Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.C(=O)([O-])ON1C(=O)CC(C[C:34]2[C:46]3C[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]=3[CH:37]=[CH:36][CH:35]=2)C1=O>ClCCl>[CH:43]1[C:44]2[CH:4]([CH2:1][O:5][C:6]([NH:8][C:9]([CH3:16])([CH3:17])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])[C:46]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[CH:41][CH:42]=1
Reactant: O=C([O-])ON1C(=O)CC(Cc2cccc3c2Cc2ccccc2-3)C1=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.59, 2.1 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and stirred for 60 min and concentrated in vacuo. Then a 10% aqueous solution of sodium carbonate (30 ml) and dioxane (30 ml) were added followed by 9H-fluorenylmethyl-succinimidyl carbonate (0.67 g, 2.1 mmol) and stirred overnight. The mixture was washed with petrol ether (2×20 ml) and the aqueous layer was acidified with 4N sulphoric acid (pH˜3) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with 1N sulfuric acid, water (4×20 ml), brine (20 ml), dried (Magnesiumsulfate) and concentrated in vacuo. The obtained product was precipitated from dichloromethane/ether and filtered to give 280 mg of (2E)-5-(((9H-flouren-9-yl)methoxy)carbonylamino)-5-methyl-hex-2-enoic acid, which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CCOCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=[O:20])=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1ccccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (33.17 g) and DMF (180 ml) were added to salicylaldehyde (24.42 g), and the mixture was stirred at room temperature for 10 minutes. Then a mixture of 4-chlorobenzyl chloride (33.82 g) and DMF (20 ml) was added at room temperature over 15 minutes, and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ether (500 ml) was added, and the mixture was washed with water (400 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 2-(4-chlorobenzyloxy)benzaldehyde. The ethanol (200 ml) and hydroxylamine hydrochloride (27.80 g) was added to the crude product, and the mixture was stirred at 80° C. overnight. After completion of the reaction, water (400 ml) was added, and the mixture was extracted with methylene chloride (200 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzyloxy)benzaldehyde oxime (32.06 g) as colorless crystals. mp. 122.5°-123.5° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][O:4][CH:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]2[N:31]=[CH:32][NH:33][C:29]=2[CH:28]=1.N(C(OCC)=O)=NC([O:41][CH2:42][CH3:43])=O>O1CCCC1.C(Cl)(Cl)Cl>[Cl:36][C:35]1[C:27]([Cl:26])=[CH:28][C:29]2[N:33]([C@H:2]3[CH2:43][C@H:42]([OH:41])[C@@H:5]([CH2:6][OH:1])[O:4][CH2:3]3)[CH:32]=[N:31][C:30]=2[CH:34]=1
Reactant: C1=COC=CO1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OC[C@H]1OC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2R,4-α-R,7R,8-α-S-perhydro-7-hydroxy-2-phenylpyrano(3,2-D)1,3)dioxin (Tetrahedron Letters, 1996, 8147 and references cited therein) (2.50 g, 10.6 mmol), triphenylphosphine (Aldrich, 4.16 g, 15.87 mmol as 99%) and 5,6-dichlorobenzimidazole (Townsend and Revankar, Chem. Rev. 1970, 70:389, and references cited therein) (3.00 g, 15.87 mmol) were stirred in anhydrous tetrahydrofuran (50 ml) at 0° C. (external ice bath) under nitrogen as a solution of diethyl azodicarboxylate (Aldrich, 2.60 ml, 15.87 mmol as 97%) in tetrahydrofuran (10 ml) was added over 30 min. The reaction mixture was allowed to warm to room temperature, stirred 72 hours, then diluted with chloroform (300 ml) and washed with saturated aqueous sodium bicarbonate (100 ml). The organic layer was dried (sodium sulfate), filtered, and the solvents evaporated under reduced pressure. The residual gum was treated with 300 ml of 80% aqueous acetic acid at 80° C. for 1 h. The reaction mixture was diluted with 100 ml of water and extracted with diethyl ether (4×100 ml). The aqueous phase was concentrated and purified by flash chromatography on silica gel 60. The title compound was eluted with 5-25% methanol-chloroform as a white solid (2.20 g, 65%); m.p. 197° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.56, 8.09, 7.99 (s, each 1H), 4.92 (d, J=5.5 Hz, 1H), 4.87 (bs, 1H), 4.69 (t, J=6.3 Hz, 1H), 4.25 (d, J=12 Hz, 1H), 3.91 (dd, J=12.9, 2.7 Hz, 1H), 3.71-2.53 (m, 4H), 2.28-2.25 (m, 1H), 1.97-1.89 (m, 1H).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(C=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>N1C=CC=CC=1.N1CCCCC1>[CH:8]1([CH:1]=[CH:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CC1CCCCC1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=CC1CCCCC1
