Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CS(O[CH:15]1[CH2:18][N:17]([C:19]([C:21]2[O:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:25]=2)=[O:20])[CH2:16]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:15]2[CH2:16][N:17]([C:19]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[O:20])[CH2:18]2)=[CH:3][CH:4]=1
Reactant: OCc1ccc(S)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
(4-Mercaptophenyl)methanol (2.38 g, 17.0 mmol) and 1C (5.00 g, 15.5 mmol) were mixed in DMF (80 mL). Cs2CO3 (6.05 g, 18.56 mmol) was added. The mixture was stirred at 90° C. overnight and then cooled room temperature. Ethyl acetate (150 mL) was added and the mixture was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic phases were combined, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with ethyl acetate/heptane (20:80, 40:60 and then 60:40). There was obtained 3.5 g (61%) of 5A as a solid. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 4.64 (m, 2H), 4.69 (s, 2H), 5.10 (m, 1H), 7.34 (m, 4H), 7.53 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 368 [M−H]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](O)=O)=[C:7]2[N:6]=[N:5]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>C(Cl)(Cl)Cl>[S:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:14]1[C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:3][O:2][CH3:1])[N:5]=[N:6][C:7]=12
Reactant: COCn1nnc2c(C(=O)O)ncn2c1=O
Reactant: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Product: COCn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Temperature: 70 °C

Procedure:
To a mixture of polyphosphate ester (see, e.g., Yalpn et al., Eur. J. Med. Chem., 1992, Vol. 27, pp. 401-406) (1 g) and chloroform (3 mL) was added 3-(methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (225 mg; 1 mmol) and 2-aminothiophenol (107 μL; 1 mmol). The mixture was carefully heated to 70° C. for 3.5 hours, then cooled and the chloroform removed under reduced pressure. The residue was added to water (100 mL), which was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4) and concentrated. The crude product was washed with ether/hexane, and purified by column chromatography to give a pale yellow powder (0.007 g; 3%). δH (DMSO d6): 9.03 (1H, s), 8.22 (1H, d, J=7.9), 8.17 (1H, d, J=7.9), 7.61 (1H, td, J=7.7, 1.3), 7.53 (1H, td, J=7.6, 1.2), 5.65 (2H, s), 3.46 (3H, s).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[N:13]([CH2:27][CH2:28][CH3:29])[C:14](=[O:26])[C:15]3[NH:16][C:17]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:18][C:19]=3[N:20]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O.C1COCC1>[CH:21]1([C:17]2[NH:16][C:15]3[C:14](=[O:26])[N:13]([CH2:27][CH2:28][CH3:29])[C:12]([NH:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=4)=[N:20][C:19]=3[N:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCn1c(NCc2ccc(C(=O)OC)cc2)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCn1c(NCc2ccc(C(=O)O)cc2)nc2nc(C3CCCC3)[nH]c2c1=O
Yield: 31.9 %

Procedure:
To a solution of 4-[(8-cyclopentyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino)-methyl]-benzoic acid methyl ester (0.081 g, 0.198 mmol) in a mixture of MeOH/H2O/THF (5 ml each) was added NaOH (0.024 g, 0.594 mmol) and the resulting reaction mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and neutralized with 1N HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by washing repeatedly with diethyl ether to give the product (0.025 g, 32%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=3)[O:11][C:9]=2[N:10]=1.Br[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([O:21][CH2:28][C:29]([OH:31])=[O:30])=[C:18]([CH3:20])[CH:19]=3)[O:11][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 430 mg of 4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol, 0.2 ml of tert-butyl bromoacetate and 423 of mg potassium carbonate in 5 ml of dimethylformamide was stirred at 60° C. for 2 h. After cooling, the solids were removed by filtration and the solvent were distilled off in vacuo. 1.3 ml of trifluoroacetic acid were added to the residue, and the solution was stirred at room temperature for 1 h. Then 10 ml of toluene were added and the solvents were removed in vacuo. The title compound was isolated by silica gel chromatography (heptane/ethyl acetate gradient) as a white solid (135 mg).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:17]([C:26]([O:28][CH3:29])=[O:27])=[C:16]([CH3:30])[N:15]=[C:14]1[O:31]C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[N:13]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:33])=[O:5])=[O:12])[C:14](=[O:31])[NH:15][C:16]([CH3:30])=[C:17]2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:21]=1
