Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]=[C:30]=[O:31].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([C:30](=[O:31])[NH:29][CH3:28])[CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN=C=O
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)N1CN(C)C(=Nc2c(C)cc(C)cc2C)C=C1c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in pyridine (10 ml) was added methyl isocyanate (0.18 ml), and the mixture was stirred at ambient temperature for 3 hours. Then the mixture was poured into water (150 ml), and the resultant precipitates were collected. The precipitates were washed with water, and dried to give 6-(3,4-dimethoxyphenyl)-3-methyl-1-(N-methylcarbamoyl)-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.99 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@H:31]([CH2:35][CH3:36])[C@@H:32]([OH:34])[CH3:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N1CCCCC1)C>C(Cl)Cl.CCOCC.CCCCCC>[C:11]([NH:30][C@H:31]([CH2:35][CH3:36])[C:32](=[O:34])[CH3:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)O
Agent: CCN1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DMSO (2.19 mL, 2.8 eq, 30.86 mmol) in DCM (30 mL) under an argon atmosphere at −45° C., was added oxalyl chloride (2 M in DCM, 7.69 mL, 1.4 eq, 15.38 mmol) dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution (2S,3R)-3-(trityl-amino)-pentan-2-ol (3.81 g, 1 eq, 11.04 mmol) in DCM (20 mL) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 4 h, when TLC (hexane:ether; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added N-ethylpiperidine (7.54 mL, 5 eq, 54.88 mmol), and the solution allowed to warm to room temperature over 16 h. The reaction mixture was diluted with more DCM (50 mL) and washed with water (200 mL). The aqueous phase was extracted with DCM (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in Et2O (100 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil. Yield: 3.78 g (100%). 1H-NMR (d6-DMSO, 250 MHz): δ0.73 (t, 3H, J=7.35 Hz, —NHCH(CH2CH3)C(CH3)O), 1.47-1.60 (m, 5H, —NHCH(CH2CH3)C(CH3)O), 3.12 (d, 1H, J=8.38 Hz, —NHCH(CH2CH3)C(CH3)O), 3.32 (m, 1H, —NHCH(CH2CH3)C(CH3)O), 7.16-7.49 (m, 15H, 3×Ph).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2ncnn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2ncnn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Ethyl 7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (20 mg, 64 μmol), 3-(trifluoromethyl)phenylboronic acid (25 mg, 0.13 mmol, 2 eq.), anhydrous copper(II) acetate (23 mg, 0.13 mmol, 2 eq.) and molecular sieve (100 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (2 ml), pyridine (10 μl, 0.13 mmol, 2 eq.) and triethylamine (18 μl, 0.13 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (10.5 mg, 36% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[O:9]1[CH2:11][CH:10]1[CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:12][CH:10]2[CH2:11][O:9]2)[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: OCC1CO1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cncc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 5-Bromo-pyridin-3-ol (0.50 g, 2.87 mmol), oxiranyl-methanol (0.38 mL, 5.74 mmol) and triphenylphosphine (1.50 g, 5.74 mmol) in anhydrous THF (20 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1.32 g, 5.74 mmol) and the reaction mixture stirred at room temperature for 18 hrs and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10%-35% ethyl acetate/hexanes to provide the desire product (0.48 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[Cl:35][CH2:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41]>C1COCC1>[Cl:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)=[O:41]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=C=NCCCCl
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 99 %

Procedure:
A solution of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 3-chloropropyl isocyanate (111 μL, 1.089 mmol) in THF (2.5 mL) was heated at 120° C. for 3 hr using microwave irradiation. The reaction mixture was concentrated in vacuo then subjected to flash chromatography eluting with a gradient of 25-100% EtOAc in cyclohexane to give the title compound (125 mg).
Reaction SMILES: [OH:1]O.[OH:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9](=[O:13])[CH:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(Cl)(Cl)Cl>CO.O>[OH:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9](=[O:1])(=[O:13])[CH:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: OO
Reactant: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(O)CCN1C(=O)CS(=O)(=O)C1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
30% Hydrogen peroxide (2.0 ml., 20 millimole) is added slowly to a stirred solution of 7-[3-(3-hydroxyoctyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid (1.98 g., 4.69 millimole) and ammonium molybdate. tetrahydrate 0.1 g., catalyst) in methanol (25 ml.) maintained at 0° to 5° C. The resulting solution is allowed to warm to room temperature and then is stirred at room temperature for 64 hours. After diluting with water, the reaction mixture is extracted with chloroform three times. The combined organic extract is washed with water until free of peroxides, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves a viscous oil which is applied to a silica gel (20 g.) column with chloroform. Elution with chloroform-acetic acid (25:1; v:v) provides the title compound as a tlc homogeneous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8].CO.C([O-])=O.[NH4+].[BH3-]C#[N:21].[Na+]>Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC(N)CC(=O)OC
Reaction time: 24 h
Yield: 75.1 %

