Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][C:26](Cl)=[O:27]>O1CCCC1>[Br:24][CH2:25][C:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=2)[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4]1)=[O:27]
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.32 g, 5.59 mmol) was dissolved in tetrahydrofuran (50 mL). This solution was treated with potassium carbonate (1.54 g, 11.2 mmol, Aldrich) and cooled to 0° C. Bromoacetyl chloride (0.93 mL, 11 mmol, Fluka) was added (white precipitation observed) and the reaction stirred for 15 min. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-(bromoacetyl)-4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (assumed 5.59 mmol, 100%). This material was analyzed by 1H NMR (amide rotomers were observed) and taken to bromide displacement reactions directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 6 H), 1.75-1.86 (m, 2 H), 3.72-3.82 (m, 2 H), 3.95 (s, 3 H), 4.31-4.69 (two singles at 4.37 and 4.63, 2 H), 7.27 (s, 1 H), 8.28 (very broad singlet, 1 H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:17][C:11]1[CH:10]=[C:9]2[C:14]([N:15]=[CH:16][C:7]([NH2:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2cnc3ccc(C)cc3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2ncc(N)nc2c1
Yield: 85.1 %

Procedure:
N-(2,4-Dimethoxybenzyl)-7-methylquinoxalin-2-amine (0.85 g, 2.75 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous NaHCO3 (200 mL) was added to the red residue, which then precipitated a pink solid. The mixture was extracted extensively with DCM. The organic layer was dried over sodium sulfate, concentrated, and dried under vacuum to afford 7-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (640 mg, 2.34 mmol, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.C[NH:13][NH2:14]>CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1/[CH:4]=[N:13]/[NH2:14]
Reactant: CNN
Reactant: O=Cc1c(F)cc(F)cc1F
Solvent: CCOCC
Product: N/N=C/c1c(F)cc(F)cc1F
Reaction time: 8 h

Procedure:
2,4,6-Trifluoro-benzaldehyde (x) (4.5 g, 27.3 mmol) was dissolved in Et2O, methylhydrazine was added (1.43 mL, 27.3 mmol) and the RM was stirred overnight. The solvent was evaporated and the solid residue was suspended in a mixture of pentane and EtOAc to afford after filtration the title compound as a bright yellow crystalline solid (tR 4.95 min (conditions 3), MH+=198.1).
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:15].CCCCCC.[F-].[K+]>C([Sn](CCCC)(CCCC)C=C)CCC.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:13][C:3]1[C:2]([CH:14]=[CH2:15])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(Br)c1F
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: C=Cc1cccc(C(=O)OCC)c1F
Temperature: 25 °C
Reaction time: 13 h
Yield: 97 %

Procedure:
A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was dissolved in 50 ml of Tol solution, 15.8 ml of tributyl(vinyl)tin, 236 mg of tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-butylphosphine 10 wt % hexane solution were added thereto in order, and stirred at room temperature for 13 hours in an atmosphere of argon. This was diluted with 300 ml of diethyl ether, mixed with 25 g of potassium fluoride and 5 ml of purified water and stirred for 30 minutes, the insoluble matter was filtered using a Kiriyama funnel, and then the mother liquid was concentrated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=40:1) to obtain 10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference Example 17-1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:32]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:32])[C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3C)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3C)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 525 and methyl iodide (10 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (9 mg) was obtained.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[NH2:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[NH:29][C:30](=[O:32])[CH3:31])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC[C@H](NC(=O)c1c(NC(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 3 h

