Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH:58]([C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:73])[C@H:59]([C:69](O)=[O:70])[CH2:60][CH2:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65]>C(#N)C.CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14]([O:15][C:69](=[O:70])[CH:59]([NH:58][C:72]([O:74][CH2:75][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)=[O:73])[CH2:60][CH2:61][C:62]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:68])=[CH:16][CH2:17][C@@:18]35[OH:21]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(OC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)=CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution comprised of oxycodone free base, 1-1, (517 mg, 1.64 mmol), DIEA (1.5 mL, 8.6 mmol) in 9 mL of anhydrous acetonitrile was stirred at rt for 20 min and mixed with a solution containing DMAP (400 mg, 3.3 mmol), DCC (1.01 g, 4.1 mmol), and HOBt (440 mg, 3.3 mmol) in 6 mL of anhydrous acetonitrile. Cbz-L-Glu(OtBu)-OH (1.1 g, 3.3 mmol) was then added to the combined solutions. The mixture was stirred for 45 h at rt, precipitated DCU removed by filtration, and the solution concentrated under reduced pressure to give a dark-brown oil. HPLC analysis indicated that 39% of the oxycodone had been converted to 3-1. The brown oil containing crude 3-1 was dissolved in 20 mL of acetone, cooled in an ice bath for 2 h, and filtered to remove precipitated DCU. The filtrate was concentrated to dryness, and subjected to flash chromatography using a gradient of 0–10% methanol in DCM. The fractions containing 3-1 were combined and concentrated to dryness. The residue was treated with 20 mL acetone and filtered to remove precipitated DCU. The filtrate was concentrated to dryness under reduced pressure to yield partially purified 3-1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:25]([C@@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[O:26])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 2-amino-1-(4-bromophenyl)ethanone hydrochloride salt (1.10 g, 4.39 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.02 g, 4.73 mmol), and diisopropylethylamine (3.10 mL, 17.4 mmol) in DMF (20 mL) was added 3-(diethoxyphosphoryloxy)-(1,2,3)-benzotriazin-4(3H)-one (DEPBT, 2.0 g, 6.68 mmol) and the solution was allowed to stir for 2 hours. The mixture was poured into H2O-ethyl acetate and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O×2, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (1:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (1.02 g, 56%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 8.16-8.21 (m, 1H), 7.90-7.92 (m, 2H), 7.73-7.75 (m, 2H), 4.59 (dd, J=5.7, 18.4 Hz, 1H), 4.51 (dd, J=5.7, 18.4 Hz, 1H), 4.13-4.19 (m, 1H), 3.24-3.27 (m, 2H, partially obscured by H2O), 2.05-2.12 (m, 1H), 1.74-1.81 (m, 3H), 1.39 (s, 3H), 1.33 (3, 6H); LCMS: Anal. Calcd. for C18H23BrN2O4: 410. found: 411 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:28](=[O:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([O:32][CH:33]([CH3:35])[CH3:34])=[C:24]([O:30][CH3:31])[CH:25]=4)[C@@H:20]3[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[CH:15][CH:14]=2)([OH:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C@H:20]2[C:21]3[C:26](=[CH:25][C:24]([O:30][CH3:31])=[C:23]([O:32][CH:33]([CH3:34])[CH3:35])[CH:22]=3)[CH2:27][C:28](=[O:29])[N:19]2[C:16]2[CH:17]=[CH:18][C:13]([C:10]3([OH:12])[CH2:11][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[CH:37][CH:38]=1
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CN(C(=O)OC(C)(C)C)C3)cc1)C(=O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reaction time: 0.5 h

Procedure:
Example 56 was obtained from example 55. A solution of 3-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (70 mg, 0.118 mmol) in DCM (1 ml) was immersed in an ice-bath followed by addition of TFA (0.045 ml, 0.590 mmol). The yellow reaction solution turned brown and was stirred for 30 minutes. The reaction mixture was treated with ice/saturated aq. sodium hydrogencarbonate solution and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound as yellowish solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH2:16]1[CH2:20]OC[CH2:17]1.C([Li])(C)C>O>[CH:16]([C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1)([CH3:20])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1CCOC1
Agent: [Li]C(C)C
Solvent: O
Product: CC(C)C1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), isopropyllithium (0.7 M pentane solution) (40.3 mL) was added at −78° C. and stirred over 4 hours until it reached −50° C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=3:1) and further purified (eluent; chloroform:methanol=30:1) to give tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 250) (0.854 g), which was a low-polarity product, as a white solid and tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 252) (0.179 g), which was a high-polarity product, as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1)[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CCc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 51.7 %