Yield: 107.4 %

Procedure:
3.34 g (32.1 mmol) of malonic acid are dissolved in pyridine (10 ml), after the weakly exothermic reaction has subsided 3.0 g (26.7 mmol) of cyclohexanecarbaldehyde and 0.23 g (2.7 mmol) of piperidine are added, and the reaction mixture is heated to reflux for 4 h. The cooled reaction solution is added to a mixture of ice and concentrated hydrochloric acid, the aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed in vacuo. 4.42 g of product are obtained, which is reacted further without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:11]=1)[NH:8][C:7]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][OH:24])[N:22]=1)=[CH:6]2.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31]>>[CH:13]1([NH:12][C:10]2[CH:11]=[C:3]([CH2:2][NH:1][C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[O:31])[CH:4]=[C:5]3[C:9]=2[NH:8][C:7]([C:18]2[S:19][CH2:20][C@@H:21]([CH2:23][OH:24])[N:22]=2)=[CH:6]3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccco1
Reactant: NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Product: O=C(NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1)c1ccco1

Procedure:
[(R)-2-(5-aminomethyl-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol prepared in Example 258 and furan-2-carboxylic acid were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7](O)=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution ethyl {4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.2 g, 0.458 mmol) in DMF (3 ml), was added sodium carbonate (0.097 g, 0.915 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.159 g, 0.687 mmol). This was stirred at room temperature for 24 hours. Water was added to the reaction mixture with rapid stirring. The resulting yellow coloured solid was collected by filtration, washed with water and dried in the vacuum oven to give the title compound (0.119 g, 0.23 mmol). LC/MS: Rt=3.82, [MH]+ 520.
Reaction SMILES: [CH3:1][C:2]1([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H].[NH3:17]>[Rh]>[CH3:1][C:2]1([C@@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:17])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: [H][H]
Reactant: CC1(C2CCC(=O)CC2)CCCCC1
Agent: [Rh]
Product: CC1([C@H]2CC[C@@H](N)CC2)CCCCC1

Procedure:
36 g (0.185 mol) of 4-(1-methylcyclohexyl)cyclohexanone were subjected to reductive amination in 210 ml of ammonia-saturated methanol in the presence of 3 g of rhodium (5% on charcoal) at 50° C. and 50 bar hydrogen pressure.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 8.21 g of L-Phenylalanine, 5.565 g of Na2CO3 in 40 ml of water and 20 ml of tetrahydrofuran (THF) was stirred at room temperature. Benzoyl chloride, 7.73 g, dissolved in 20 ml of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30° C. to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to pH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50° C. The product was recrystallized from aqueous ethanol, yielding 8.37 g, m.p. 183° C.-184° C., which migrated at a single compound on thin layer chromatography in five separate solvent systems.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[C:15]1([CH:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:15]1([CH:21]([NH:23][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: CC(N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.59 g, 7.57 mmol), 1-phenylethanamine (0.92 g, 7.57 mmol) and N,N-diisopropylethylamine (1.95 g, 15.1 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.28 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 7.80 (t, 1H), 7.31 (m, 5H), 6.33 (t, 1H), 6.22 (d, 1H), 4.58 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.C1(C)C=CC=CC=1.Cl>O>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.254 part), zinc amalgam (0.56 part), toluene (1 volume part), 35% hydrochloric acid (0.5 volume part) and a small proportion of water were refluxed for 5 hours. The toluene layer was separated and the water layer was extracted with diethyl ether. The toluene layer was combined with the ethereal layer, washed with water and dried. The solvents were then distilled off under reduced pressure and the residue was recrystallized from ligroine. The foregoing procedure provided 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formula II-2 wherein R=H3CO, X=H, n=8, in the free form) (0.14 part) as colorless powdery crystals melting at 62.5°-66° C.
