Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][O:7][CH2:6]1.C([Mg]Cl)(C)C.CN([CH:23]=[O:24])C>C1COCC1>[F:14][C:12]1[CH:11]=[CH:10][C:3]([O:4][CH:5]2[CH2:9][CH2:8][O:7][CH2:6]2)=[C:2]([CH:13]=1)[CH:23]=[O:24]
Reactant: Fc1ccc(OC2CCOC2)c(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1OC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of 3-(2-bromo-4-fluorophenoxy)tetrahydrofuran (50.0 g, 191 mmol) in 400 ml of dry THF at −78° C., isopropyl magnesium chloride (2M in THF) (240 ml, 479 mmol) was added drop wise, stirred the reaction mixture at room temperature for 4 h, again cooled the reaction mixture at −78° C., DMF (22.1 ml, 287 mmol) was added, stirred the reaction mixture at room temperature for 1 h, quenched with NH4Cl solution (400 ml), diluted with EtOAc (1.0 L), washed with water and brine solution, dried over sodium sulfate and concentrated to dryness to afford the title product 38.0 g (crude).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].C(O)(=O)C.O.[CH3:12][C:13]([CH3:15])=O>>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:13]([CH3:15])[CH3:12])=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)NN
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)NN=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Hydrazinecarboxylic acid methyl ester (5.01 g) were dissolved in acetone (28 mL), and acetic acid (0.0636 mL) was added. The reaction mixture was stirred at room temperature for 24 hours. Water (50 mL) was added, and mixture was extracted three times with DCM (50 mL) and evaporated under vacuum, giving N′-Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g, 89%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CS(C)=O>[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:5]=[CH:6][CH:7]=2)[NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=[O:16])=[CH:34][CH:33]=1
Reactant: COc1ccc(CN)cc1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CNc2cccc(NC(CC(=O)O)c3ccccc3)c2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-difluoronitrobenzene (200 mg, 1.26 mmol) in DMSO (2 mL) was added 3-amino-3-phenylpropionic acid (228 mg, 1.39 mmol) and potassium carbonate (347 mg, 2.52 mmol). The suspension was heated to 100° C. for 0.5 hour, and 4-methoxybenzylamine (180 μL, 1.39 mmol) was added, and heating continued for a further 3 hours. The suspension was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid (pH<4), and then extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.75 min, MH+ 422].
Reaction SMILES: O1CCCCC1[O:7][C@H:8]([CH3:11])[CH2:9][OH:10].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1.CN(C=O)C>[CH2:14]([O:10][CH2:9][C@H:8]([OH:7])[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](CO)OC1CCCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.5 %

Procedure:
(2R)-2-tetrahydropyranyloxy-1-hydroxypropane (60 g, 0.37 mol) was dropwise added to a suspension of sodium hydride (60%) (22 g) in THF (100 ml) under ice cooling. After completion of the dropwise addition, a solution of benzyl bromide (70 g) in DMF (300 ml) was dropwise added, followed by agitating the mixture at room temperature for 6 hours, pouring it into water (500 ml), extracting with toluene (300 ml), washing the resulting organic layer with water, concentrating it, dissolving the concentrate in ethanol (300 ml), adding 6N-hydrochloric acid (20 ml), agitating the mixture at 20° C. for 2 hours, distilling off ethanol, adding toluene (300 ml), washing the resulting organic layer with an alkali and then with water and distilling it under reduced pressure to obtain (R)-1-benzyloxy-2-propanol (b.p. 105°-107° C./5 mmHg) (28 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:29]1([CH2:28][CH2:27][N:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)N(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A mixture of N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester from Example 4b (6.4 g, 17.5 mmol), 4-(2-chloroethyl)morpholine hydrochloride (9.77 g, 52.5 mmol), and potassium carbonate (10 g, 72.4 mmol) in dry DMF (60 mL) was heated to 70° C. for 16 hours. After cooling to room temperature, mixture was poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over MgSO4, and concentrated to afford an oil which was purified by chromatography (40/100 acetone/hexane) to give N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester, (6.86 g, 81.86%) as an oil. The proton NMR was consistent with N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester. HR mass calculated for C23H30N2O5S2 : 478.1597.Found: 478.1596.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:17].[K+].[OH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])=[O:22])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Br)c(F)c1
Reaction time: 4 h

