Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCONC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (1.9 mmol) of N-(tert-butoxycarbonyl)-L-phenylalanine were dissolved in 10 ml of DMF, and 466 mg (3.8 mmol) of 1,2-oxazinane hydrochloride (Starting Material 5), 433 mg (2.3 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 382 mg (2.8 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 731 mg (5.7 mmol) of N,N-diisopropylethylamine were added in succession. The mixture was stirred at RT overnight. The reaction was then poured into a mixture of semisaturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated off, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 620 mg (98% of theory) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:7]=[C:8]([F:25])[C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:10][CH:11]=1)[C@@H:3]([OH:5])[CH3:4].Cl.O1CCOCC1.C(OCC)C>C(Cl)Cl>[F:25][C:8]1[CH:7]=[C:6]([C@H:2]([OH:1])[C@@H:3]([OH:5])[CH3:4])[CH:11]=[N:10][C:9]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: C[C@H](O)[C@@H](O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](O)[C@@H](O)c1cnc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 106 (3.0 g, 8.65 mmol) in DCM (25 mL) was added 4N HCl in dioxane (2.51 mL, 43.2 mmol). The resulting reaction mixture was stirred at a temperature of about 25° C. in a closed vessel for 16 h; a suspension formed. The suspension was stirred with diethyl ether; a solid precipitated. The precipitate was collected by filtration and washed several times with ether to provide 107 (91% yield) as a tan solid which, being >99% pure as analyzed by LC/MS, was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:41]([C:44]1[C:45]([CH3:50])=[N:46][CH:47]=[CH:48][CH:49]=1)=[C:42]=[O:43].NC(N)=O>>[CH3:50][C:45]1[C:44]([NH:41][C:42]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[O:43])=[CH:49][CH:48]=[CH:47][N:46]=1
Reactant: Cc1ncccc1N=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: NC(N)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccnc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and a crude product (59.7 mg) of 3-isocyanato-2-methyl-pyridine obtained in Step A instead of 2-chlorophenyl isocyanate, urea was formed in the same manner as Example 1-D-217, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (2-methyl-pyridin-3-yl)-amide as a yellow solid (103 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-274) as a yellow powder (14.4 mg, 22%).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH2:15]([N:19]([C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[C:24]([CH3:30])[N:23]=1)[CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:15]([N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:30])[N:25]=[C:26]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:27]=1[CH3:28])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(C(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.1 %

Procedure:
A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml of DMSO was treated with NaH (60% in oil, 20 mg, 0.50 mmol) and stirred at room temperature for 20 minutes, butyl-(6-chloro-2,5-dimethylpyrimidin-4-yl)-ethylamine (100 mg, 0.414 mmol) was added and the resulting mixture was heated at 130° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 160 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 5.49 (s, 1H), 3.2–3.4 (m, 2H), 3.0–3.2 (m, 2H), 2.51 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.66 (s, 3H), 1.35–1.50 (m, 2H), 1.1–1.3 (m, 2H), 1.05 (t, 3H), 0.84 (t, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1cc(C)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(C)c1
Product: Cc1cc(C)c(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.95 g, 0.0044 mol), N-[3-(2,4,6-trimethylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.5 g, 0.0036 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.16 g (82%), m.p. 169°-171 ° C.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.O.[NH2:19][NH2:20]>C(O)C>[O:3]=[C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCCC2=O
Yield: 70 %

Procedure:
10.0 g (42 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 100 mL of ethanol, 2.1 mL of hydrazine hydrate were added and the solution stirred at reflux for one day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give 6.0 g of the title compound (70% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[N:4][CH:5]=[C:6]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:7]=1>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[C:3]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(COc3ccc(S(C)(=O)=O)cc3)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(COc3ccc(S(C)(=O)=O)cc3)c(Cl)c2)CC1
Reaction time: 4 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 4-[3-chloro-2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (Example 70) (50 mg, 0.104 mmol) in ethyl acetate (1 mL) was added platinum oxide (5 mg). The mixture was hydrogenated at room temperature for 4 hours and filtered through Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound as a white amorphous (13 mg, yield 26%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:23][CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[O:14])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: NCc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccncc1)c1ncc2cccnc2c1O

