Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)[CH:10]=1>CN(C)C=O>[Cl:1][C:19]1[S:18][C:17]([NH2:20])=[N:16][C:15]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nc(-c2cccnc2)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(Cl)s1
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
N-Chlorosuccinimide (14,7 g) was added all at once to a solution of 4-(pyridin-3-yl)-thiazol-2-amine (17,7 g) in N,N-dimethylformamide (130 ml) at 0°-5° C. After five minutes, the product precipitated, and after ten minutes, precipitation was completed by addition of water and ammonium hydroxide solution. The product was filtered and dried in vacuo at 60° C. to give 5-chloro-4-(pyridin-3-yl)-thiazol-2-amine, (18,2 g) Mp 202° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[N:35]=3)[CH:22]=2)[CH2:17][CH:16]1[C:43](=[O:55])[NH:44][C:45]1([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:47][CH:46]1[CH:48]=[CH2:49])=[O:14])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:53]([O:52][C:50]([C:45]1([NH:44][C:43]([CH:16]2[CH2:17][CH:18]([O:20][C:21]3[C:30]4[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[N:35]=4)[CH:22]=3)[CH2:19][CH:15]2[C:13]([OH:14])=[O:12])=[O:55])[CH2:47][CH:46]1[CH:48]=[CH2:49])=[O:51])[CH3:54]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h

Procedure:
TFA (5 mL) was added at room temperature to a solution of 2-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-[2-(6-isopropyl-pyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-cyclopentanecarboxylic acid tert-butyl ester (109, 590 mg, 0.90 mmol) and triethylsilane (280 mg, 2.5 eq) in CH2Cl2 (5 mL). After 2 h, the reaction mixture was concentrated under reduced pressure to afford the desired product 110, which was used in the next step without further purifications.
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5cc(F)cc(F)c5OC)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Ethane sulfonyl chloride 337 (47 mg, 0.3665 mmol) was added to the reaction and stirred it for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 338. 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.52 (d, 1H), 8.17 (d, 1H), 7.84 (s, 1H), 7.72 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m, 1H), 3.96 (m, 2H), 3.68 (s, 3H), 3.06 (m, 2H), 3.00 (m, 3H), 2.29 (m, 2H), 2.14 (m, 2H), 1.40 (m, 5H), 1.25 (m, 5H) and MS ES+502.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:36])[CH2:17][OH:16])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]=1[CH3:26]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine (compound 341) (95 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, the mixture was stirred at 0° C. for 30 min, and the mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (63 mg, yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([N:32](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.SCC(O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (1.8 g) was dissolved in 30 mL dry DMF, then 505 μL (670 mg) mercaptoacetic acid and 2.6 mL (2.6 g) DBU were added at rt. The reaction stirred for 3 h, then was partitioned between saturated aqueous NaHCO3 and diethyl ether. The organic layer was washed successively with aqueous NaHCO3, water, and brine, then was dried with Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 893 mg desired product after drying. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.61 (d, 1H), 7.50-7.42 (m, 3H), 7.27-7.15 (m, 5H), 7.09 (m, 2H), 6.80 (d, 1H), 6.67 (d, 1H), 6.61 (m, 1H), 5.19 (s, 2H), 5.10 (m, 1H), 4.34 (m, 1H), 4.02 (m, 1H), 3.63 (s, 3H), 3.47 (t, 1H), 3.15 (t, 1H), 2.75 (m, 2H), 2.10 (s, 1H), 1.69-1.48 (m, 2H), 0.78 (t, 3H).
Reaction SMILES: C[N:2]1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][C:3]1=O.P(Cl)(Cl)([Cl:19])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:19][C:3]1[CH:4]=[CH:5][C:6]2[C:15](=[C:14]3[C:9](=[CH:8][CH:7]=2)[CH:10]=[CH:11][CH:12]=[N:13]3)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)ccc2ccc3cccnc3c21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc2ccc3cccnc3c2n1
Yield: 75 %

Procedure:
Under a stream of argon, to compound (2) (8 g; 38 mmol), phosphorus oxychloride (72 mL) and phosphorus pentachloride (9.8 g; 47.6 mmol) were added in an ice bath. The resulting reaction mixture was stirred and refluxed for 8 hours, and excess phosphorus oxychloride was removed under reduced pressure. To the resulting reaction concentrate, ice water and concentrated aqueous ammonia were added and the resulting mixture was made alkaline to precipitate crude crystals. The crude crystals were separated by filtration and washed with water, and then dried under reduced pressure to give 6.1 g (yield: 75%) of the title compound (3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:10]S(C)=O.C1(=O)C=CC(=O)C=C1>C(Cl)Cl>[O:1]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[CH:2][CH2:10]1
Reactant: CS(C)=O
Reactant: c1ccc2occc2c1
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCl
Product: C1=Cc2ccccc2OC1
Reaction time: 36 h
Yield: 12 %