Procedure:
4-Bromo-3-fluorotoluene (40.0 g, 0.212 mol) was heated at 90° C. in H2O (200 mL)-pyridine (200 mL) with mechanical stirring under Ar. Potassium permanganate (KMnO4) (67 g, 0.424 mol) was added portionwise over 3 h. After 4 h, an HPLC of a filtered sample indicated 50% conversion to the acid. An additional 30 g of KMnO4 was added and heating continued overnight. HPLC indicated 81% conversion. Further KMnO4 was added portionwise with reaction monitoring by HPLC until >95% conversion was obtained. The reaction mixture was filtered through Celite, the filter pad washed with H2O, aq NaOH and EtOH. The filtrate was concentrated to a small volume, then partitioned between 3N NaOH solution and diethyl ether. The aqueous basic layer was separated, cooled in an ice-H2O bath and acidified slowly with 6N HCl solution to precipitate the white solid product. This was collected by suction filtration and dried at 40° C. in a vacuum oven overnight to give the title compound. mp 190-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (3.67 g), methyl bromoacetate (0.81 mL), and potassium carbonate (4.66 g) in DMF (21 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered. The solid was combined with the filtrate and washed with water, dried over sodium sulfate and evaporated to give a brown solid which was recrystallized in methanol to give methyl {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetate (2.80 g). 1H-NMR (400 MHz; DMSO-d6): 9.62 (s,1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.94-7.85 (m, 2H), 7.63 (d, 1H), 7.17 (s, 1H), 5.04 (s, 2H), 4.00 (s, 3H), 3.72 (s, 3H); MS (EI) for C18H15N3O4Cl2: 408 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[NH3:19]>>[C:8]([C:6]1[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:9])[NH2:19]
Reactant: N
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Product: CNc1nc(C(N)=O)c(-c2ccncc2)s1
Reaction time: 120 h

Procedure:
A solution of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.36 g) in 26% methanolic ammonia (100 ml) was allowed to stand at ambient temperature for 5 days. The reaction mixture was evaporated in vacuo and the residue was washed with tetrahydrofuran to give 4-carbamoyl-2-methylamino-5-(4-pyridyl)thiazole (1.0 g). mp 212°-213° C. (from tetrahydrofuran-methanol).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][CH2:9][CH2:8][CH2:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCO)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)s1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Compound 48-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.27 g) and N-bromosuccinimide (1.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (650 mg) as a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([CH3:8])=[O:7].C=CC1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(Cl)Cl>O>[O:7]1[CH:6]([C:8]2[CH:16]=[CH:15][C:14]([S:17]([N:1]=[N+:2]=[N-:3])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a slurry of 17.5 parts of sodium azide in 20 parts of water and 40 parts of acetone at room temperature was added with rapid stirring a solution of 18 parts of p-styrenesulfonyl chloride in 61 parts of methylene chloride. After stirring at room temperature for 18 hours, the orange-colored reaction mixture was diluted with 150 parts of water and separated. The water layer was re-extracted with 61 parts of methylene chloride and then the combined methylene chloride layers were washed with water and dried over magnesium sulfate. After removal of the methylene chloride solvent 12 parts of the resulting p-styrenesulfonylazide was dissolved in 110 parts of glacial acetic acid containing one part of sodium acetate at 20° C. To the solution was added with agitation 40% peracetic acid in an amount in excess of that required to convert the styrene group to an epoxyethyl benzene group. The reaction was allowed to come to room temperature and stirred until the peracetic acid content remained constant. Then it was diluted with 250 parts of water and 133 parts of methylene chloride. The methylene chloride layer was removed and washed 6 times with water and then dried over sodium sulfate. The methylene chloride solvent was removed to give 12.5 parts of 4-(epoxyethyl)benzenesulfonylazide. The product was analyzed by infrared analysis for azide nitrogen and oxirane oxygen. The results of this analysis are tabulated below:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][N:15]=[N+]=[N-])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2].[ClH:22]>CO.[Pd].C(O)C>[ClH:22].[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][NH2:15])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
0.80 g of 5-acetyl-5'-azido-2',5'-dideoxyuridine was dissolved in 100 ml of methanol and 10 ml of 0.27M hydrogen chloride in methanol were added. 0.1 g of 5% palladium-on-charcoal catalyst was added as a slurry in ethanol and the mixture was hydrogenated for 3 hours at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 0.91 g of hydroscopic 5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride of melting point 73°-85° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:18])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 50 °C
Yield: 1230.1 %

Procedure:
step a—To a solution of 3-bromo-2-chloro-6-methyl-pyridine (2.0 g, 0.687 mmol) in CHCl3 was added MCPBA (3.3 g, 19.1 mmol) and the resulting solution was heated at 50° C. overnight. The resulted solution was cooled and partitioned between DCM and sat'd. aq. NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30 to 80% EtOAc) to afford 1.88 g (87%) of 3-bromo-2-chloro-6-methyl-pyridine 1-oxide (357a) as a white solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 309.2 %

Procedure:
To a solution of pyridine (440 μL, 5.45 mmol) in dichloromethane (5.0 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (840 μL, 4.99 mmol) was added. The resultant mixture was stirred for 5 min, and methyl (R or S)-(5-hydroxy-4-methyl-indan-1-yl)acetate (1.00 g, 1.34 mmol, from Step H) was added as a solid. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 1.46 g of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 1.69-1.91 (m, 1H), 2.33 (s, 3H), 2.38-2.56 (m, 2H), 2.69-2.79 (m, 1H), 2.79-3.01 (m, 2H), 3.49-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (s, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](OC(=O)C)(=O)[CH3:24]>>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([CH3:24])[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccc3nc(N4CCN(C(C)C)CC4)sc3c2)no1
Yield: 16.7 %