Reaction SMILES: C=O.[C:3](O)(=O)C.[H-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]2[CH2:32][CH2:31][N:30]([CH3:3])[CH2:29]2)=[CH:26][CH:27]=1
Reactant: Brc1ccc(C2CCNC2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
Formalin (0.0452 ml, 0.557 mmol), 0.0319 ml (0.557 mmol) of acetic acid, and 118 mg (0.557 mmol) of triacetoxy borohydride hydride were added to a solution of 42 mg (0.186 mmol) of 3-(4-bromophenyl)pyrrolidine, synthesized in the same manner as in Reference Example 1, in chloroform-ethanol 3:1 (2 ml), and the mixture was stirred at room temperature for 40 min. The reaction solution was diluted with ethyl acetate, and the diluted solution was washed with a 10% aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, was filtered, and was then concentrated under the reduced pressure to give 43 mg (yield 97%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:33](OCC)(=[O:39])[C:34](OCC)=[O:35]>CN(C=O)C>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH:2]=[C:33]([OH:39])[C:34]([OH:35])=[C:5]2[C:6]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-benzylpiperazin-2-one (0.49 g, 2.1 mmol) in DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (2.5 mL, 2.5 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.43 mL, 3.1 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (10 mL, 10 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:21]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:14](=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nc(NC(=O)OC(C)(C)C)cs1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1nc(NC(=O)OC(C)(C)C)cs1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.5 %

Procedure:
Ethyl 2-(4-tert-butoxycarbonylaminothiazol-2-yl)acetate (5.1 g) was added to a solution of selenium dioxide (2.96 g) in dioxane (60 ml) and water (2 ml) at 110° C. and stirred for 4.5 hours at 110° C. The mixture was evaporated and the residue was dissolved in ethyl acetate and water. The separated ethyl acetate layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. After removing the solvent, the residue was subjected to column chromatography on silica gel and eluted with methylene chloride. The fraction containing an object compound was evaporated to give ethyl (4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate (4.2 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[N:11]=[C:10]([C:12]2[CH:24]=[CH:23][C:22]([C:25](=[O:40])[NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:29])=[O:28])=[CH:21][C:13]=2[C:14]([O:16]C(C)(C)C)=[O:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]([CH2:41][CH2:42][CH2:43][CH3:44])[C:6]1[N:11]=[C:10]([C:12]2[CH:24]=[CH:23][C:22]([C:25](=[O:40])[NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:28])=[O:29])=[CH:21][C:13]=2[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 2-(2-(dibutylamino)pyrimidin-4-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoate (110 mg, 0.18 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo to give the title compound (95 mg, 95%), which was used in subsequent reaction without purification. MS(ESI+) m/z 561.2 (M+H)+.