Procedure:
Dimethyl-3-oxoglutarate (10 g, 57 mmol) was added to methanol (225 ml) followed by ammonium formate (36 g, 570 mmol) and NaBH3CN (3.7 g, 57 mmol) at 25° C. After 24 h, the methanol was removed in white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride, dried over Na2 SO4, and evaporated to give dimethyl-3-aminoglutarate (7.5 g). 1H NMR (d6-DMSO) δ1.76 (bs, 2H), 2.45 (dd, 4H, J=8.1 Hz, 16.6 Hz), 3.69 (s, 6H), 5.45 (m, 1H); MS (FAB) m/z 176.0 (MH+).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:18]=[CH:17][N:16]=[C:15]2[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Temperature: 110 °C
Yield: 14.8 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (1.27 g, 7.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (3.9 g, 28.3 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia, (100/8/1) to give an oil which was triturated with ethyl acetate to give 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 15%) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9].C(S)C>C(O)CC.CCCO.CCCO.CCCO.CCCO.[Zr].[Zr]>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: CCSSCC
Reactant: Oc1ccccc1
Agent: [Zr]
Solvent: CCS
Solvent: CCCO
Product: CCSc1ccccc1O
Temperature: 200 °C
Yield: 41.2 %

Procedure:
To phenol (35.3 g, 0.37 moles) was added 10.6 g of zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.025 mole) and 10.8% free n-propanol. The mixture was distilled at atmospheric pressure removing n-propanol. Ethyl disulfide (30.6 g, 0.25 moles) was added, and the mixture was heated under nitrogen while ethyl mercaptan was removed continuously by distillation. Heating was continued for a total of 6.5 hours during which temperature slowly increased to 200° C. Distillation of the mixture at 0.5 mm mercury to a maximum head temperature of 84° C. yielded 31.7 g of distillate. GC analysis indicated the distillate contained 12.4 g of phenol (35% recovered) and 15.9 g of ortho-(ethylthio)phenol (41% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC2CCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a cold (10°) stirred solution of N-tertiarybutoxycarbonyl-L-tyrosine (11.25 g, 40 mM) in dry DMF (150 ml) under argon was added sodium hydride (2.76 g, 80% dispersion in oil, 92 mM). After one hour at 10° cyclopentyl bromide (5.96 g, 40 mM) was added and the reaction was allowed to warm and stir to room temperature overnight. Water (200 ml) and dichloromethane (300 ml) were then added and the aqueous layer was separated. The separated aqueous layer was washed with dichloromethane, acidified with hydrochloric acid and re-extracted with dichloromethane (300 ml×2). These latter dichloromethane extracts were dried and concentrated in vacuo to an oil. Column chromatography of this material on silica eluting with ethyl acetate gave the title compound as a foam (7.05 g). This was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:18][CH3:19].[BH4-].[Na+].C(O)(=O)C.Cl.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc2c(C3=CCN(C)CC3)c[nH]c2cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(C3CCN(C)CC3)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A suspension of 6-fluoro-5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (15.7 mmole, 4.09 g) in tetrahydrofuran (30 mL) at room temperature was added sodium borohydride (31.4 mmole, 1.19 g). To this suspension was carefully added acetic acid (47.1 mmole, 2.83 g). Severe frothing occurred during the addition. The reaction was stirred at room temperature for 1.0 hours. To the heavy suspension was added 5N hydrochloric acid (30 mL). The resulting solution was stirred at room temperature for 1.0 hour. Reaction was reduced in volume, cooled to 0° C. and the pH was adjusted to >12 with 50% wt/wt sodium hydroxide. The reaction was extracted with ethyl acetate (3×25 mL), organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to a solid. The resulting material was subjected to Waters LC2000 normal phase chromatography, eluting with a linear gradient of 0 to 10% methanol containing 1% ammonium hydroxide:chloroform over a thirty minute period collecting 150 mL fractions. Fractions containing the title compound were combined, reduced in volume and set aside. The resulting crystals were collected by filtration to afford 2.30 g (82%) of the title compound: mass spectrum (ion spray): m/z=263 (M+1); 1H NMR (DMSOd6): 10.65 (s, 1H), 7.16 (d, 1H), 7.13 (d, 1H), 7.03 (d, 1H), 3.83 (s, 3H), 2.81 (m, 2H), 2.63 (m, 1H), 2.20 (s, 3H), 1.98 (m, 2H), 1.86 (m, 2H), 1.62 (m, 2H); Calculated for C15H19FN2O: C, 68.21; H, 7.33; N, 6.66. Found: C, 68.09; H, 6.95; N, 10.52.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:17]1[S:21](=O)[CH2:20][CH2:19][CH2:18]1.C(OC(C)C)(C)C.[C:30]12([C:40]([O:42][CH:43]([C:51]([F:54])([F:53])[F:52])[C:44]([F:50])([F:49])[S:45]([O-:48])(=[O:47])=[O:46])=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.C([N+](C)(C)C)C1C=CC=CC=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[C:30]12([C:40]([O:42][CH:43]([C:51]([F:54])([F:52])[F:53])[C:44]([F:49])([F:50])[S:45]([O-:48])(=[O:46])=[O:47])=[O:41])[CH2:31][CH:32]3[CH2:38][CH:36]([CH2:35][CH:34]([CH2:33]3)[CH2:39]1)[CH2:37]2.[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S+:21]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][CH:6]=1
Reactant: O=S1CCCC1
Reactant: FC(F)(F)COc1cccc2ccccc12
Agent: CS(=O)(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Solvent: CC(C)OC(C)C
Solvent: O
Product: FC(F)(F)COc1ccc([S+]2CCCC2)c2ccccc12
Reaction time: 8 h

