Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:23][C:24]1[CH:25]=[C:26]([CH3:49])[C:27]2[O:31][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[N:29][C:28]=2[CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]4[O:31][C:27]5[C:26]([CH3:49])=[CH:25][C:24]([CH3:23])=[CH:48][C:28]=5[N:29]=4)=[CH:38][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
A mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.15 g, 0.00036 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.16 g, 0.00045 mol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) and sodium carbonate (0.095 g, 0.0009 mol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature. Additional tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) was added to the mixture. The reaction was stirred at 80° C. for 3 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-50% methanol t dichloromethane as a mobile phase to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.033 g, 0.00006 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1 M ammonium acetate over 10 min, 1 mL/min) Rt 11.6 min. MS: MH+ 527.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20][CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7].O>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:4]([Cl:3])[C:5]=1[C:6]([NH:8][C:9]1[C:17]2[O:16][C:15]3[CH2:18][CH2:19][S:20](=[O:1])[CH2:21][C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(Nc1cccc2c3c(oc12)CCSC3)c1c(Cl)cccc1Cl
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1cccc2c3c(oc12)CCS(=O)C3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrogen peroxide in trifluoroacetic acid (1M, 0.32 ml) wa s added to a solution of 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano-[4,3-b]benzofuran (120 mg) in trifluoroacetic acid (2.5 ml) at 4° C. The mixture was stirred at ambient temperature for 30 minutes and to the mixture was added water. The separated solid was collected and dried. The obtained solid was suspended in hot ethanol and to the mixture was added water. The mixture was cooled and the separated solid was collected to give 6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano[4, 3-b]-benzofuran 2-oxide (70 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28]([NH:1][CH2:2][CH2:3][CH:4]2[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:5]2)=[O:29])[O:24]1
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (Example 11, step 2) (178 mg, 0.534 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (68.9 mg, 0.534 mmol), T3P® (50% in DMF) (510 mg, 0.801 mmol), Huenig's base (466 μl, 2.67 mmol) in DMF (1781 μl) was stirred at room temperature. Another 1 equivalent of 2-oxo-2,3-dihydrooxazole-5-carboxylic acid was added and the reaction mixture was left stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:23][C:24]([O:26]CC)=[O:25])[NH:21][CH:22]=1.N1C=CC=C1.Cl(O)(=O)(=O)=O>CCOCC>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[NH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=2[CH3:17])=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cc(C)c[nH]1
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: c1cc[nH]c1
Solvent: CCOCC
Product: CN=C(c1ccc(Cl)cc1)c1[nH]c(CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
N-Methyl 4-chlorobenzimidoyl chloride (2.37 g, 12.6 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform and chlorosulfonic acid (0.15 g, 1.3 mmole). The reaction was placed under a nitrogen atmosphere and stirred at room temperature while ethyl 4-methyl-1H-pyrrole-2-acetate (2.11 g, 12.6 mmole) was added dropwise over a five-minute period. Upon addition of the pyrrole, the reaction mixture turned dark brown and the reaction temperature rose. The reaction was stirred overnight at room temperature, then quenched with saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was extracted with saturated aqueous sodium bicarbonate, washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in absolute ethanol, treated with 70% perchloric acid (2.0 g, 14 mmole) cooled and diluted with ether. A brown viscous liquid separated which was suspended in methylene chloride and treated with saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate, filtered, and concentrated. The residue was placed on a silica gel column and eluted with methylene chloride/methanol (99/1) to remove nonpolar impurities. The silica gel was extracted with methanol to yield 0.47 g (12%) of the title compound as a dark brown solid, m.p. 79°-80° C. (dec).
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:6]2)[CH2:2]1.[Br:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:3]3([CH2:4][CH2:5][N:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2]3)[CH2:6][N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])=[O:15])[C:8]2=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (15.2 g, 36.5 mmol) was dissolved in t-butanol (240 mL) and water (40 mL). Thereafter, N-bromosuccinimide (7.9 g, 44.4 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 60° C. for 15 hours. Thereafter, an aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (12.9 g, 71%) in the form of a white amorphous product.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=1
Reactant: Nc1ccc(CO)cc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(CO)ccc2N)cc1
Yield: 138 %