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.[OH2:22]>Cl>[OH:15][CH2:14][CH:13]([CH2:18][OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: O
Agent: Cl
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 24 h
Yield: 49 %

Procedure:
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-ethyl]purine (0.59 g, 1.9 mmol) in hydrochloric acid (1.0 M, 4 ml) was stirred at 60°60 C. for 24 hours. The solution was diluted with water and neutralised with Amberlite IR 45 (OH- form). The mixture was filtered, the resin washed with water and the solvent evaporated under reduced pressure. The residue was recrystallised from water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (238 mg, 49%), m.p. 275°-277° C.; λmax (H2O) 253 (ε11,500) and 270 (shoulder, ε8,630) nm; νmax (KBr) 3420, 3140, 1690, 1645, and 1605 cm-1 ; δH [(CD3)2SO] 1.3-1.5 (3 H, m, CHCH2CH2), 3.42 (4 H, d, J 5 Hz, 2×CH 2 O), 3.99 (2 H, t, J 7 Hz, CH2N), 4.41 (2 H, br, D2O exchangeable, 2×OH), 6.44 (2 H, s, D2O exchangeable, 2-NH2), 7.71 (1 H, s, 8-H), and 10.55 (1 H, br, D2O exchangeable, 1-H); (M+ found 253.1176. C10H15N5O3 requires M+ 253.1175).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:9]([C:5]1[C:6]([NH2:8])=[CH:7][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 59.7 %

Procedure:
A 500 mL round bottom flask equipped with a reflux condenser was charged with 2-chloro-5-nitropyridin-4-amine (2.00 g, 11.5 mmol, 1.0 equiv), pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equiv), potassium carbonate (4.78 g, 34.6 mmol, 3.0 equiv) and acetonitrile (50 mL). The mixture was heated at 70° C. overnight under nitrogen then cooled to room temperature. The yellow solids were collected by filtration and washed with acetonitrile, water and hexanes. The solids were dried to obtain the title compound as a bright yellow solid (1.43 g, 1st crop). The solvents from the filtrate were removed and the aqueous was extracted with ethyl acetate. The organic extracts was dried (Na2SO4), filtered and removed in vacuo to obtain additional product as an orange/yellow solid (820 mg, 2nd crop). The 2nd crop of product was triturated with ethyl acetate (3 mL) and then filtered and washed with ethyl acetate (2×1 mL) and diethyl ether (3 mL) to obtain a bright yellow solid (751 mg). The total yield of 5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine obtained was 2.18 g (91%). m/z (ES+) 209.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 7.39 (br s, 2H), 5.63 (s, 1H), 3.40 (br s, 4H), 1.93 (br s, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([O:15]CC=C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CCC(NC(=O)CCCCCCCCC)C(=O)OCc1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Pd(O)-catalyzed deprotection of the allyl ester proceeded as follows to yield 2-Decanoylamino-pentanedioic acid 1-benzyl ester (8). To a solution of 752 mg (1.74 mmol) of 2-decanoylamino-pentanedioic acid 7 in 10 mL of CH2Cl2 was added 100 mg (0.087 mmol) of tetrakistriphenylphosphine Pd(O) followed by 0.52 mL (1.9 mmol) of tributyltin hydride. After 15 min, the reaction mixture was quenched with 10 mL of a 10% HCl solution. The aqueous layer was reextracted with 15 mL of CH2Cl2 and the organic layer dried (Na2SO4) , concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 9:1) to provide 545 mg (79.9%) of 8 as a thick oil: [α]D +2.8° (c 1.2, CHCl3, 21° C.); IR (neat) 3351, 3064, 2995, 2852, 1738, 1712, 1657, 1536, 1454, 1380, 1364, 1265, 1209, 1183, 1121, 739 cm-1 ; 1H NMR δ 10.9-10.7 (bs, 1 H), 7.22 (s, 5 H), 6.58 (d, 1 H, J=7.8 Hz), 5.09 (s, 2 H), 4.63 (dd, 1 H, J=8.1, 12.9 Hz), 2.4-2.25 (m, 2 H), 2.2-2.1 (m, 3 H), 2.0-1.9 (m, 1 H), (m, 6 H), 1.53 (t, 2 H), J=6.6 Hz), 1.19 (bs, 12 H), 0.81 (t. 3 H, J=6.0 Hz); 13C δ 176.9, 174.0, 171.8, 134.9, 128.5, 128.4, 128.1, 67.3, 51.4, 36.2, 31.7, 29.9, 29.3, 29.2, 29.1, 27.0, 25.5, 22.5, 14.0; MS (El) m/z (relative intensity) 391 (54), 373 (62), 279 (13), 256 (19), 178 (27), 178 (23), 155 (13), 146 (6), 130 (7), 102 (100); HRMS (El) m/z calculated for C22H33NO5 :391.2358, found: 391.2350.