Procedure:
In 6 g of Eaton's reagent (Aldrich, diphosphorus pentoxide/methanesulfonic acid solution) was dispersed 3 g (0.0127 mol) of 1-(2,2,2-trifluoroethoxy)naphthalene in Synthesis Example 1-3. With stirring, 2.6 g (0.0253 mol) of tetramethylene sulfoxide was added dropwise to the dispersion. The solution was matured overnight at room temperature and combined with 30 g of water and 30 g of diisopropyl ether, from which a water layer was separated. The water layer was again washed with 30 g of diisopropyl ether. This aqueous solution was combined with 5.5 g (0.0101 mol) of benzyltrimethylammonium 2-(adamantane-1-carbonyloxy)-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-2, after which extraction was effected twice with 50 g of dichloromethane. The organic layer was washed with water, and the solvent was distilled off in vacuum. The residue was purified by silica gel column chromatography (elute, dichloromethane/methanol). It was dissolved in methyl isobutyl ketone and washed with water, followed by solvent removal and vacuum drying. The product was poured into isopropyl ether for crystallization, filtered and dried, obtaining the target compound. White crystal, 5.6 g, yield 78%.
Reaction SMILES: [NH:1]([C:103]([CH3:105])=[O:104])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@H:53]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([C:81]([NH:83][C@H:84]([C:94]([O:96]C1C=CC=CC=1)=[O:95])[CH2:85][CH2:86][C:87](=[O:93])[O:88][C:89]([CH3:92])([CH3:91])[CH3:90])=[O:82])[CH2:75][O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:72])[CH2:65][O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:62])[C@@H:54]([CH3:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])[CH2:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].OO.[OH-].[Na+].Cl>O>[NH:1]([C:103]([CH3:105])=[O:104])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@H:53]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([C:81]([NH:83][C@H:84]([C:94]([OH:96])=[O:95])[CH2:85][CH2:86][C:87](=[O:93])[O:88][C:89]([CH3:92])([CH3:91])[CH3:90])=[O:82])[CH2:75][O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:72])[CH2:65][O:66][C:67]([CH3:68])([CH3:69])[CH3:70])=[O:62])[C@@H:54]([CH3:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])[CH2:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)C(C)C

Procedure:
A solution of Ac-Ser(tBu)-Asp(OtBu)-Ala-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 (22.73 g, 15.2 mmol) in TFE: H2O (270 mL: 20 mL) was treated with 3% H2O2 (15.5 ml, 15.2 mmol, 1 eq.) with stirring (magnetic). The reaction mixture was adjusted to pH 10.5 by addition of 1N NaOH and maintained at pH 10.5 over a period of 3 h by addition of 1N NaOH (triggered by an autotitrator). The reaction mixture was adjusted to pH 3 (1N HCl), filtered and the solid washed with H2O (200 mL) and dried in vacuo. Yield: 21.85 g (98.8%); mp >245° dec; [α]D25 -16.31° (c 0.4, TFE); Rf 0.67 (CHCl3 :MeOH:AcOH; 85-10-5). Amino Acid Anal. (6M HCl, 110°, 24 h): Asp (1.99); Thr (0.96); Ser (2.83); Glu (1.02); Ala (1.99); Val (1.01). Anal. calc. for C67H118N10O22.2H2O (1451.79): C, 55.43; H, 8.19; N, 9.65. Found: C, 55.24; H, 8.24; N, 9.56.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:57][C:58]([F:62])([F:61])[CH2:59][NH2:60]>CN(C=O)C.C(#N)C.O>[NH2:1][C:2]1[C:7]([C:8]([NH:60][CH2:59][C:58]([F:62])([F:61])[F:57])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1
Reactant: NCC(F)(F)F
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)NCC(F)(F)F

Procedure:
300 mg (0.82 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylic acid (example 102A), 0.230 ml (1.65 mmol) of triethylamine and 139 mg (0.91 mmol) of 1-hydroxyl-1H-benzotriazole were dissolved in 2.2 ml of DMF, and 174 mg (0.91 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. While cooling with ice, 70 μl (90 mg, 0.91 mmol) of 2,2,2-trifluoroethylamine were added, and the mixture was reacted at room temperature overnight. The mixture was brought into solution with 4 ml of acetonitrile/water and purified by means of preparative HPLC [column: Reprosil C18, 10 μm, 250*40 mm; eluent: acetonitrile/0.05% formic acid; gradient: 15% acetonitrile→95% acetonitrile]. Thus, 110 mg (28% of theory) of the target compound were obtained.