Procedure:
Using the procedure of example 1, 2-ethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 32 (44 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=8.0 Hz, 1H), 8.21-8.18 (m, 3H), 7.51 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=5.2 Hz, 1H), 7.03 (dd, J=8.0 Hz, 4.8 Hz, 1H), 2.71 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:25]=[C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: N=C(NO)c1cccnc1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(-c3cccnc3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 4.35 g (20.95 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 35 mL of toluene, 3.703 g (22.8 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 15 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-nicotinimidamide (compound of Example 53; 6 g, 43.7 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [NH:1]([C:8](=[O:44])[CH:9]([C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:26]=[CH:25][C:24]=2[NH:34]C(=O)OC(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[CH2:10][NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:34][C:24]1[CH:25]=[CH:26][C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH:9]([CH2:10][NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:44])=[CH:43][CH:42]=1
Reactant: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-({[(methylamino)-carbonyl]-amino}methyl)-2-oxoethyl]benzoyl}amino)-4-(3-thienyl)phenyl]carbamate (49 mg, 0.08 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 3 h. Concentration yielded a yellow residue that was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and evaporated to give N-[2-amino-5-(3-thienyl)-phenyl]-4-[2-anilino-1-({[(methylamino)carbonyl]amino}methyl)-2-oxoethyl]benzamide as a white solid. 1H NMR (DMSO-d6) δ 10.19 (s, 1H), 9.66 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 7.54-7.52 (m, 2H), 7.49-7.47 (m, 3H), 7.38 (dd, J=4.8, 1.3 Hz, 1H), 7.33 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (t, J=7.9 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.08 (t, J=6.0 Hz, 1H), 5.77 (q, J=4.4 Hz, 1H), 5.00 (s, 2H), 4.01 (dd, J=9.1, 5.6 Hz, 1H), 3.52 (ddd, J=13.5, 8.8, 5.0 Hz, 1H), 3.42 (dt, J=12.8, 6.4 Hz, 1H), 2.51 (d, J=4.7 Hz, 3H). MS (ESI) calcd [M+H]+ 514.1, found 514.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH:22]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34])([CH3:24])[CH3:23]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)N(C(=O)CN(C(=O)CN)c1ccccc1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc2)c1
Yield: 36.3 %

Procedure:
The procedure is analogous to that described in Example 81, but 0.6 g of 2-(2-amino-N-phenylacetamido)-N-isopropyl-N-phenylacetamide and 0.24 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 30 g of silica (0.065-0.200 mm) contained in a column 1.5 cm in diameter [eluent: dichloromethane/ethyl acetate (80/20 by volume)], collecting 20 cm3 fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diethyl ether, 0.3 g of N-isopropyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-N-phenylacetamide melting at 170° C is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[O:63][C:64]([F:67])([F:66])[F:65])[CH2:58][NH2:59]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:59][CH2:58][C:57]2[CH:60]=[CH:61][C:62]([O:63][C:64]([F:65])([F:66])[F:67])=[C:55]([F:54])[CH:56]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 78.4 %

Procedure:
To a solution of the compound (1.35 g) obtained in Example 783, Step 2 in chloroform (15 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (625 mg), 1-hydroxybenzotriazole hydrate (499 mg) and 3-fluoro-4-trifluoromethoxybenzylamine (620 mg) with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and chloroform, and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:l) to give the title compound (1.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)=[O:15]
Reactant: O=C(O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 55 %