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)NCCCC(=O)OC(C)(C)C)C1c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)O)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Into a solution of methyl 1-{[(4-tert-butoxy-4-oxobutyl)amino]carbonyl}-6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate (77.3 mg, 0.166 mmol) in dichloromethane (2.00 mL) at 0° C. was slowly added trifluoroacetic acid (189 mg, 1.66 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (58.1 mg, 88.9%). ESMS m/e: 394.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:69][O:70][C:71](=[O:80])[C@H:72]([CH2:74][CH2:75][C:76]([O:78][CH3:79])=[O:77])[NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:73][CH:72]([CH2:74][CH2:75][C:76]([O:78][CH3:79])=[O:77])[C:71]([O:70][CH3:69])=[O:80])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), HATU (110 mg, 0.29 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (66 mg, 0.31 mmol). The mixture was heated at 50° C. for 15 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as white solid. Yield: 130 mg, 81%.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Li+].[CH3:14]CC[CH2-].IC>O1CCCC1>[CH3:14][C:3]1[C:4]2[O:5][CH2:6][O:7][C:8]=2[CH:9]=[CH:10][C:2]=1[C:1]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a round bottom flask equipped with an overhead stirrer and a nitrogen inlet was added piperonylic acid (50.0 g, 301 mmol) and tetrahydrofuran (753 mL). This was cooled to −75° C. in a dry ice-acetone bath. N-Butyllithium (1.6 M in hexanes) (414 mL, 662 mmol) was added dropwise maintaining the temperature of the reaction at or below −65° C. When the addition was complete the cooling bath was removed and the reaction was allowed to warm to −20° C. The reaction was returned to the bath and cooled to at least −60° C. at which time iodomethane (37.5 mL, 602 mmol) was added dropwise. Cooling was removed and the reaction allowed to warm to 10° C. at which time the reaction was placed in an ice bath and stirred at 0° C. for 30 minutes. The reaction was quenched by addition of 1N HCl and the tetrahydrofuran removed by evaporation. The residue was slurried in 1N HCl and filtered. The filtrate was washed with water, and dried at 50-60° C. in vacuo to give a pale yellow solid, 4-methyl-benzo[1.3]dioxole-5-carboxylic acid (52.8 g, 293 mmol) in 97% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.44 (s, 3H), 6.10 (s, 2H), 6.77 (d, 1H), 7.64 (d, 1H). TLC Rf=0.54 (1:1 ethyl acetate/hexane, piperonylic acid=0.41).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br.C(OC(=O)C)C>ClCCl>[Br:20][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])=[N:13]2
Reactant: BrBr
Reactant: C[SiH](C)OCc1ccc2cccc(C(C)(C)C)c2n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[SiH](C)OCc1ccc2c(Br)ccc(C(C)(C)C)c2n1
Yield: 64.2 %

Procedure:
To a 500 mL flask was added 400 mL dichloromethane and 31.5 g 8-(t-butyl)dimethylsiloxyquinaldine. The mixture was vigorously stirred while 33.14 g bromine (Aldrich) dissolved in 20 mL dichloromethane was added dropwise. The reaction progress was monitored by TLC (5:95 ethylacetate:hexanes). The starting material was found to be completely consumed. Excess bromine was removed by addition of 200 mL of saturated sodium thiosulfate (Aldrich). The organic layer was separated, washed with 150 ml water, 150 ml brine and then dried over MgSO4. After filtering off the salts, the filtrate was concentrated to an oil which was purified by column chromatography, eluting with 20% dichloromethane/hexanes to give 26.04 g of 5-bromo-8-(t-butyl)dimethylsiloxyquinaldine (compound 2ii) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:7][CH:8]=1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)O)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
To 429 mg (2.22 mmol) of methyl (E)-3-(3-methoxy-6-pyridyl)acrylate were added 12 ml of methanol and 1.11 ml of a 4N potassium hydroxide aqueous solution, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added 1N hydrochloric acid, and the solution was extracted with ethyl acetate and with chloroform. The ethyl acetate layer and the chloroform layer were separately washed with a saturated aqueous solution of sodium chloride. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 277 mg (1.55 mmol) of (E)-3-(3-methoxy-6-pyridyl)acrylic acid (yield: 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Oc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
3-(N-t-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-5-hydroxy-1H-indole and 2-chloro-3-nitropyridine were used. Sodium hydride (60% in oil) was the base, tetrahydrofuran was the reaction solvent, the reaction was stirred at room temperature for 3 hours, and the chromatographic solvent system was diethyl ether/hexanes [gradient 1:1 to 4:1] to afford the title compound (62%) as a yellow solid: top, 206.0°-208.0° C. with effervescence; 1H NMR (DMSO-d6) δ8.53 (dd, J=1.8 and 8.3 Hz, 1H), 8.33 (dd, J=1.8 and 4.4 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.50 (br s, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.30 (dd, J=4.4 and 8.3 Hz, 1H), 6.94 (dd, J=2.0 and 8.6 Hz, 1H), 6.05-6.01 (m, 1H), 4.02-3.94 (m, 2H), 3.54 (br t, J=5.6 Hz, 2H), 2.54-2.45 (m, 2H), 1.42 (s, 9H); TLC [methylene chloride/hexanes, 1:1]: Rf =0.2; TLC [diethyl ether]: Rf 32 0.3.