Procedure:
(±) 1,5-Dimethoxy-2′-isopropenyl dihydrofuroanoxanthone (107). DMSO (118 mL) was added to a mixture of (106) (1.21 g, 3.56 mmol), Pd[(CH3CN)4BF)2] (0.79 g, 1.78 mmol) and benzoquinone (recrystallized from EtOH, 3.84 g, 35.6 mmol). The solution was stirred 36 h, then poured into a separatory funnel containing CH2Cl2 (400 mL), and washed with H2O (2×300 mL). The layers were separated and the H2O layer was washed with CH2Cl2 (200 mL). The organic layers were combined and washed with sat. NaCl (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (50% EtOAc/hex), loading the product on the column in a minimum amount of CH2Cl2 to afford 0.15 g chromene (12%) and then 0.97 g (81%) of benzofuran (107) as a white solid. (LH-64-50).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O.Cl[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:12]([C:13]([OH:15])=[O:14])[CH3:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 40 °C

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety. N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40° C. and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p.=148-149° C.
Reaction SMILES: [C:1]12[CH2:9][CH:5]([C:6]1(C)C)[CH:4]([OH:10])[CH:3](C1(C3CC4CC(C4(C)C)=C3C)CC3CC(C3(C)C)=C1C)[C:2]=2[CH3:31].BrCBr.[CH2:35]([Mg]Cl)[CH2:36][CH2:37]C>C(OCC)C>[CH:36]([C:4]1([OH:10])[CH2:5][CH2:9][C@:1]2([CH3:6])[C@@H:2]([CH2:31]2)[CH2:3]1)([CH3:37])[CH3:35]
Reactant: CCCC[Mg]Cl
Reactant: CC1=C2CC(CC1C1(C3C(C)=C4CC(C3O)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Solvent: CCOCC
Solvent: BrCBr
Product: CC(C)C1(O)CC[C@@]2(C)C[C@H]2C1
Reaction time: 16 h
Yield: 85 %

Procedure:
Prepared as described in Example 10 from Terpinen-4-ol (2 g, 13 mmol) and dibromomethane (9.15 g, 52 mmol) in diethyl ether by dropwise addition of tent-butyl magnesium chloride 2M in diethyl ether (26 ml, 52 mmol) at 10°-20° C. Work-up after 16 h at 25° C. and bulb-to-bulb distillation gave 2.1 g (85%) of a colorless oil. Odour: Agrestic. 1H-NMR (CDCl3): δ 0.3 (dd, 1H), 0.43 (dd, 1H), 0.6 (dddd, 1H), 0.89 (d, 3H), 0.91 (d, 3H), 1.03 (s, 3H), 1.1-1.2 (m, 2H), 1.2-1.3 (m, 1H), 1.5-1.7 (2 m, 2H), 1.75-1.9 (2H), 2.2 (m, 2H) ppm. 13C-NMR: δ 14.4 (s), 16.2 (q), 16.4 (q), 17.7 (d), 19.9 (t), 27.2 (q), 28.1 (t), 31.6 (t), 31.9 (d), 35.7 (t), 72.8 (s). syn-configuration confirmed by COSY, HSQC, HMBC, NOESY in CDCl3. MS (EI): m/z (%) 168 [M]+, 3), 150 ([M-18]+, 8), 125 (32), 107 (65), 86 (38), 71 (80), 43 (100). IR (film): 3419 (br), 2936 (m), 2863 (m), 1458 (m), 1379 (w), 1302 (w), 1225 (w), 1133 (m), 1049 (w), 992 (s), 957 (w), 906 (w), 863 (w).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:13]=[CH:14][CH:15]=[CH:16][CH2:17][CH2:18][CH:19]=[CH2:20].N12CCCC1=NCCC2>C(O)C.C1C=CC=CC=1>[CH2:17]([CH:16]1[C:2]2[C:1](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4](=[O:11])[C:3]=2[CH2:13][CH:14]=[CH:15]1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CC=CCCC=C
Reactant: O=C1CCC(=O)C2CC=CC=C12
Agent: C1CN=C2CCCN2C1
Solvent: c1ccccc1
Solvent: CCO
Product: C=CCCC1C=CCC2=C1C(=O)C1=C(CCCC1)C2=O
Reaction time: 24 h
Yield: 49.1 %

