Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH:11]=[O:25])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccccc2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at −72 to −69° C. After 4 hours at −75° C., 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbalde-hyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0° C. to a solution, in which previously 5 g of triethyl-2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0° C. with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydro-furan/heptane/ethylbenzene. After 20 hours at room tempera-ture, water is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to 90° C. with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2SO4) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=O)[CH2:9]1.O.[OH-].[Na+]>CCOCC>[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCNc2ccccc21
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a refluxing suspension of 10 g (0.26 mol) of lithium aluminum hydride in 100 ml of ether was added dropwise over a period of 1 hour a solution of 21.0 g (0.21 mol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline in 200 ml of ether-tetrahydrofuran (2:1, volume per volume). Refluxing was continued for 16 hours, and then to the cooled reaction mixture was added 50 ml of water and 50 ml of 10% sodium hydroxide. The aqueous phase was extracted with ether, and the combined ether extracts were dried (MgSO4) and evaporated in vacuo to give 17.2 g (89% yield) of the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate (0.331 g, 0.736 mmol in methanol/TH was added 1.23 mL (3.5 eq) of a 1.0N solution of LiOH and the reaction was stirred at room temp overnight. The solvent was removed in vacuo and the residue was suspended in water, adjusted to pH to 3 with 2N HCl. The resulting solid was rinsed with ether and dried in vacuo to afford 0.27 g (89%) of [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetic acid. Electrospray Mass Spec 392.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.Br[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH3:19])=[CH:17][N:6]2[C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:13]=3[C:12]3[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]2=3)=[CH:21][CH:22]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cn1c2c(c3cc(C)cnc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a degassed solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.0 mmol), 1-(2-bromo-1-methyl-vinyl)-4-fluoro-benzene (279 mg, 1.3 mmol), potassium phosphate (530 mg, 2.5 mmol) in DMF (4 mL), L-proline (28 mg, 0.25 mmol) and cuprous iodide (47 mg, 0.25 mmol) were added. The reaction mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (4×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by silica gel flash chromatography to yield 9-[2-(4-fluoro-phenyl)-propenyl]-3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.1 (s, 1H), 7.57 (m, 3H), 7.07 (t, 2H), 6.92 (s, 1H), 3.62 (s, 2H), 2.8 (s, 4H), 2.6 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:9][CH:10]=[CH2:11])[CH2:6][CH:7]=[CH2:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.O>[CH2:6]([CH:5]([CH2:9][CH:10]=[CH2:11])[CH2:4][OH:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(CO)CC=C
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a stirred solution of 2-allylpent-4-enoic acid ethyl ester (prepared above, 14.5 g, 86.2 mmol) in diethyl ether (125 mL) was added lithium aluminum hydride (3.3 g, 87 mmol) in portions slowly over a 30 minute period to cause vigorous gas evolution. When addition of the lithium aluminum hydride was complete, the reaction mixture was stirred for one more hour a room temperature, then 3.5 mL of water were added very slowly. Then 7 mL of a 10 weight percent solution of sodium hydroxide in water were added, followed by the addition of 10 more mL of water. The precipitated white solid was removed from the colorless solution by filtration. Solvent was removed from the solution at reduced pressure to leave 10.1 g of 2-allylpent-4-en-1-ol as a colorless oil whose structure was confirmed by NMR analyses.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][N:4]=1.[Na+].[I-]>CO.[Pd]>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1)[CH3:10]
Reactant: C=Cc1ccc(OC)nc1
Agent: [Pd]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(=O)[nH]c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a solution of 2-methoxy-5-vinyl-pyridine (2 g) in anhydrous MeOH was added Pd/C (10 wt %, 100 mg). The mixture was stirred under H2 atmosphere for 5 hours before it was filtered through a pad of celite. The solvent was removed in vacuo and the residue was taken directly into next step without further purification. The crude product from previous step was dissolved in anhydrous MeCN. To this solution was added NaI (3.3 g, 21.9 mmol) and TMSCI (2.8 mL, 21.9 mmol). The resulting mixture was heated to 65° C. for 5 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (1.5 g, 83% yield). 1H NMR (300 MHz, CDCl3): δ 1.17 (t, J=7.5 Hz, 3H), 2.39-2.49 (m, 2H), 6.50-6.58 (m, 1H), 7.15 (s, 1H), 7.35-7.45 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C:8]1[C:12]([NH:13][C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:11][S:10][CH:9]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:12]1[C:8]([CH2:7][C:6]([OH:22])=[O:5])=[CH:9][S:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
