CC=2)[C:4](=[O:19])[O:3]1.[ClH:21].[H][H]>CO.CCOCC.[Pd]>[ClH:21].[NH2:8][CH2:7][C@@H:5]([OH:6])[C:4]([O:3][CH3:2])=[O:19]
Reactant: [H][H]
Reactant: CC1(C)OC(=O)[C@@H](CNC(=O)OCc2ccccc2)O1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](O)CN

Procedure:
Benzyl [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]methylcarbamate (7.76 g) prepared by the method described in Step B above was dissolve in methanol (70 mL) with 0.62 g 10% Pd/C. A 1 M HCl in ether solution was added (25 mL). This mixture was hydrogenated using a hydrogen balloon for 22 hours. The reaction mixture was purged with nitrogen, filtered though a pad of Celite, and evaporated under vacuum to give the title compound as a yellowish solid. 1H NMR (CD3OD, 500 MHz) δ 4.45 (dd, J=4 and 8 Hz, 1H), 3.82 (s, 3H), 3.31 (dd, 1H), 3.15 (dd, J=8 and 13 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (46.6 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A mixture of 4-trifluoromethylaniline (40 mmol, 5 ml), di-tert-butylcarbonate (40 mmol, 8.7 g), 1N solution of aqueous NaOH (20 ml) in THF (20 ml) was stirred at room temperature for 12 hours. di-tert-butylcarbonate (20 mmol, 4.2 g), 1N solution of aqueous NaOH (20 ml) were added and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated and EtOAc was added. The solution was washed with 2N HCl aqueous solution and brine and then evaporated. The crude mixture was purified by chromatography over SiO2 eluting with hexane/EtOAc mixtures and affording 9.3 g (yield 90%) of the expected product.
Reaction SMILES: [N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3F)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO.Cl.[O:32]1CCOC[CH2:33]1>C(Cl)(Cl)Cl.CO>[ClH:21].[N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[O:32][CH3:33])[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Reactant: C1COCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(F)cc1-c1nc(N2CCCCCC2)c2sccc2n1
Temperature: 120 °C
Reaction time: 120 h

Procedure:
A mixture of 514 mg of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine, 300 mg of sodium methoxide and 10 ml of MeOH was stirred in a sealed tube for 5 days at 120° C. After the reaction mixture was concentrated under reduced pressure, 40 ml of water was added to the obtained residue and extracted twice with 40 ml of chloroform. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a solid. After 0.6 ml of 4M HCl-dioxane solution was added to 10 ml of chloroform-MeOH with this solid, the resultant was concentrated under reduced pressure to give a solid. After the obtained solid was recrystallized three times from EtOAc and EtOH, the crystal generated was filtered and washed with EtOAc to give 223 mg of 4-azepane-1-yl-2-(4-chloro-5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[N:3]2
Reactant: OCCC1CCNCC1
Reactant: Clc1ccc2c(Cl)cccc2n1
Product: OCCC1CCN(c2ccc3c(Cl)cccc3n2)CC1

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 4.78 g (24.14 mmol) of 2-chloro-5-chloroquinoline (J. Med. Chem., 2002, 45, 3130–3137) and 3.43 g (26.55 mmol) of 2-(4-piperidyl)ethanol, 7 g of product are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH:18]([C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1)([CH3:20])[CH3:19]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:18]([C:21]1[S:25][C:24]([NH:26][S:14]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13]3)(=[O:16])=[O:15])=[N:23][N:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1nnc(N)s1
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Acetylamino-indan-5-sulfonyl chloride (500 mg) was dissolved in 5 ml of pyridine and a catalytic amount of 4-dimethylamino pyridine was added. After addition of 262 mg of 5-isopropyl-[1,3,4]thiadiazol-2-ylamine the mixture was stirred at 60° C. for 1 hour followed by evaporation. The resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=95:5).
Reaction SMILES: C([C@@H]1[C@H](N)C2C=CSC=2CC1)CC.[CH2:14]([CH:16]1[CH2:17][CH2:18][C:19]2[O:23][CH:22]=[CH:21][C:20]=2/[C:24]/1=[N:25]\O)[CH3:15]>>[CH2:14]([C@@H:16]1[C@H:24]([NH2:25])[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17]1)[CH3:15]
Reactant: CCC1CCc2occc2/C1=N\O
Agent: CCC[C@H]1CCc2sccc2[C@H]1N
Product: CC[C@H]1CCc2occc2[C@H]1N

Procedure:
Following the procedure for the preparation of cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine but substituting (4E) and (4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.02, 1.30–1.73, 2.50–2.67, 3.84, 6.38, 7.27; HRMS (FAB) calcd for C10H15NO+H 166.1232, found 166.1231. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33; H, 9.14; N, 8.08.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1.[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH2:14]([O:8][C:7]1[CH:6]=[C:5]([CH:11]=[CH:10][CH:9]=1)[O:4][CH2:3][CH2:2][OH:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCOc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCOc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of O-(2-Hydroxyethyl)resorcinol (4 g) and sodium hydroxide (1.04 g) dissolved in methanol (60 mL) was added benzyl bromide (4.44 g), and the resulting reaction mixture was stirred overnight. After this time, approximately 30 mL of the methanol was removed in vacuo, and the mixture was diluted with methylene chloride (100 mL). The organics were washed with water and aqueous 1N NaOH, dried, and concentrated to provide 2-(3-benzyloxyphenoxy)ethanol (5.03 g).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.[C:22](=[O:24])=[O:23]>C1COCC1>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([C:22]([OH:24])=[O:23])=[C:18]([F:20])[CH:17]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(F)cc(Br)cc1F
Temperature: -50 °C
Yield: 38 %