Procedure:
A mixture of 13.8 g of tetrahydronaphthoquinone (0.085 mole) and 10 g (0.092.5 mole) of 1,3,7-octatriene was refluxed for 11/2 hours in 100 ml of ethanol. After the addition of 1 ml of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), the mixture was stirred while exposed to air for 24 hours. The ethanol was then blown off and the residue was dissolved in benzene and chromatographed on acidic alumina. From the eluate, 11.2 g of crude product were obtained (49% yield). The crude product was rechromatographed on acidic alumina using a 3:1 mixture of cyclohexane/benzene as the eluent. After removal of the solvent, the product was recrystallized from methanol to yield an analytical product having a mp of 47° to 48° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]([CH3:47])([OH:46])[CH3:45])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>COCC(O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C:44]([CH3:47])([OH:46])[CH3:45])[CH2:41][CH2:42]4)[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(CC(C)(C)O)CC4)c3)nn12
Yield: 14.5 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 1-[4-(3-Amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol (0.217 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL) and the reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 29.84 mg of 1-(4-{3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-2-methyl-propan-2-ol as a lyophilized powder. (M+H)=473.8. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.96 (s, 1H), 7.72 (dd, 1H, J=1.64, 5.93 Hz), 7.46 (m, 1H), 7.33 (m, 1H), 7.18 (m, 2H), 7.08 (m, 2H), 6.91 (m, 2H), 6.53 (dd, 1H, J=1.84, 6.29 Hz), 3.77 (s, 3H), 3.55 (m, 2H), 3.34 (m, 2H), 3.19 (m, 4H), 3.05 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[Na].Cl.O.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(CCC(CO)CO)c2n1
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in a solution of sodium benzoxide (1 M in benzyl alcohol, 2 ml) was stirred at 70° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5 M, 0.4 ml) and water (0.6 ml) were added and the solution was stirred for 1 hour at room temperature. The solution was then partitioned between chloroform and water. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with aqueous sodium bicarbonate, dried (magnesium sulphate) and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (10:1, 5:1) to afford 2-amino-6-benzyloxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a white crystalline solid (0.17 g, 50%), m.p. 146°-147.5° C.; λmax (EtOH) 212 (32,300), 250 (8,380), and 283 (10,100) nm; νmax (KBr) 3340, 3220, 1655, 1605, and 1580 cm-1 ; δH [(CD3)2SO] 1.3-1.6 (1 H, m, 3'-H), 1.72 (2 H, q, J 7 Hz, 2'-H), 3.38 (4 H, AB part of ABX, 2×4'-H), 4.03 (2 H, t, J 7 Hz, 1'-H), 4.36 (2 H, t, J 5.5 Hz, D2O exchangeable, 2×OH), 5.47 (2 H, s, PhCH2), 6.37 (2 H, s, D2O exchangeable, 2-NH2), 7.3-7.6 (5 H, m, C6H5), and 7.84 (1 H, s, 8-H); (Found: C, 58.89; H, 6.12; N, 19.87%; C17H21N5O3 requires C, 59.46; H, 6.16; N, 20.40%).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:28]=[N:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: OCCCCCOc1nnnn1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2nnnn2-c2ccccc2)cc1
Reaction time: 6 h
Yield: 54 %

Procedure:
0.5 g of pyridine and 0.31 g of p-toluenesulfonyl chloride were added to a solution of 0.4 g of the compound obtained in Example 1a in dichloromethane (10 ml) and the mixture was stirred for 6 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.35 g of the title compound (yield: 54%).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].Cl>CN(C)C1C=CN=CC=1.C(#N)C.C(N(CC)CC)C>[CH3:54][S:55]([NH:58][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1)(=[O:57])=[O:56]
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(CC(=O)NS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 32.3 %

Procedure:
A solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 2-methyl-6-nitrobenzoic acid anhydride (190 mg), 4-dimethylaminopyridine (56 mg), triethylamine (200 μL) and methanesulfonamide (46 mg) in acetonitrile (5 mL) was stirred at room temperature for 18 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (76 mg, yield 33%) as white crystals from a fraction eluted with ethyl acetate. melting point 141° C.
Reaction SMILES: Cl[CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4].C[Si]([N-:29][Si](C)(C)C)(C)C.[Li+].FC(F)(F)C(O)=O>O1CCCC1>[NH2:29][CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
0.82 g (2.27 mmol) of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 10 ml of tetrahydrofuran and then cooled to −78° C. under a nitrogen atmosphere. 2.3 ml (2.3 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise. The solution was then stirred overnight while slowly warming to room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.52 ml (6.8 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 1 g of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:6])[CH3:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100 %

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (1.0 g, 11.2 mmol), triethylamine (1.7 mL, 12.2 mmol) and N-(benzyloxycarbonyloxy)-succinimide (3.1 g, 12.4 mmol) in THF (100 mL) at 0° C. were reacted for 0.5 hours then at room temperature for an additional hour. The reaction was concentrated and extracted with ethyl acetate (100 mL). The organic extract was washed sequentially with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-20%) to give the title compound as a colorless oil (2.5 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1conc1-c1ccc(F)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(F)c(Cl)c1
Yield: 96 %

Procedure:
A mixture of 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (4.34 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (4.39 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 39–40° C.