Procedure:
A mixture of nitroterephthalic acid (Aldrich, 20 g, 0.095 mol) in anhydrous methanol (100 mL) was heated to reflux in the presence of concentrated sulphuric acid (10 mL) for 1 h. The solvent was evaporated and the residue poured into saturated sodium bicarbonate (200 mL). The aqueous layer was washed with chloroform and 2N hydrochloric acid added to the aqueous layer to bring the pH close to 2. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water and brine. The organic extract was concentrated after drying over sodium sulphate and the residue was recrystallized from ethyl acetate-hexane to give 11.8 g (55%) of 4-methoxycarbonyl-2-nitrobenzoic acid as cream-colored crystals, mp 131°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
4-Methoxyphenylacetyl chloride (76 g, 0.413 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (62.8 g, 0.413 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 3 days. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled on a kugelrohr apparatus to give the product as a yellow oil (19.7 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH:31]=[CH:32]N(C)C)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:38][C:39]([NH2:41])=[NH:40].[OH-].[Na+].[NH4+].[Cl-]>CO>[NH2:40][C:39]1[N:41]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:28]=2)[CH:31]=[CH:32][N:38]=1
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1nccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C

Procedure:
A suspension of 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (24 mg, 0.048 mmol) in MeOH (1 mL) is treated with guanidine hydrochloride (12 mg, 0.13 mmol) and NaOH (4 mg, 0.1 mmol) at 80° C. for 34 h. After cooling down to room temperature, the mixture is treated with saturated aqueus NH4Cl solution (2 mL) and extracted with EtOAc (3×2 mL). The organic layers are concentrated and purified by preparative thin layer chromatography (silica gel, 2.5% MeOH/CH2Cl2) to provide the titled compound 6-[4-(2-amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1H NMR (CDCl3) δ(ppm) 8.35(b, 1H), 8.34(s, 1H), 8.14 (d, 2H), 7.92 (d, 2H), 7.51 (t, 2H), 7.46 (d, 2H), 7.35(t, 1H), 7.32(d, 2H), 7.12(d, 2H), 7.03(d, 1H), 5.34(b, 2H); HPLC-MS calculated for C27H18ClN7O (M+H+): 492.1. Found: 492.2.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1.[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[F:19][C:20]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)sc2C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)sc2C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (230 mg, 0.71 mmol) obtained in Example 80e and 2-fluoro-3-(trifluoromethyl)phenylboronic acid (190 mg, 0.92 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.71 mL, 1.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (60 mg, 0.071 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (200 mg, 68%) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:20]=[C:21]([S:25]([CH2:33][CH3:34])(=[N:27]C(OCC)=O)=[O:26])[CH:22]=[CH:23][CH:24]=4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.ClCCl.CO>CO>[CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:20]=[C:21]([S:25]([CH2:33][CH3:34])(=[NH:27])=[O:26])[CH:22]=[CH:23][CH:24]=4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CC4)c3cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(NC4CC4)c3cc2OC)c1
Yield: 92 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[4-(cyclopropylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (47 mg, 0.097 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 92% yield (37 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:2]1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O>>[CH3:13][CH:10]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[NH:1][C:2]=2[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])=[CH:17][NH:12][CH2:11]1
Reactant: CC(CN)c1c[nH]c2ccccc12
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C1=CNCC(C)c2c1[nH]c1ccccc21

Procedure:
In a manner similar to Example 1, the title compound was prepared from 2-(1H-indol-3-yl)propylamine and ethyl pyruvate. MS(ESI): 271 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:4]1[C:5]([O:13][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2ccoc2cc1O
Reactant: BrCCCc1ccccc1
Product: CC(=O)c1cc2ccoc2cc1OCCCc1ccccc1
Yield: 81 %

Procedure:
5-Acetyl-6-hydroxybenzofuran (60 mg, 0.34 mmol) and 1-bromo-3-phenylpropane were reacted according to General Procedure A. The crude residue was purified by flash chromatography, eluting with diethyl ether:petroleum ether (1:9) to afford the title compound as a white solid (81 mg, 81%). 1H NMR (300 MHz, CDCl3): δ 2.26-2.16 (m, 2H), 2.69 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 6.72 (d, J=1.7 Hz, 1H), 6.99 (s, 1H), 7.32-7.19 (m, 5H), 7.54 (d, J=2.2 Hz, 1H), 7.99 (s, 1H). MS (ES+) m/z 294.9 (M+H+).