357 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid tert.-butyl ester are heated to the boil with 10 mg of p-toluenesulfonic acid in toluene for 2 hours. The reaction solution is washed with water, dried and concentrated to give 4-(2,6-dichloroanilino)-3-thiophenacetic acid (m. 179° to 180°).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([C:9](OCC)(OCC)[CH2:10][NH2:11])[CH:6]=[CH:5][N:4]=1.Cl.[C:20](=[NH:25])(OCC)[CH3:21]>C(O)C>[CH3:18][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([C:9]2[N:25]=[C:20]([CH3:21])[NH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(CN)(OCC)c1ccnc(N(C)C)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc(-c2ccnc(N(C)C)c2)c[nH]1

Procedure:
A mixture of 1.0 g. (4 mmoles) of 2-(2-dimethylamino-4-pyridyl)-2,2-diethoxyethylamine, 500 mg. (4.1 mmoles) of ethyl acetimidate hydrochloride and 15 ml. of ethanol is heated to reflux for 1.5 hours. The mixture is concentrated, and the residue taken up in 10 ml. of concentrated hydrochloric acid. After heating at steam bath temperatures for 1 hour, the cooled acid solution is made basic by the addition of solid sodium carbonate, and the product is extracted with chloroform (3×10 ml.). The combined extracts are dried and concentrated to give the crude product, which is purified further by chromatographing on silica-gel using chloroform-methanol as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[C:12](O)(=O)[CH2:13][OH:14].Cl.O.C>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:12]([CH2:13][OH:14])[NH:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)CO
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(CO)[nH]c2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
1,2-Diamino-4-nitrobenzene (5.00 g, 0.0326 mol), glycolic acid (3.72 g, 0.0490 mol), 4.00 M hydrogen chloride in water (13.1 mL, 0.0522 mol), water (13.1 mL, 0.725 mol), and activated charcoal (100 mg) were refluxed overnight. The reaction was cooled to room temperature, filtered and neutralized with aqueous ammonia. The product was filtered and dried in a vacuum desiccator overnight to obtain (6-nitro-1H-benzoimidazol-2-yl)-methanol as a brown solid (6.29 g, 100%). m.p.=157-162° C.; LCMS (m/e) 194 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 10.24 (bs, 1H), 8.39 (d, 1H, J=1.9 Hz), 8.09 (dd, 1H, J=1.9 and 8.8 Hz), 7.66 (d, 1H, J=8.8 Hz), 5.93 (bs, 1H), 4.77 (s, 2H).
Reaction SMILES: [N:1]([C@@:4]1(O)[C@@H:8]([CH2:9]O)[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].CS(Cl)(=O)=O>N1C=CC=CC=1>[CH3:18][C:17]1[C:15](=[O:16])[N:14]=[C:12]2[N:11]([C@@H:6]3[O:7][C@H:8]([CH2:9][O:13]2)[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:5]3)[CH:19]=1
Reactant: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cn2c(nc1=O)OC[C@H]1O[C@@H]2C[C@@H]1N=[N+]=[N-]
Reaction time: 1 h

Procedure:
The 5'-hydroxyl of 3' azidothymidine (3.0 g, 11.2 mMol) was mesylated by the addition of methanesulphonyl chloride (2.7 mL) to a solution of the starting material in dry pyridine (20 mL). The reaction was allowed to proceed at 5° C. for one hour, then poured onto ice water. The precipitate was collected by filtration. The desired product was obtained by reacting the 3'-azido-4'-mesylthymidine obtained from the first step with potassium carbonate (0.78 g, 5.6 mMol) in DMF (75 mL). The reaction was heated in an 80° C. oil bath for six hours, then poured into ice water. The product was extracted from the water with ethyl acetate. The solvent was removed in vacuo and the resultant oil was flash chromatographed on silica gel by elution with CHCl3 :MeOH (9:1 v/v). The product was obtained in low yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O[C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[CH3:14].ICC([NH2:35])=O.O>CC(N(C)C)=O.CCOC(C)=O.CCCCCC>[NH2:35][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[CH3:14]
Reactant: NC(=O)CI
Reactant: Cc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
Potassium carbonate (77 mg) was added to a solution of 6-(5-hydroxy-6-methyl-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and iodoacetamide (95 mg) in DMA (1 ml) and the mixture was stirred at 20-25° C. for 2 hours. To the reaction mixture, potassium carbonate (235 mg) was added and heated at 150-155° C. for 2 hours. After addition of water, the mixture was extracted with CHCl3, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give 6-(5-amino-6-methyl-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (97 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([NH:17][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31](=[O:35])(=[O:34])[NH:32][CH3:33])[C:21]([Cl:36])=[CH:20][N:19]=3)[CH:15]=[CH:16][C:6]1=2.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:35])(=[O:34])[NH:32][CH3:33])=[N:23][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:6]3[N:5]([CH2:4][C:3]([OH:37])=[O:2])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=3[CH:13]=2)=[N:19][CH:20]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CC(=O)OC)ncc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CC(=O)O)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
{7-[5-Chloro-4-(2-methylsulfamoyl-phenylamino)-pyrimidin-2-ylamino]-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetic acid methyl ester (67 mg, 0.123 mmol) was taken up in THF (1 ml). 1N NaOH (1 ml) was added, and the mixture was stirred 18 hours at room temperature. 10% citric acid was added to make the mixture acidic. It was washed with ethyl acetate, and the organic phase was then washed with water, concentrated, and triturated with dichloromethane. Filtration yielded the title compound as a tan solid, 44 mg. (69% yield) 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 9.57 (s, 1H), 9.27 (s, 1H), 8.40-8.52 (m, 1H), 8.29 (s, 1H), 7.70-7.86 (m, 2H), 7.42-7.68 (m, 3H), 7.24-7.32 (m, 1H), 7.09-7.15 (m, 1H), 4.36 (s, 2H), 2.58-2.85 (m, 2H), 2.35 (s, 3H), 1.95-2.23 (s, 4H); MS (m/e) 531 (M+1); mp 192-195° C.; retention time 6.97 minute.