Procedure:
n-BuLi (220 mL, 550 mmol, 2.5 M) was added dropwise to a solution of diisopropylamine (61 g) in THF (500 mL) with stirring at −50° C. under N2. After the addition, the reaction mixture was stirred at −50° C. for 15 minutes, and then warmed to 0° C. for 1 hour. The reaction was cooled to −50° C. and then a solution of 3,5-difluorobromobenzene (96 g, 0.5 mole) in THF (500 mL) was added dropwise. After the addition, the reaction mixture was stirred at −50° C. for 2 hours and then dry ice (about 200 g) was added portion-wise. The resulting mixture was warmed gradually to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between CH2Cl2 (1 L) and water (1 L). An aqueous NaOH solution was added to adjust the pH of the mixture to 10. The organic layer was discarded and the water phase was adjust the pH to 2 with HCl solution. The mixture was extracted with CH2Cl2 (3×400 mL), and the extracts were combined, dried over MgSO4, filtered and evaporated under vacuum to provide the title compound (45 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
3-Nitrophthalic anhydride (1.93 g, 0.01 mol, 1 eq) and 2-(4-hydroxyphenyl)-ethylamine (2.06 g, 0.015 mol, 1.5 eq) were refluxed under heating in toluene (20 ml) for 3 hours. The reaction mi i t ure was cooled to room temperature, and ethyl acetate (100 ml) was added to this reaction mixture. The organic layer was washed twice with dil. aqueous hydrochloric acid solution (30 ml), further washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (2.92 g, 92.8%) as a colorless solid. This was further purified by recrystallization from methanol to give colorless crystals (1.9 g, 60.8%).
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:1][C:2](=[O:27])[CH2:3][N:4]([C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([OH:14])=[O:13])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Benzyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (220 mg, 0.561 mmol) was dissolved in MeOH (20 ml) and CHCl3 (5 ml), then Pd/C 5% (119 mg, 0.056 mmol) was added. The solution was shaken under hydrogen atmosphere at 30 psi on a Parr apparatus for 30 minutes. The catalyst was filtered off and the solvent removed under vacuum to give 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoic acid (150 mg, 89% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2-:10].[Na+].C1(C)C(C)=CC=CC=1>O>[NH2:10][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: [NH2-]
Reactant: CCCc1ccncc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCc1ccnc(N)c1

Procedure:
75 g (0.62M) of 4-n-propylpyridine and 28 g (0.73M) of sodium amide were added to 250 ml of xylene, and the mixture was heated under reflux for 10 hr. Water was added in small portions to the reaction mixture under ice cooling to decompose excess sodium amide, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and then purified by column chromatography (dichloromethanemethanol 50:1→20:1). The yield was 33 g. (blackish purple solid)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17]O)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OO)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 1d), the alkylation of the (RS)-1-(4-hydroxyoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 4-fluorobenzylbromide in presence of potassium carbonate yields the (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light yellow powder; MS: m/e=344 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(=O)=O>CN(C=O)C>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in step d, in DMF (5 mL) was added NaH (95%, 26 mg, 1.1 mmol). The reaction was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-4-piperidinemethanol methanesulfonate (293 mg, 1.0 mmol), as prepared in the preceding step, was added and the reaction mixture was stirred at 50° C. under nitrogen for 3 h. The reaction mixture was then partitioned between water (50 mL) and ethyl acetate (150 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (325 mg, 69%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.78 (d, 2H), 1.91 (m, 1H), 2.74 (t, 2H), 3.72 (d, 2H), 4.13 (m, 2H), 6.69 (m, 2H), 6.76 (dd, 1H), 7.16 (m, 1H), 7.37 (t, 1H), 7.62 (m, 2H), 7.95 (dd, 1H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[SH:14].C(N(CC)CC)C>CC(C)=O>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[S:14][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: Cc1nc(S)n(C)c1C
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)CSc1nc(C)c(C)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloroacetone, 2.55 grams (0.28 mol) in 250 mL of acetone, was added to a solution of 3.55 g (0.025 mol) of 1,4,5-trimethyl-2-mercaptoimidazole and 3.15 g (0.031 mol) of triethylamine in 250 mL of acetone and the resulting mixture stirred at room temperature for 16 hours. At the end of this period the acetone was removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed successively with water and brine, and then dried over magnesium sulfate. After drying, the solvent was evaporated from the filtered dry solution to obtain 3.39 grams of 1,4,5-trimethyl-2[(2-oxopropyl)thio]imidazole. The latter was purified by flash chromatography on silica gel using 1 percent methanol in chloroform as an eluant to obtain 3.0 grams of purified 1,4,5-trimethyl-2[(2-oxopropyl)thio]imidazole.