Procedure:
0.40 g (1.05 mmol) of (S)-N-(α-ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide (compound of Ex. 69) were heated in 25 ml of acetic anhydride at 70° C. for 1 hour and then at 100° C. for additional 3 hours.
Reaction SMILES: [N:1]([CH:4]([CH:10]([C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[N:1]([CH:4]([CH:10]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O)c1cccnc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 3.90 g of ethyl 2-azido-3-(2-chloropyridin-3-yl)-3-hydroxypropionate (prepared as described in Preparation 76), 8.6 g of t-butyldimethylsilyl chloride, 10 g of imidazole and 80 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.6 g of the title compound having Rf=0.31 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:18]=[CH2:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][O:10][C:5]([CH:18]=[CH2:19])([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC1(C(=O)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of crude 2-vinyl-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (3.284 mmol) in tetrahydrofuran/methanol/water (50 mL, 2:2:1) was treated with lithium hydroxide monohydrate (413.3 mg, 9.852 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo and the residue was cooled to 0° C. and quenched with hydrochloric acid (1 M). The aqueous layer was extracted with dichloromethane (2×). The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound (761.4 mg, 90% over 2 steps) as colorless needles. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.31-3.42 (m, 1H), 3.45-3.61 (m, 2H), 3.87-3.94 (m, 2H), 4.02 (d, J=13.6 Hz, 1H), 5.44 (d, J=10.7 Hz, 1H), 5.60 (d, J=17.4 Hz, 1H), 5.85 (dd, J=17.4, 10.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](C(C)(C)C)[CH:3]=1.C([O-])(O)=O.[Na+].[C:20](Cl)(Cl)=[S:21]>C(Cl)(Cl)Cl>[C:5]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:20]=[S:21])=[CH:10][CH:9]=1)([CH3:9])([CH3:6])[CH3:4]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1cc(N)ccc1C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(N=C=S)cc1
Reaction time: 1.5 h
Yield: 185.9 %

Procedure:
t-Butyl-4-aminobenzoate 1, (25.0 gm, 129.4 mmol) was taken into CHCl3 (250 ml) and saturated NaHCO3 (100 ml) in ice bath. To the stirred mixture thiophosgene (9.9 ml, 129.4 mmol) was added dropwise, and stirring continued for another 90 min. at room temperature after addition was complete. The organic layer was washed with water, dried over Na2SO4, and further purified by column chromatography to provide 28.3 gm of 4-isothiocyanato-benzoic acid t-butyl ester 2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][O:31][C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>>[CH3:30][O:31][C:32]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(S)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methylchloroformate, using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of (R)-pyrrolidin-2-ylmethanol (0.7 g, 6.93 mmol) in CH2Cl2 (5 mL) was added (Boc)2O (1.66 g, 7.62 mmol) and triethylamine (1.40 g, 13.86 mmol) at 0° C. After stirring at 0° C. for about 10 minutes, the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was quenched with aqueous acetic acid, then diluted with CH2Cl2 (20 mL), extracted with H2O (2×20 mL). The organics were dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl (hydroxymethyl)pyrrolidine-1-carboxylate (1.26 g, 91%) as a solid. A solution of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.26 g, 6.26 mmol) in CH2Cl2 (25 mL) was treated with CBr4 (3.13 g, 9.45 mmol) and PPh3 (2.48 g, 9.45 mmol) at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 16 h. Silica gel was added to the mixture, and then the mixture was concentrated to dryness. Purification by flash column chromatography (silica gel, Hexane/EtOAc, 100:0 to 3:1) gave the title compound (0.99 g, 60%) as a solid: 1H NMR (500 MHz, DMSO-d6) δ 4.08-3.98 (m, 1H), 3.69-3.50 (m, 1H), 3.48-3.21 (m, 3H), 2.10-1.75 (m, 4H), 1.47 (s, 9H); ESI MS m/z 164 [M+H]+.
Reaction SMILES: [CH2:1]([C:7](=[CH2:10])[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][C:13]([CH3:15])=[CH2:14]>[I-].[Zn+2].[I-]>[CH2:1]([C:7]1[CH2:10][CH2:14][C:13]([O:12][CH3:11])([CH3:15])[O:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=C(C)OC
Reactant: C=C(C=O)CCCCCC
Agent: [I-]
Agent: [Zn+2]
Product: CCCCCCC1=COC(C)(OC)CC1
Reaction time: 6 h
Yield: 15.4 %

