Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:26]([C:27](=[O:36])[C:28](=[N+:34]=[N-:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][C:24]([I:37])=[CH:23][N:22]=1.O>C(OC(C)C)(C)C.C(Cl)(Cl)Cl>[Cl:20][C:21]1[C:26]([C:27](=[O:36])[C:28](=[N:34][NH2:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][C:24]([I:37])=[CH:23][N:22]=1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(I)cnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(=NN)C(=O)c1cc(I)cnc1Cl
Reaction time: 18 h
Yield: 70.8 %

Procedure:
Triphenylphosphine(1.95 g) is added in one portion to a solution of ethyl 3-(2-chloro-5-iodo-3-pyridinyl)-2-diazo-3-oxopropanoate (Preparation 19, 2.57 g) in diisopropyl ether (25 mL) and chloroform (15 mL) at room temperature. The yellow solution is stirred under nitrogen for 18 h. The mixture is then treated with water (0.125 mL), heated to reflux for 2 h, and then stirred overnight at room temperature. The mixture is filtered, and the solids are washed with hexane and dried to give 1.83 g of the title compound. After concentration, the filtrate is purified by flash chromatography on silica gel eluted with 10% ethyl acetate/hexane to provide an additional 0.36 g to yield a combined total of 2.19 g (85%) of the title compound as a pale yellow solid. Physical characteristics: 1H NMR (300 MHz, CDCl3) δ1.39, 1.63, 4.38, 7.94, 8.63; IR (drift) 3378, 3182, 1675, 1651, 1568, 1564, 1483, 1324, 1303, 1286, 1199, 923, 770, 664, 620 cm1; MS (ESI+) m/z 382 (M+H)+. Anal. Found: C, 31.78; H, 2.43; N, 10.91; Cl, 9.63.
Reaction SMILES: C([O:5][P:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:16]=1)[F:14])(=[O:12])[O:7]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:17]2[CH:16]=[C:15]([CH:13]([P:6](=[O:5])([OH:7])[OH:12])[F:14])[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=P(O)(O)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.5 %

Procedure:
The above fluoromethylphosphonic acid di-tert-butyl ester (1.29 g, 2.7 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and a solid was formed in the aqueous phase. This was filtered off and dried in vacuo at 50° C. affording 55 mg (6%) of the title compound as a solid,
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23][O:24][C:25]2[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19]1.CCN(CC)CC>C(OCC)C.ClCCl>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:1]2[C:2](=[O:3])[O:33][C:32](=[O:34])[C:31]=2[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:23][C@@H:21]3[CH2:20][O:19][C:18]([CH3:35])([CH3:17])[O:22]3)[CH:26]=2)=[CH:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccccc21
Reactant: CC1(C)OC[C@@H](COc2cccc(CC(=O)O)c2)O1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=C(c3cccc(OC[C@@H]4COC(C)(C)O4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Oxalyl chloride (1.05 eq., 4.15 mL) was added dropwise to a solution of N-methylindole (5.8 mL, 50 mmol) in diethyl ether (395 mL) at 0° C. Yellow precipitates were formed. After the completion of the addition, the reaction mixture was stirred at 0° C. for 30 min., and then the volatiles were removed under vacuo. The residue was re-dissolved in dichloromethane (375 mL) and added to a solution of 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetic acid (13.3 g, 50 mmol) and Et3N (12.5 mL, 2.2eq.) in dichloromethane (375 mL) at 0° C. The resulting mixture was stirred at 0° C. and then allowed to warmed up slowly to room temperature. After stirring overnight, the volatiles were removed and the residue was purified on a silica gel column with dichloromethane to give 3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]furan-2,5-dione (5.4 g, 27% yield).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:24]5[N:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=5)[CH2:19][CH2:18]4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(Oc3ccc4c(c3)CCN(C3CCC3)CC4)CC2)nc1
Temperature: 180 °C

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (60 mg, 0.2 mmol), 6-chloronicotinonitrile (31 mg, 0.22 mmol) and triethylamine (0.03 ml, 0.22 mmol) were dissolved in acetonitrile (2 ml) and heated to 180° C. in a microwave reactor for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) to afford the title compound (E160); MS (ES+) m/e 403 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Yield: 89.4 %

Procedure:
A solution of (R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid (2.2 g, 7.5 mmol) and 5%Rh/C (0.22 g) in methanol (220 ml) was stirred at room temperature, under hydrogen (150p.s.i.) for 24 hours and then filtered through celite. The filtrate was concentrated in vacuo to leave the title compound as an oil (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:11]=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:6]=2[CH:19]=1.[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[C:12]([CH3:18])=[CH:11][C:10]([C:7]2[C:6]3[CH:19]=[C:2]([N:1]=[C:20]=[O:21])[CH:3]=[CH:4][C:5]=3[S:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc3ccc(N=C=O)cc23)cc1C
Yield: 98.2 %