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added 1-pyridin-4-ylmethanamine (0.029 g, 0.270 mmol) and the mixture was heated to reflux for 16 hours. The solution was reduced to a smaller volume and refluxed for 4 additional hours. The solvent was removed under reduced pressure and the residue redissolved in DMF and filtered and the solution solution was purified by preparative HPLC (Gilson semipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D., C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 ml three-necked flask provided with a mechanical agitator and a thermometer were added a solution of 22.4 g (133.2 mmol) in theoretical amount of 3-phenylpropionyl chloride which was prepared in the step 1, dissolved in 100 ml dichloromethane, 14.4 g (205.9 mmol) methylphenyl ether and 150 ml dichloromethane, the mixture was cooled in an ice salt bath to lower than −5° C., while maintaining the inside temperature at −5° C. to −10° C., 17.8 g (133.2 mmol) anhydrous AlCl3 was added portionwise, upon the completion of addition. The mixture was stirred at this temperature for 1 hour and then at room temperature for 1 hour, the resultant was poured under stirring into a mixture of 100 g ice, 100 g water and 40 ml concentrated hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice ×20 ml, the organic layers were combined and washed with saturated brine, then with saturated aqueous sodium bicarbonate solution, and then with saturated brine until neutrality, dried over anhydrous magnesium sulfate, filtrated and concentrated under a reduced pressure to obtain a crude product, which was recrystallized with petroleum ether and ethyl acetate (2:1) to obtain a 23.5 g product, the mother liquid was concentrated and recrystallized to obtain a 3.3 g product in a yield of 83.7% in total, mp: 96-97□. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=8.16 Hz), 3.25 (2H, t, J=8.16 Hz), 3.86 (3H, s, OCH3), 6.92 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 240.1 (M+, 37), 135 (100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[C:13](=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 95.6 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (500 mg, 2.99 mmol) and potassium carbonate (0.42 g, 3.0 mmol) were dissolved in 6.0 mL of N,N-dimethylormamide. After addition of iodemethane (0.38 mL, 6.0 mmol) at room temperature, the mixture was stirred for 5 h at the same temperature. The reaction mixture was diluted with ethyl acetate and water, and separated. The organic layer was washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to obtain the title compound as a pale yellow powder (518 mg, 96%).
Reaction SMILES: [OH-].[OH-].[C:3]1([B+2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[K+].Br[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[C:3]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1cccs1
Reactant: [B+2]c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: c1ccc(-c2cccs2)cc1
Yield: 99.2 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-bromothiophene (0.097 mL, 1.0 mmol) were added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ethyl acetate (30 mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 159 mg (99%) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:12].S(=O)=O.[Li].[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>O1CCCC1.CCOCC.C1C=CC=CC=1>[F:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: Fc1cccc(C(F)(F)F)c1Br
Reactant: O=S(=O)(Cl)Cl
Agent: O=S=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=S(=O)(Cl)c1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65 %

Procedure:
2-bromo-1-fluoro-3-trifluoromethylbenzene (1.0 eq.) was taken up in tetrahydrofuran (0.5 M) and diethyl ether (0.5 M) and cooled to −78° C. nbutyllithium (2.5M, 1.0 eq.) was added dropwise and the reaction stirred for 40 minutes. A volume of sulfur dioxide equal to the volume of THF was condensed and diluted with two volumes of ether. The lithium salt of the benzene was canulated into the sulfur dioxide and the reaction was allowed to slowly warm to room temperature. The solvent was removed and the resulting salt was washed with ether then taken up in hexanes (1.0M) and cooled in and ice bath. Sulfuryl chloride (1.06 eq.) was added and the reaction warmed to room temperature and stirred for 5 hours. The solvent was removed to give 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride as a white, oily solid in 65% yield. The product was used crude. 1H NMR (400 MHz, DMSO-D6) □ ppm 7.46 (m, 1H), 7.52 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:10]([CH3:24])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([O:22][CH3:23])([CH3:21])[CH2:13][CH2:12]2>N1C=CC=CC=1>[C:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([O:22][CH3:23])([CH3:21])[CH2:13][CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: c1ccncc1
Product: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (135 mL) was added dropwise to a solution of 6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman (71.8 g, 303.85 mmol) in pyridine (90 mL) which was cooled by an ice/water bath. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 18 h, the reaction mixture was added to 1 L of ice water. This mixture was allowed to stir for 2 h and was then extracted with diethyl ether (3×200 mL). The combined organics were washed with 2N HCl (200 mL), brine (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic solution was dried (sodium sulfate) and concentrated in vacuo to give 74.11 g (87% crude yield) of a yellow solid which was used crude in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12](O)[C:11]1=[O:23])=[O:4].P(Br)(Br)[Br:31]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([Br:31])[C:11]1=[O:23])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](Br)CCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To a solution of 3-((3S,6S)-6-cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (200 mg, 0.75 mmol, 1 equiv) in CH2Cl2 (1.0 mL) was added PBr3 (1.0 M in CH2Cl2, 0.09 ml, 0.38 mmol, 0.8 equiv.) at room temperature and the resulting solution was stirred at room temperature for 18 hours. The reaction solution was then concentrated under vacuum and the residue was purified by silica gel column chromatography, (EtOAc/Heptane, 10%˜60%) to give product 166 mg (yield 76%). MS: 481 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:1][NH:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: CNc1nc2ccccc2o1
Product: CNc1nc2ccc([N+](=O)[O-])cc2o1
Reaction time: 8 h

