Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20](O)[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20]([N:29]4[C:25](=[O:35])[C:26]5[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:28]4=[O:30])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)O)s3)s2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of Example 3B (314 mg, 0.87 mmol), phthalimide (140 mg, 0.95 mmol) and triphenylphophine (341 mg, 1.3 mmol) in tetrahydrofuran (25 mL), at room temperature was slowly added diethyl azodicarboxylate (205 uL, 1.3 mmol). The reaction mixture was stirred at room temperature, overnight. The solvent was removed under vacuum and the product was purified on a silica-gel column using a gradient of 10-15% ethyl acetate in hexane and yielded the product as white powder (210 mg). 1H NMR (300 MHz, CDCl3) δ ppm 7.63-7.97 (m, 5H) 7.12-7.24 (m, 2H) 7.00 (d, J=3.68 Hz, 1H) 6.81-6.96 (m, 3H) 5.73 (q, J=7.35 Hz, 1H) 4.44-4.59 (heptet, J=6.25 Hz, 1H) 196 (d, J=7.35 Hz, 3H) 1.34 (d, J=6.25 Hz, 6H), MS (DCI): m/z 491 (M+H).
Reaction SMILES: S=[C:2]1[C:7]([C:8](OCC)=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2.[NH2:28][NH2:29]>C(O)C>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:5]3[C:4]4[CH:25]=[CH:26][S:27][C:3]=4[C:2]4=[N:28][NH:29][C:8](=[O:9])[C:7]4=[N:6]3)=[CH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: NN
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=S
Solvent: CCO
Product: O=c1[nH]nc2c3sccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-thioxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydrothieno[3,2-c]pyridazine-3-carboxylate (23 mg, 0.058 mmol) and hydrazine (1.0 mL, 31 mmol, 550 equiv) were combined in absolute ethanol (7 mL) and placed into an oil bath preheated to 85° C. for 2 hours. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]56[CH2:24][CH:19]7[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]7)[CH2:22]5)[CH2:16]6)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:49])=[CH:51][CH:52]=2)[S:36]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 86.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate (1.34 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.83 g).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.C(O)(C(F)(F)F)=O>C(O)C>[N:1]1([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCCCCC1
Agent: NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: NCCCN1CCCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-(azepan-1-yl)propyl)isoindoline-1,3-dione (3.5 g) in Ethanol (20 mL) was added hydrazine (0.58 mL). The reaction mixture was reflux for 13 h and then cooled down to room temperature. TFA (2.0 mL) was added, the resulted white solid was filtered and the solvent was evaporated to give 3-(azepan-1-yl)propan-1-amine, used without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([CH3:25])[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[N:12]1([C:18]2[CH:19]=[C:20]([CH3:25])[N+:21]([O-:9])=[CH:22][C:23]=2[Br:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(N2CCCCC2)c(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(N2CCCCC2)c(Br)c[n+]1[O-]
Reaction time: 16 h

Procedure:
m-Chloroperbenzoic acid (7.3 g) in dichloromethane (100 ml) was added dropwise to a stirred solution of 4 -piperidino-5 -bromo-2 -picoline. After 16 hours, the solution was washed with 10 % aqueous sodium carbonate, dried (K2CO3) and stripped. The residue was chromatographed (silica gel, chloroform:methanol) to give 4 -piperidino-5 -bromo-2 -picoline-N-oxide, 6.79 g, m.p. 115°-6 ° from ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[OH-:19].[Na+].OO.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:19]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1F
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)c(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.24 g, 8.82 mmol, 1.0 eq) in a mixture of NaOH (1M aqueous solution, 26.4 mL, 26.4 mmol, 3.0 eq) and THF (20 mL) at 0° C. was added H2O2 (3 g, 26.4 mmol, 3 eq). The reaction mixture was stirred at room temperature for 4 h, then the pH of the reaction mixture was adjusted to pH 5 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 50:1) to give the title compound as a colorless oil (850 mg, 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18].C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-(1,1-dimethylethoxycarbonyl)-4-piperidone (IX, 1.50 g) in methanol (15 ml) under nitrogen is cooled in an ice bath, treated with butylamine (X, 0.93 ml) and sodium cyanoborohydride (235 mg), adjusted to pH 5 with glacial acetic acid as determined on moistened pH test paper, and stirred at 20°-25° for 24 hrs during which additional sodium cyanoborohydride (115 mg) is added. The mixture is then adjusted to pH 3 using hydrochloric acid (3M) and concentrated under reduced pressure, the residue is diluted with water (20 ml) and extracted with ether (2×20 ml), and the organic phase is discarded. The aqueous phase is adjusted to pH 12 with potassium hydroxide, saturated with sodium chloride, and extracted with methylene chloride (3×25 ml). The combined organic phase is dried over sodium sulfate and concentrated under reduced pressure to give the title compound, Anal. Calcd for C14H28N2O2 : C=65.59, H=11.01, N=10.93, found: C=65.44, H=11.05, N=10.81.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.CC(C)=O>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCC(=O)OC(C)(C)C)ccc12