Procedure:
A solution of 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole (157 g, 0.581 mol) in toluene is treated with phosgene (1,074 mL of a 20% solution in toluene, 2.06 mol), heated to and stirred at reflux for 5 hours, treated with additional phosgene (100 mL of a 20% solution in toluene), refluxed overnight, and concentrated in-vacuo to give the title product as a yellow-orange solid (169 g, 98.2%) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[CH:52]1[CH:53]=[CH:54]C2N(O)N=[N:58][C:56]=2[CH:57]=1.C(N(C(C)C)CC)(C)C.[C:71](=O)([O-])[OH:72].[Na+]>CN(C=O)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:58]3[CH2:54][CH2:53][CH:52]([O:72][CH3:71])[CH2:57][CH2:56]3)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC(OC)CC2)CN(C(=O)OC(C)(C)C)C1

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (95 mg), WSC.HCl (50 mg), HOBt (34 g) and diisopropylethylamine (0.088 ml) in DMF (5 ml) was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give an amorphous solid (65 mg).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C=Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Product: C=Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 44 %

Procedure:
2-Chloro-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 2-(piperazin-1-yl)-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde (44% yield) as a yellow solid. ESI/MS 332 (M+H), RT 2.57 min; NMR (CDCl3) 10.29 (1H, s); 8.28 (1H, d, J=6 Hz); 7.62 (2H, d, J=6 Hz); 7.38 (4H, m); 7.00 (1H, d, J=9 Hz); 6.85 (1H, dd); 5.89 (1H, d, J=15 Hz); 5.42 (1H, d, J=18 Hz); 3.38 (4H, m); 2.77 (4H, m).
Reaction SMILES: [C:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]>CCO.[Ni]>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH2:1][NH2:2])[CH2:8][CH3:9]
Reactant: CCC(C#N)C(=O)OC
Agent: [Ni]
Solvent: CCO
Product: CCC(CN)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of Raney-Ni (1.9 g, 50% in H2O, rinsed 3 times with EtOH before use) in EtOH (20 mL) was added methyl 2-cyanobutanoate (200 mg, 1.57 mmol). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. The liquid was then carefully decanted into another flask and the metal was washed twice with EtOH. The combined EtOH solution was concentrated in vacuo to give the title compound in 200 mg, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH2:14][O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[C:13]2[CH2:12][C:11]3C(=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.Cl[CH2:30]Cl>>[CH:10]1[C:11]2[CH:14]([O:15][C:16](=[O:17])[N:18]([CH3:30])[C:19]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([Br:21])=[CH:23][CH:24]=3)=[S:20])[C:1]3[C:13](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2
Reactant: Nc1ccc(Br)cc1
Reactant: ClCCl
Product: CN(C(=O)OC1c2ccccc2-c2ccccc21)C(=S)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
A solution of fluorenylmethyloxycarbonyl isothiocyanate (1.36 g, 4.84 mmol, Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998, 63, 196-200) in dichloromethane (40 mL) was added via a pipet to a solution of 4-bromoaniline (0.86 g, 5.00 mmol) in dichloromethane (10 mL) maintained at 0° C. and the resulting mixture stirred at ambient temperature for 14 h. The reaction was diluted with dichloromethane (60 mL) and washed with aqueous hydrochloric acid (0.5 M, 2×10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated to afford the 9H-9-fluorenyl-methyl-N-[(4-bromoanilino)carbothioyl]carbamate (2.25 g, 4.97 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 14.25 min.
Reaction SMILES: Cl.[CH:2]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:24]([O:33][CH3:34])[N:23]=3)=[CH:15]\[C@@H:16]3[NH:20][C:19](=[O:21])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH:2]1([S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][NH:31][CH:32]=4)=[C:24]([O:33][CH3:34])[N:23]=3)[CH2:15][C@@H:16]3[NH:20][C:19](=[O:21])[CH2:18][CH2:17]3)=[CH:12][CH:13]=2)(=[O:6])=[O:7])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1-c1cn[nH]c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10% palladium-activated carbon (175 mg) and concentrated hydrochloric acid (1 mL) were added to a solution of (5R)-5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}pyrrolidin-2-one obtained in Example 4-376(1) (175 mg) in methanol (3 mL) in a hydrogen gas stream, and the mixture was stirred at room temperature for five hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of (5R)-5-{2-[4-(cyclopropylsulfonyl)phenyl]-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethyl}pyrrolidin-2-one as a colorless amorphous (129 mg, 73%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8]C2C=CC=CC=2N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:18]([CH2:21][CH3:22])CC)C.[F:23][CH:24]([F:34])[O:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:31](Cl)=[O:32].O>C1(C)C=CC=CC=1>[C:1]1([CH:7]=[CH:8][C:27]2([C:31]([NH:18][C:21]3[CH:22]=[CH:3][CH:2]=[CH:1][CH:6]=3)=[O:32])[CH:26]([O:25][CH:24]([F:34])[F:23])[CH:30]=[CH:29][S:28]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1C=Cc1ccccc1
Reactant: O=C(Cl)c1sccc1OC(F)F
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)C1(C=Cc2ccccc2)SC=CC1OC(F)F
Temperature: 50 °C
Yield: 189.2 %