Procedure:
To a degassed solution of crude 2-bromo-4-hydroxymethylaniline (3.2 g, 15.8 mmol), 4-methoxybenzeneboronic acid (2.89 g, 19 mmol) and potassium carbonate (4.77 g, 34.8 mmol) in toluene/ethanol 2/1 (45 mL) a catalytic amount of Pd(PPh3)4 (0.2 g, 1 mmol %) was added and the mixture was heated at 90 C for 5 hours. The residue was extracted into ethyl acetate and washed with water and then saturated brine and dried over sodium sulphate. The solvent was removed under reduced pressure to afford 5 g of crude product. C14H15BNO2 Mass (calculated) [229.28]; (found) [M+H+]=230 Lc Rt=0.88, 89%. NMR (400 MHz, CDCl3): 3.75 (3H, s, MeO); 4.5 (2H, s, CH2O); 6.65 (1H, d, J=8.5 Hz, aryl-H); 6.9 (2H, d, J=8.5 Hz, aryl-H); 7-7.1 (2H, m, aryl-H); 7.25 (2H, d, J=8.5 Hz, aryl-H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:20]([S:24](Cl)=[O:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([S:24]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfinylamino-1-ethoxycarbonyl piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:16][CH:15]3[S:17](=[O:19])(=[O:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:17](=[O:19])(=[O:18])[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)([OH:9])[CH3:20])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromo-phenyl)-(8,8-dioxo-8-thia-bicyclo[3.2.1]oct-3-yl)-methanone (885 mg, 2.58 mmol) in THF (7 ml) at −10° C. to −8° C. was added methylmagnesium bromide 1.4M in toluene/THF 3/1 (3.68 ml, 5.16 mmol). The reaction mixture was stirred for 30 min. The solution was cooled with an ice bath and quenched with a solution of aqueous saturated NH4Cl and water 1/1 (7.5 ml), diluted and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product (940 mg, 2.54 mmol, 97%) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3O)[C:6]=2[N:7]=1.O.CC#N.[C:25](OC(C)(C)C(Br)=O)(=[O:27])C.C([O-])(O)=O.[Na+]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH3:25])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]4[O:15][C@@H:12]34)[C:6]=2[N:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)Br
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(N)nc2c1ccn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
To a mixture of 2-amino-7-(β-D-ribofuranosyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g, 6.0 mmol) in acetonitrile (80 mL) were added a solution of H2O/CH3CN (1:9, 1.08 mL) and then α-acetoxyisobutyryl bromide (3.5 mL, 24 mmol). After 2 h stirring at room temperature, saturated aqueous NaHCO3 (170 mL) was added and the mixture was extracted with EtOAc (300+200 mL). The combined organic phase was washed with brine (100 mL), dried (Na2SO4) and evaporated to a pale yellow foamy residue. This was suspended in anhydrous MeOH (80 mL) and stirred overnight with 25 mL of DOWEX OH− resin (previously washed with anhydrous MeOH). The resin was filtered, washed thoroughly with MeOH and the combined filtrate evaporated to give a pale yellow foam (1.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][C:18]2[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=2[O:16][CH3:17])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 87.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), vanillin (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 22 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formyl-2-methoxy-phenoxy)-benzonitrile (0.98 g, 88%) as an off-white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C(O)C>[CH2:8]([O:7][C:1]([CH:2]([C:3](=[O:4])[CH3:5])[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2ccccc2c1)C(C)=O
Reaction time: 6 h
Yield: 114.1 %

Procedure:
In a four-necked flask equipped with a thermometer, dropping funnel and stirrer were placed 179 g (1.375 moles) of ethyl acetoacetate and 500 ml of ethanol, and then 31.5 g (1.375 moles) of sodium was added in portions thereto to form a solution. Then, a solution of 276.4 g (1.25 moles) of 2-bromomethylnaphthalene in 1000 ml of ethanol was added dropwise to the above solution at room temperature over a period of 2 hours. After completion of the addition, the resulting mixture was brought up to 65° C. and stirred at the same temperature for 6 hours. After completion of the reaction ethanol was distilled off under reduced pressure, the residue obtained was extracted by addition of 1500 ml of toluene, and the organic layer was separated. The organic layer was washed with 10% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water in said order and then concentrated under reduced pressure to obtain 385.4 g of 2-(2-ethoxycarbonyl-3-oxobutyl)naphthalene as a crude product.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8]([O:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:12][C:11]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[N:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc2ccc(F)c(C)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(F)c(CBr)c2n1
Yield: 102.3 %