Reaction SMILES: [ClH:1].Cl.C([S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:9]/[C:8]/1=[CH:26]\[C:27]1[N:31]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:30]=[N:29][CH:28]=1)(=O)C.[CH2:38](O)C>>[ClH:1].[CH:16]1([C:14](=[O:15])[CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([SH:6])/[C:8](=[CH:26]/[C:27]3[N:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]=[N:29][CH:28]=3)/[CH2:9]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:18][CH2:17]1
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)piperidine hydrochloride (2.0 g) in ethanol (5.0 ml) with stirring at 0° C. for one hour, and the resulting mixture was stirred at room temperature under tightly sealed condition for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified using preparative HPLC [YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid solution (33:67, v/v)]. The eluate was treated with hydrogen chloride (4 N dioxane solution, 2 ml). The solvent and excess hydrogen chloride were removed under reduced pressure to afford the title compound (1.29 g, yield: 68%) as a colourless amorphous solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].Cl[CH:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH3:15][C:14]1[N:6]=[C:2]2[N:3]([C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:5][S:1]2
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2sccn12
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
A mixture of 1,3-thiazol-2-amine (10 g, 100 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 100 mmol) and ethanol (100 mL) was stirred at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→350/50) and washed with diisopropyl ether to give the title compound (5.5 g, 26%) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:19][C@@H:20]([C@H:22]2[CH2:26][N:25]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[CH3:28])[C:24](=[O:37])[CH2:23]2)[CH3:21])[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.CCN(CC)CC.N(CC)CC>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([O:19][C@@H:20]([C@H:22]2[CH2:26][N:25]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[CH3:28])[C:24](=[O:37])[CH2:23]2)[CH3:21])[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(OCc4ccccc4)cc4nc(C)sc34)CC2=O)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCNCC
Solvent: ClCCl
Product: Cc1nc2cc(O)cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccc(O)cc4)C3)c2s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
(R)-4-((R)-1-(5-(benzyloxy)-2-methylbenzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 4.03F (490 mg, 0.95 mmol) was dissolved in DCM (10 mL) under Ar. The solution was cooled to −78° C., and a 1.0 M solution of BBr3 in DCM (7.1 mL, 7.1 mmol) was added over 1 min. The resulting mixture was allowed to warm to r.t. and was stirred for an additional 45 min. The mixture was then cooled in an ice water bath, and MeOH (4.6 mL, 110 mmol) was added over 1 min. Et3N (4.1 mL, 29 mmol) and Et2NH (0.31 mL, 3.0 mmol) were then added, and the mixture was removed from the cold bath. After an additional 15 min, the mixture was concentrated, and the crude residue was dissolved in MeOH (30 mL) and concentrated. The resulting residue was partitioned between EtOAc (50 mL) and water (30 mL). The phases were separated, and the organic phase was washed with a mixture of water (25 mL), 3 M aqueous HCl (7.5 mL), and brine (25 mL). The organic phase was washed with a mixture of saturated aqueous NaHCO3 (20 mL) and brine (20 mL) and was dried over Na2SO4, filtered, and concentrated to afford crude (R)-4-((R)-1-(5-hydroxy-2-methylbenzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-hydroxyphenyl)ethyl)pyrrolidin-2-one that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:23].[NH4+].[Cl-]>C1COCC1>[CH3:23][N:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(1-(4-nitrophenyl)piperidin-4-yl)acetamide (568 mg, 2 mmol) in THF (15 mL) was added NaH (60%, 200 mg, 5 mmol) at room temperature. The reaction was stirred at 20° C. for 15 minutes. After that, iodomethane (300 mg, 4 mmol) was dropped into the reaction and stirred at 60° C. for 18 hours. The reaction was treated with sat. NH4Cl solution and extracted with n-BuOH, washed with brine, dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 278 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:13][N:12]=[C:11]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][N:12]=[C:11]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: O
Product: O=C(O)Cc1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a solution of ethyl 2-(4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)acetate, 12-b, (90 mg, 0.27 mmol) in TRF (6 ml) was added LiOH monohydrate (19 mg, 0.8 mmol) in H2O (3 ml). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and the remaining aqueous solution was extracted with ethyl acetate (5 ml). The separated aqueous phase was adjusted to pH=2 with Conc. HCl. The solid crashed out and was filtered to give compound 12-c (40 mg, 48.5%). 1HNMR (DMSO-d6, 300 MHz): δ 12.56 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 7.84 (s, 1H), 7.32-7.52 (M, 5H), 6.59 (s, 1H), 5.57 (S, 2H), 3.61 (s, 2H). (M+H)+=311.1.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][C:36]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)Cc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.42 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.29 ml, 0.49 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (138.2 mg, 0.41 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon. After 25 minutes, a solution of phenylacetyl chloride (65 microliter, 0.49 mmol) in tetrahydrofuran (1/2 ml) was added. Stirring was continued at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500 micron silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[N:24][C:25]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])[CH:8]=3)[C:4]([S:3][CH2:1][CH3:2])=[CH:5]2)=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Product: CCSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
The product 29a) (1.5 g, 5.17 mmol, 1.0 eq) and 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol, 1.0 eq) were reacted as described in procedure 1c). Yield: 700 mg. Mass spectroscopy: m/z: [M+H]+=446.6/448.7