Procedure:
The compound ethyl 3-phenyl-3-(6-hydroxyindol-3-yl)propionate 4 prepared analogously to Example 1.1-1.3 (3.23 mmol) is stirred overnight at 60° C. with 0.94 ml (6.4 mmol) of tert-butyl bromoacetate and 1.8 g (13 mmol) of potassium carbonate in 20 ml of acetone. When the reaction is complete (TLC check toluene/acetone 4:1), the residue is filtered off, the solution is evaporated, and the crude product is purified by chromatography on silica gel (eluent toluene/acetone 9:1), giving ethyl 3-phenyl-3-[6-(tert-butoxycarbonylmethoxy)indol-3-yl]propionate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 4-hydroxypiperidine (2.2 g, 20 mmol), and K2CO3 (1.0 g, 7 mmol) in DMF (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated in vacuo, and the oily residue was triturated with 70/30 EtOAc/CHCl3 (8 mL) to yield a yellow solid. The solid product was collected by filtration, washed with 70:30 EtOAc/CHCl3 (8 mL), and dried in vacuo (0.63 g, 38%).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl[CH2:13][C:14](Cl)=[O:15].[OH-].[Na+]>C(O)C>[C:2]1([N:1]2[CH2:8][CH2:9][O:10][CH2:13][C:14]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1COCCN1c1ccccc1
Temperature: 38 °C

Procedure:
In a 26-liter tank, 1.65 kg (12.0 mol) of 2-anilinoethanol are dissolved at room temperature in 1.53 l of ethanol and subsequently admixed with 4.58 l of water with stirring. The solution is heated to 38° C. 4.07 kg (3.0 equivalents) of chloroacetyl chloride and 6.60 kg of 45% sodium hydroxide solution (6.2 equivalents) are then added simultaneously at an internal temperature of 38 to 43° C. within 60 to 80 minutes, so that the pH is kept between 12 and 12.5. The mixture is stirred at a pH of 12 to 12.5 for 10 minutes, then cooled to 2° C. and stirred at this temperature for 30 minutes. The precipitated product is filtered off and washed twice with 3.3 kg each time of demineralized water at 2° C. The moist product is dried to constant mass at 50° C. under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].[N+:20]([O-])([OH:22])=[O:21]>C(OCC)(=O)C>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([N+:20]([O-:22])=[O:21])[C:10]=1[Br:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Br
Temperature: 40 °C
Yield: 65 %

Procedure:
Concentrated sulfuric acid (20 mL) was slowly added to 2-bromo-5-nitro-benzoic acid methyl ester (20.52 g, 78.91 mmol) with stirring. After a few minutes, fuming nitric acid (20 mL) was added and the mixture was capped and heated at 40° C. for approximately 60 hours at which point the flask was cooled to ambient temperature, carefully opened, and the reaction was poured onto ice water and ethyl acetate. The product was extracted into ethyl acetate and washed twice with H2O, twice with saturated aqueous NaHCO3, brine, dried (Na2SO4), and filtered to afford Intermediate 6(a) (15.64 g, 51.26 mmol) as a cream solid in 65% yield.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CCCCI
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)CCCCN1CCCCC1

Procedure:
30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine were dissolved in 250 ml. of benzene and heated at 60° C for 3 hours with stirring. A colorless solid began to appear shortly after the materials were combined. The solid was removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distilled as 23.5 g. (95%) of colorless liquid, b.p. 122°-24° C (12.5 mm.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][C:5]=1[CH2:15][CH:16]=[CH2:17].C(S)CC.CC(C)([O-])C.[K+].BrC[C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:30]([O:32][CH3:33])=[O:31])[C:7]=2[O:6][C:5]=1[CH:15]=[CH:16][CH3:17]
Reactant: C=CCc1oc2c(OC)cccc2c1CCO
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: CCCS
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=Cc1oc2c(OCC(=O)OC)cccc2c1CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
3-(2-hydroxyethyl)-7-methoxy-2-(2-propenyl)benzofuran (1.43 g), n-propanethiol (0.84 ml) and potassium t-butoxide (968 mg) were dissolved in DMF (15 ml) and the solution was stirred at room temperature for 5 minutes and then at 100° C. for 5 hours. After cooling the reaction temperature to room temperature, methyl bromoacetate (0.87 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (630 mg, yield: 35%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:64][CH2:65][O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.O>CN(C)C(=O)C>[CH2:67]([O:66][CH2:65][CH2:64][N:19]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[CH3:60])[C:17]([O:24][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:48])[CH3:47])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCOCc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2 g) in N,N-dimethylacetoamide (36 mL) were added sodium hydride (55%, 0.26 g) and benzyl 2-bromoethyl ether (0.76 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]2=[O:17])=[CH:5][CH:4]=1.[BrH:18].BrBr>O>[Br:18][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:17])[NH:11][C:12](=[O:16])[NH:13][C:14]1=[O:15]
Reactant: Br
Reactant: COc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Agent: BrBr
Solvent: O
Product: COc1ccc(C2(Br)C(=O)NC(=O)NC2=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(4-Methoxyphenyl)barbituric acid (222 mg) in 3 ml of water, cooled to 0-5° C. with ice bath, are added 136 μl of 48% hydrobromic acid and 56 μl of bromine, dropwise. After 1 hour at a temperature below 10° C., the solid which separated is collected by filtration and washed on the filter with water. The solid is dried for several hours under vacuum at 50° C., to give 283 mg of the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[Na+].Cl>CCO.O.O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:20])[CH3:21])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]([NH2:15])=[O:25])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1
Reactant: [OH-]
Reactant: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1ncc(Oc2cc(C(N)=O)c(OC)cc2C(C)C)c(N)n1
Temperature: 100 °C
Yield: 27.1 %