Procedure:
A solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (700 mg, 2.19 mmol) in acetic anhydride (20 mL) was heated at 130° C. for 6 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 125 mg (16.7%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-methyl-[1,2,4]oxadiazol-3-yl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([C@@H:38]1COC(=O)[N:39]1C([C@@H](C(C)C)CS(N1CCN(C2N=CC(C3C=CC(C#N)=CC=3)=CN=2)CC1)(=O)=O)=O)C1C=CC=CC=1>>[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:39]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)O
Yield: 14 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4 fluorophenyl)pyrimidin-2-yl] piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(2-{4-[2-(R)-(4-(R)-benzyl-2-oxooxazolidine-3-carbonyl)-3-methylbutane-1-sulfonyl]piperazin-1-yl}pyrimidin-5-yl)benzonitrile (0.70 g), to give the title compound as a white solid (0.07 g, 14%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1.CC(O)=O.CO>[Zn].CCO>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: Nc1ccc(Br)nc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a stirred mixture of 6-bromo-3-nitro-2-pyridinamine (2.5 g, 11.47 mmol) in a mixture of glacial HOAc (10 mL), MeOH (10 mL) and EtOH (10 mL) at 0° C. was added portionwise zinc dust (3.73 g, 57.35 mmol). The mixture was stirred at rt for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, separated and dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-bromopyridine-2,3-diamine (1.30 g, 60%) as a solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.61 (d, J=7.7 Hz, 1H), 6.47 (d, J=7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s, 2H). LCMS (ESI) m/z 188 and 190 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cn(C)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)c1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A mixture of 130b (100 mg, 0.18 mmol) and lithium hydroxide hydrate (189 mg, 4.5 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 min. The mixture was evaporated under reduced pressure and the residue was added water (5 mL). It was then extracted with dichloromethane (3×10 mL). The combined extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 130 (41.1 mg, 44.4%) as white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56-8.53 (m, 2H), 7.90 (d, J=2.0 Hz, 1H), 7.78 (dd, J=2.0, 12.5 Hz, 1H), 7.61 (s, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.41-7.39 (m, 2H), 7.37 (d, J=2.0 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 5.04-5.02 (m, 1H), 4.41-4.39 (m, 2H), 3.59 (s, 3H), 3.58 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7]1)C.CC[O:18]C(C)=O>O1CCOCC1.O.C(O)CCC>[O:15]=[C:12]1[N:11]2[CH:6]([CH2:4][CH2:3][CH2:2][CH:1]=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: CCOC(C)=O
Reactant: CCCC(C)C1CCCc2noc(=O)n21
Solvent: O
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=CCCCC1CCCc2noc(=O)n21

Procedure:
Ex-28) The product of Example 27 (0.42 g; 2 mmol) and NaIO4 (0.86 g; 4 mmol) were dissolved in a mixture of 12 mL of dioxane and 8 mL of H2O. Two drops of a 2% solution of OSO4 in n-butanol was added to the mixture. The reaction mixture was stirred until tlc (100% EtOAc) indicated that the starting material was consumed. A precipitate had formed and was filtered. This solid was washed with dioxane. The filtrate was concentrated and the residue was partitioned between H2O/CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford the title compound as an oil.
Reaction SMILES: [OH-].[K+].[SH2:3].[CH2:4]([O:6][C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:13]Cl)/[CH:10]=[CH:11]/Cl)[CH3:5]>C(O)C.O>[S:3]1[CH:11]=[CH:10][C:9]([CH:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([O:6][CH2:4][CH3:5])=[O:20])=[CH:13]1
Reactant: S
Reactant: CCOC(=O)C(C(=O)OCC)=C(/C=C/Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccsc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Potassium hydroxide (0.14 g, 2.0 mmol) in ethanol (50 ml) was saturated with hydrogen sulphide at 0° for one hour. To this was added 4-trans ethyl-2-ethoxycarbonyl-5-chloro-3-chloromethylpenta-2,4-dienoate (0.62 g, 2.45 mmol), and addition of hydrogen sulphide was continued for one hour at room temperature. The reaction mixture was stirred for a further four hours. Potassium hydroxide (0.20 g, 2.8 mmol) was added and hydrogen sulphide passed for thirty minutes. The reaction mixture was stirred at room temperature for sixteen hours, diluted with water (50 ml) and extracted with ether (3×50 ml). The extracts were washed with saturated brine, N sodium bicarbonate solution, saturated brine, dried (Na2SO4) and evaporated to give the title compound (78% yield) purified by distillation, b.p. 119°-127°/0.5 mm. δ (CDCl3) 1.27 (6H, t, J 7 Hz, CH3), 4.20 (4H, q, J 7 Hz, OCH2), 4.75 (1H, s, CH), 7.20-7.43 (3H, m, thienyl protons), νmax (film) 1730 cm-1, λmax (ethanol) 234 nm. C11H14O4S requires M, 242.0649. Found M+, 242.0609.