Procedure:
At room temperature, a solution of 0.3 g (0.0015 mol) of 2-(2-phenyl-ethen-1-yl)-aniline in 2 ml of toluene is admixed with a solution of 0.15 g (0.0015 mol) of triethylamine in 10 ml of toluene. At room temperature, 0.33 g (0.0015 mol) of 3-difluoromethoxy-thiophene-2-carbonyl chloride are added to this mixture with stirring. The mixture is subsequently heated to 50° C. and stirred at this temperature for 2 hours. For work-up, the reaction mixture is then cooled to room temperature and admixed with water. The organic phase is separated off, dried over sodium sulphate and then concentrated under reduced pressure at 60° C. The residue that remains is chromatographed over silica gel using diethyl ether. Concentration of the eluate gives 0.53 g (95% of theory) of 2-(2-phenyl-ethen-1-yl)-3-difluoromethoxy-thiophene-2-carboxanilide in the form of a solid substance of melting point 80 to 82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[CH:12]=[C:11]([N:22]3[CH2:25][CH2:24][CH2:23]3)[N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:21][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:12]=[C:11]([N:22]3[CH2:23][CH2:24][CH2:25]3)[N:10]=[C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:29]4[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=4)=[CH:3][CH:4]=3)[N:14]=2)[NH:20][N:19]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccc(Sc3nc(Nc4cc(C)n[nH]4)cc(N4CCC4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
2-(4-Aminophenylthio)-6-(azetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.57 mmol) was taken up in pyridine (2 mL) and p-toluoyl chloride (0.187 mL, 1.42 mmol) was added dropwise at room temperature. After 15 minutes the reaction mixture was concentrated in vacuo and the residue taken up in methanol (3 mL). Sodium methoxide (25% w/w solution in MeOH, 1 mL) was added and the resulting cloudy solution stirred at room temperature for 15 minutes. The reaction mixture was purified directly by chromatography (silica, 5-100% EtOAc-petrol gradient elution) to give the title compound (91 mg, 34%) as a white solid. 1H NMR: (400 MHz, DMSO) 1.99 (3H, brs), 2.33 (2H, qn), 2.40 (3H, s), 3.88 (4H, t), 5.38 (1H, brs), 5.59 (1H, vbrs), 7.36 (2H, d), 7.53 (2H, d), 7.87 (2H, d), 7:91 (2H, d), 9.20 (1H, brs), 10.36 (1H, s), 11.66 (1H, brs); MS (ES+) 472.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(OCC)(=O)C>C(O)(=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1O
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccccc3o2)cc1
Yield: 6.9 %

Procedure:
In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0 eq.), a solution including 2-aminophenol (1.0 eq.) and 4-methoxybenzaldehyde (1.0 eq.) was refluxed. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and acetone (25:1) to obtain a solid Compound 124.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=[N:27][C:26]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=3[CH3:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(-c2ccc(OC)c(OC)c2)cc(=S)n(C)c1=O
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CI
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 37 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.59 g) in tetrahydrofuran (50 ml) was added methyl iodide (10 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (2 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.29 g); mp 57°-61° C. Thus obtained compound was recrystallized from a mixture of ethanol and water (3:1) to give the desired compound as crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]5)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3[nH]c(=O)ccc3c2)C1=O
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2ccc3[nH]c(=O)ccc3c2)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetic acid (compound aa3-3) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]ethyl]acetate (compound ap1-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].I[C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C1COCC1.CCOCC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[CH3:2]
Reactant: Oc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC)cc2n1CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCn1c(-c2cccc(O)c2)c(C#N)c2ccc(OC)cc21
Temperature: 65 °C
Yield: 71.8 %

Procedure:
1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, was combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)2Cl2 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture was heated at 65° C. overnight. The reaction mixture was diluted in EtOAc, and was filtered through celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (4:1, CH2Cl2/EtOAc) to yield crude product. Ether trituration yielded 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.