Procedure:
To a solution of 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.3 g, 0.92 mmol) in EtOH/H2O (1:1, 10 ml) was added a solution of NaOH (0.37 g, 9.17 mmol) in H2O (1 ml). The reaction mixture was heated at 100° C. for 24 hrs and neutralized with 3N HCl. Ethanol was removed in vacuo and the remaining aqueous solution was extracted into methylene chloride. The combined extract was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (3 to 8% EtOAc in Hexanes) gave 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.086 g, 27%) as a white solid. (M+H)=346.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:33].Cl.[S:35]1[CH:39]=[C:38]([CH2:40][C@@H:41]([C:43]([N:45]2[CH2:52][CH2:51][CH2:50][C@H:46]2[C:47]([NH2:49])=[O:48])=[O:44])[NH2:42])[N:37]=[CH:36]1.C(N(CC)CC)C>CN(C)C=O>[ClH:33].[ClH:33].[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:42][C@H:41]([C:43]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([NH2:49])=[O:48])=[O:44])[CH2:40][C:38]1[N:37]=[CH:36][S:35][CH:39]=1)=[O:9]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 2 h

Procedure:
L-Pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in N,N-dimethylformamide (50 ml). To this solution was added the solution of DCC (3.09 g, 15 mmol) in N,N-dimethylformamide (10 ml) under ice-cooling and the resulting mixture was stirred for 2 h at, the same temperature. 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and triethylamine (4.6 ml. 33 mmol) were added successively to the solution and the reaction mixture was stirred overnight. After the precipitation which appeared was filtered off, to the filtrate was added sodium hydrogencarbonate aq. to adjust pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml, aq. MeOH) to give the compound (I-1) (2.54 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.[C:22](OCC(Cl)(Cl)Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)CCCC.C(Cl)(O)C(Cl)Cl>N1C=CC=CC=1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: CCCCC(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CCCCC(=O)Cl
Agent: OC(Cl)C(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
2-Amino-6-methoxy-9-β-D-arabinofuranosyl-9H-purine (1.0 g, 3.2 mmol) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2.0 mL of trichloroethyl valerate (Trichloroethyl valerate was synthesized by addition of 36 g of valeryl chloride (Aldrich) over 30 minutes to 45 g of trichloroethanol (Aldrich) in 50 mL of pyridine at 0° C. The product was purified by successive washing with 2×250 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H-NMR (200 MHz, CDCl3): δ4.74 (s, 2H, Cl3CH2 --), 2.48 (t, 2H, J=7.6 Hz, CH3CH2CH2CH2CO2 --), 1.68 (m, 2H, CH3CH2CH2CH2CO2 --), 1.53 (M, 2H, CH3CH2CH2CH2CO2 --), 0.93 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --)). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot #38F-0356), which had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 24 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (90:10) as the eluant. Product fractions were pooled and lyophilized from water to yield 0.85 g of the desired product as a white powder; m.p. 105° C.; TLC Rf =0.39 (silica gel; CH2Cl2:CH3OH (90:10)); UV λmax (ε;, mM- 1 cm-1) at pH 7.0, 279 nm (9.3); MS (Cl) 382 (M+1), 280 (M-C5H9CO2). 1H-NMR (200 MHz, DMSO-d6): δ7.83 (s, 1H, H8), 6.45 (s, 2H, 2-NH2), 6.15 (d, 1H, J=3.7 Hz, H1 '), 5.76(d, 1H, J=4.2 Hz, 2'--OH), 5.65 (d, 1H, J=3.5 Hz, 3'OH), 4.28 (m, 2H, H2' and H3'), 4.08(m, 2H H5'), 3.94 (s, 3H, --OCH3) 3.92 (m, 1H, H4'), 2.29 (t, 2H, J=7.1 Hz, CH3CH2CH2CH2CO2 --), 1.49(m, 2H, CH3CH2CH 2 CH2CO2 --) 1.28 (m, 2H CH3CH2CH2CH2CO2 --), 0.83 (t, 3H, J=7.2 Hz, CH3CH2CH2CH2CO2 --). Anal. Calcd. for C16H23N5O6.0.36 H2O: Calcd: C, 49.54; H, 6.16; N,18.05. Found: C, 49.52; H,6.15; N, 18.10.