Procedure:
2-Methylaminobenzoxazole (2.0 g, Hetzheim, Annemarie; Schlaak, G.; Kerstan, Christa., Pharmazie, (1987), 42, 80) was added in portions to conc. nitric acid (15 ml) at room temperature. Stirring was continued over 8 h. The reaction mixture was poured onto crushed ice/sodium hydrogen carbonate with vigorous stirring. The precipitated title compound (1.76 g) was collected by filtration and dried in vacuo at 40° C. m/z (API+): 194 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:17][O:16]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH:15]([OH:16])[CH2:17][N:28]3[CH2:29][CH2:30][N:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH3:18])[CH2:26][CH2:27]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Clc1ccc(-c2ccn(CC3CO3)n2)cc1Cl
Solvent: CCO
Product: Cc1ccccc1N1CCN(CC(O)Cn2ccc(-c3ccc(Cl)c(Cl)c3)n2)CC1
Yield: 71.4 %

Procedure:
A solution of 3-(3,4-dichloro-phenyl)-1-oxiranylmethyl-1H-pyrazole (30 mg, 0.11 mmol) and 1-(2-methylphenyl)-piperazine (22 mg, 0.12 mmol) in EtOH (1 mL) was heated to 80° C. overnight. Removal of solvent and purification by column chromatography (silica, 0-5% acetone/CH2Cl2) afforded 35 mg (70%) of the title compound. 1H NMR (400 MHz, CDCl3): 7.89 (d, J=2 Hz, 1H), 7.61 (dd, J=2, 8.7 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.16 (m, 2H), 6.99 (m, 2H), 6.54 (d, J=2.3 Hz, 1H), 4.31 (m, 1H), 4.18 (m, 2H), 2.93 (m, 4H), 2.60 (m, 2H), 2.47 (m, 3H), 2.88 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O>FC(F)(F)C(O)=O>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2c1nnc(C(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(Cl)cc5F)ncnc43)[C@H](O)[C@@H]2O)o1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
9-{(3aR,4R,6S,6aR)-6-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-(4-chloro-2-fluorophenyl)-9H -purin-6-amine (2.35 g) was dissolved in trifluoroacetic acid (20 ml) and water (2 ml) with ice bath cooling, and the mixture allowed to stand at 4° C. for 17 h. The mixture was poured slowly into ice cold saturated aqueous sodium bicarbonate (400 ml) and extracted with ethyl acetate (3×200 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a buff solid (2.30 g).
Reaction SMILES: Cl.CN(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20](/[C:29](/[C:36]2[NH:41][C:40](=[O:42])[C:39]([CH3:43])=[CH:38][CH:37]=2)=[CH:30]\[CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:21]=[CH:22][C:23]=1[S:24][CH2:25][CH2:26][CH2:27][OH:28].CN(C)CCN>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:28][CH2:27][CH2:26][CH2:25][S:24][C:23]2[CH:22]=[CH:21][C:20](/[C:29](/[C:36]3[NH:41][C:40](=[O:42])[C:39]([CH3:43])=[CH:38][CH:37]=3)=[CH:30]\[CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:19][C:18]=2[Cl:17])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(/C(=C/C2CCCC2)c2ccc(SCCCO)c(Cl)c2)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCSc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(=O)[nH]3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
Triethylamine (148 μL), trimethylamine hydrochloride (50 mg) and 4-methylbenzenesulfonyl chloride (74 mg) were sequentially added to a solution of 6-[(E)-1-{3-chloro-4-[(3-hydroxypropyl)sulfanyl]phenyl}-2-cyclopentylethenyl]-3-methylpyridin-2(1H)-one obtained in Example 1-22 (143 mg) in chloroform (5 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water and N,N-dimethylethylenediamine were added to the reaction solution, followed by extraction with chloroform. The organic layer was sequentially washed with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg, 18%) as a colorless amorphous.