Reaction SMILES: [Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C(O)=CC=CC=1.[Si:23](Cl)(Cl)(Cl)[Cl:24]>>[Cl:24][Si:23].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: Cc1ccccc1O
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: Oc1ccccc1
Product: [Si]Cl
Reaction time: 5 h

Procedure:
About 0.25 mol of fine granular hydrated silica 0.5 mol of fine granular magnesium silicate, 0.5 mol of phenol, 0.5 mol of cresol, and 1 mol of silicon tetrachloride are slowly added simultaneously while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing a phenol chlorosilicon acid resinous product and magnesium chloride. About 1 mol of ethylene chloride is added to the resinous product while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing an organic silicon acid resinous product. The granular resinous product is then washed with water and filtered to remove the magnesium chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)([OH:18])[C:14]([F:16])([F:17])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: C(OC(N[C@@H](C([N:16]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:17][C:18](=[O:45])[C@@H:19]([CH:24]([C:34](=[O:44])NOCC1C=CC=CC=1)[CH2:25][CH2:26][CH2:27]C1C=CC=CC=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=O)C)=O)C1C=CC=CC=1.[C:50]([O:54]C(C([C@@H](CC(C)C)C(O)=O)CC=C)=O)([CH3:53])([CH3:52])[CH3:51]>>[C:50]([O:54][C:34]([CH:24]([C@@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:18]([NH:17][NH:16][CH2:46][CH:47]([CH3:48])[CH3:49])=[O:45])[CH2:25][CH:26]=[CH2:27])=[O:44])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)NOCc1ccccc1
Reactant: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Product: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NNCC(C)C

Procedure:
In an analogous manner to that described in Example 1, part (i), but using 2(R)-[1(RS)-(tert-butoxycarbonyl)-3-butenyl]-4-methylvaleric acid in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid there was obtained 2(R)-[1(RS)-(tert-butoxycarbonyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C(C)C)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].O>CN(C=O)C>[CH:27]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:29])[CH3:28]
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2) 2-chloro-6-(4-methoxybenzylamino)purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine (Yield=508 mg, 89%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CCCNC1)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (1.2 g, 3.54 mmol) was treated with 4.0 M HCl solution in dioxane (4.3 mL, 17.2 mmol). Formation of a white precipitate was observed. The reaction was complete after three hours. The solvent and excess HCl were removed under reduced pressure to obtain benzyl ((S)-piperidin-3-yl)methylcarbamate hydrochloride as a white solid. This solid was suspended in DMF/CH2Cl2 (3 mL/3 mL), followed by the addition of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (958 mg, 3.54 mmol) and then triethylamine (1.8 mL, 1.3 g, 12.85 mmol). The mixture was stirred at room temperature under an N2 atmosphere for 16 h. The reaction was then partitioned between H2O and CH2Cl2, separated, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0-5% MeOH in CH2Cl2 gave benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as a thick yellow oil (855 mg, 51%). LC/MS: m/z 483.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([O:14][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
BocSer(Bzl) 60 g (0.2 mol) was added to 400 ml of ethyl acetate, to which triethylamine 21 g (0.2 mol) and benzyl bromide 35.4 g (0.2 mol) were added and reacted under refluxing condition for 4 hours. After cooled, the salt produced was separated by filtration. The filtrate was washed with an aqueous NaHCO3 solution and an aqueous NaCl solution and then dried over Na2SO4 and concentrated to dryness to obtain 54 g of white powder (Yield: 68%).