Procedure:
To a zinc iodide suspension (0.21 g, 0.671 mmol) in 42 g (0.3 mol) of 2-hexyl-2-propenal there were added dropwise, at 60° C. and under nitrogen, 18.5 g (0.25 mol) of 2-methoxypropene. Once the introduction was completed (23 min), the reaction was allowed to continue for 6 h at 60° C. and the mixture was then distilled on a Vigreux column to give 8.16 g of 5-hexyl-3,4-dihydro-2-methoxy-2-methyl-2H-pyran (B.p. 73°-74°/3 Pa; yield 15.4%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].ClCCl.N1C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 15 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ˜15° C. and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ˜15° C. and the addition of 2,6-difluorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25° C. After complete addition, the reactor contents were warmed to 20-25° C. and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55° C. with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ˜3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ˜3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0° C. The solids were filtered and rinsed with cyclohexane (2×100 mL). The solids were air dried overnight to obtain methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCS(C)(=O)=O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 2-(methylsulfonyl)ethylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 614.00 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])CO)[CH3:11].S(=O)(=O)(O)O>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH2:7][CH:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: COC(=O)C(=O)N(C)C
Reactant: CCCCC(CC)CO
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCC(CC)COC(=O)C(=O)N(C)C
Temperature: 80 °C

Procedure:
In a 1,000 mL reactor, are mixed at 20-25° C., methyl 2-(dimethylamino)-2-oxoacetate (compound 1) (390 g, 2.98 mol), 2-ethyl-hexan-1-ol (464 g, 3.5 mol) and 98% sulfuric acid (66 g, 0.67 mol). The temperature of the mixture is brought to and maintained at 80° C. for 24 hours. The progression of the reaction is tracked by gas chromatography analysis. At the end of the reaction, the methanol formed is removed from the reaction medium by distillation under reduced vacuum (Pmin=150 mbars) and an aqueous solution of sodium hydrogencarbonate is then added to the reaction medium so that the final pH is 7. The organic phase is separated from the aqueous phase. The latter is counter-extracted with 500 mL of dichloromethane. The organic phases are collected and then the reaction medium is concentrated in order to remove the dichloromethane. To the residue, are added 5 g of potassium carbonate and the thereby obtained medium is then distilled under partial vacuum (Tbp 150° C., P<1 mbar). The expected product is obtained with a purity of more than 98% (578 g).
Reaction SMILES: FC(F)C1NC2C=CC=CC=2N=1.FC(F)C1NC2C=C(O[Si](C(C)(C)C)(C)C)C=CC=2N=1.[F:33][CH:34]([F:70])[C:35]1[N:39]([C:40]2[N:45]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH:43]=[C:42]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:41]=2)[C:38]2[CH:58]=[CH:59][C:60]([O:62][Si](C(C)(C)C)(C)C)=[CH:61][C:37]=2[N:36]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:70][CH:34]([F:33])[C:35]1[N:39]([C:40]2[N:41]=[C:42]([N:52]3[CH2:53][CH2:54][O:55][CH2:56][CH2:57]3)[CH:43]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:45]=2)[C:38]2[CH:58]=[CH:59][C:60]([OH:62])=[CH:61][C:37]=2[N:36]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2CCOCC2)n1
Agent: CC(C)(C)[Si](C)(C)Oc1ccc2nc(C(F)F)[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FC(F)c1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(c1)nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
In accordance with the procedure of the Example 1 except that 2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by 2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazole, obtained was 2-(2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazol-1-yl)-4,6-dimorpholinopyrimidine. 0.55 g (1.0 mmol) of the obtained compound dissolved in THF (10 ml) was added with a solution of tetrabutylammoniumfluoride (1 M) in THF (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.40 g (yield: 93%) of the titled compound as colorless crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8](=[O:16])[CH:7]=1>C(Cl)(Cl)Cl>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8](=[O:16])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1oc2ccccc2c(O)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Fuming nitric acid (30 ml) was added to a stirred suspension of 4-hydroxycoumarin (5.0g) in chloroform (500 ml) at room temperature over 2 hours. After a further 2 hours, the solvent was removed in vacuo at room temperature and water (250 ml) added to the residue. Filtration gave the product, m.p. 174°, -5°, (C9H5NO5 required C, 52.18; H, 2.43; N, 6.76. Found: C, 52.00; H, 2.38; N, 6.62).
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:52]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:52])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CCOCC
Agent: OO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 5 ml of acetic acid is dissolved 900 mg of BOC-Tyr-(D)-Met-Gly-Phe-NHNHCONH2 followed by addition of 0.24 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 760 mg; m.p. 114°-121° C.; [α]D21.5 -2.6° (c=0.89, DMF); Rf2 0.38.