Procedure:
To 7-fluoro-8-methyl-2-(methyloxy)quinoxaline (50 g, 260 mmol) in dry chloroform (1 L) were added N-bromosuccinimide (52 g, 292 mmol) and benzoyl peroxide (70%, 0.42 g) and the mixture was heated under reflux, illuminated with a 120 W lamp, for 2 h. After cooling, the mixture was washed with water. The aqueous phase was re-extracted twice with dichloromethane and the combined organic fractions were washed with water, dried and evaporated to give product (72.1 g, 100%).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])OC(C)(C)C.[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([NH2:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(OCC)(=O)C>CO.C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:21][CH2:22][N:23]([N:26]2[CH2:2][CH2:3][CH2:4][NH:5][C:6]2=[O:12])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NCCCN1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47 %

Procedure:
A solution of tert-butyl (3-oxopropyl)carbamate (4.2 g) and 4-benzylpiperazin-1-amine (4.6 g) in methanol (60 mL) was heated under reflux for 3 hours, and the solvent was distilled off under reduced pressure. After the residue was dissolved in methanol (60 mL), acetic acid (4.1 mL) and sodium triacetoxyborohydride (3.2 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, made alkaline with 1N sodium hydroxide and potassium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was dissolved in ethyl acetate (10 mL). and then a 4N hydrochloric acid-ethyl acetate solution (100 ml) was slowly added at 0° C., followed by stirring at room temperature for 5 hours. The precipitate was collected by filtration, dried, and then suspended in acetonitrile (200 mL). DBU (14.6 g) and CDI (7.8 g) were added thereto, and the mixture was heated under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from diethyl ether to obtain the title compound (3.1 g, 46%) as white crystals.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][CH2:9][C:10](=O)[CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCN(CC)CC>[CH2:9]([C:10]1([CH2:11][CH3:12])[O:6][C@@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1)[CH3:8]
Reactant: OCC[C@H](O)CO
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCC1(CC)OC[C@H](CCO)O1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1,2,4-butanetriol intermediate 67a (6.76 g, 63.68 mmol) in freshly distilled pentan-3-one (320 mL) was added p-toluenesulfonic acid (p-TSA) (6.06 g, 31.84 mmol). The reaction mixture was stirred at 53° C. for 16 hours, then Et3N (10 mL) was added and the reaction mixture stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Gradient flash chromatography (CH2Cl2/MeOH, 100:0 to 97:3 to 95:5) afforded the protected alcohol intermediate 67b (9.84 g, 89%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17]N(C)C)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17][N:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)OCc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36 g (129 mmol) of methyl 2-benzyloxycarbonylamino-3-dimethylaminoacrylate and 24.12 g (142 mmol) of diphenylamine were dissolved in 630 ml of isopropanol at 40° C. Subsequently, the solution was admixed with 17.4 ml of concentrated hydrochloric acid within 5 min and stirred at 40° C. for a further 30 min. The reaction solution was concentrated to 300 ml and admixed slowly with 300 ml of water. The crystallized product was filtered off with suction and dried at 40° C. under reduced pressure.
Reaction SMILES: [Na].[Na].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].Cl[CH2:16][P:17](=[O:20])([CH3:19])[CH3:18]>>[CH3:16][P:17]([CH3:18])([N:9]1[C:8]2[C:7](=[O:13])[N:6]([CH2:16][P:17](=[O:20])([CH3:19])[CH3:18])[C:5](=[O:14])[N:4]([CH3:3])[C:12]=2[N:11]=[CH:10]1)=[O:20]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CP(C)(=O)CCl
Agent: [Na]
Product: Cn1c(=O)n(CP(C)(C)=O)c(=O)c2c1ncn2P(C)(C)=O

Procedure:
The title substance was prepared from 22 g (0.1 mol) of 3-methylxanthine disodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and crystallized from methanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:14])=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8][CH3:9])=[O:7].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:14][C:4]1[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:12]([F:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc(F)c(CN)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)c(CNC(=O)C(C)(C)C)c1Cl
Yield: 81.7 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 3-(aminomethyl)-2-chloro-4-fluorobenzoate (340 mg, 1.42 mmol), DIPEA (550 mg, 4.27 mmol) and pivaloyl chloride (204 mg, 1.7 mmol) in CH2Cl2 (5 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.81-7.74 (m, 2H), 7.36-7.30 (t, J=9.0 Hz, 1H), 4.39-4.37 (d, J=4.5 Hz, 2H), 3.85 (s, 3H), 1.06 (s, 9H).