Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](=[N:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=1)[NH:4][C:5](=O)[CH2:6][C@@H:7]([O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8].[NH:40]([C:42]1[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=1)[NH2:41]>CN(C=O)C.[Hg](Cl)Cl>[CH3:24][C:23]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][C@@H:7]([CH3:8])[CH2:6][C:5]1[N:40]([C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)[N:41]=[C:3]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=2)[N:4]=1)([CH3:26])[CH3:25]
Reactant: CSC(=Nc1ccc(F)c(C(F)(F)F)c1)NC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1cc(NN)ccn1
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc(Nc3ccc(F)c(C(F)(F)F)c3)nc2C[C@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccn1
Temperature: 80 °C

Procedure:
Mercury(II) chloride (1.8 g, 6.5 mmol) was added to a stirred solution of intermediate D9 (prepared according to Description 9) (3.8 g, 6.5 mmol) and 4-hydrazino-2-methylpyridine (0.8 g, 6.5 mmol) in DMF (65 mL) at room temperature. The reaction mixture was heated at 80° C. for 140 min. The cooled reaction mixture was poured onto ice and the precipitated product was collected by filtration to give a yellow semi-solid. Yield: 4.2 g of intermediate D14 (101.2%).
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.[C:23]1([CH:29](C)[CH2:30][C:31](O)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:35]CN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>C(#N)C>[C:23]1([CH2:29][CH2:30][CH2:31][CH2:35][NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:10]3[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=3)=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(CC(=O)O)c1ccccc1
Reactant: Cc1ccc(C)n1-c1cccc(-c2ccc(CCN)cc2)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cccc(-c2ccc(CCNCCCCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 200 mg (0.687 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine (Example 100D), 113 mg (0.687 mmol) 3-phenylbutyric acid, 132 mg (0.687 mmol) EDAC, 10 mg N-hydroxybenzotriazole, 5 mL dry acetonitrile, and 211 uL (1.51 mmol) triethylamine. The reaction was stirred at room temperature for 12 h, poured into dilute aqueous citrate solution, and extracted into ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The resulting yellow oil, 300 mg (100%) was used directly.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[C:40](=O)([O:51][CH2:52][C:53]1[S:57][CH:56]=[N:55][CH:54]=1)[O:41]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C>C(OCC)(=O)C>[S:57]1[C:53]([CH2:52][O:51][C:40]([N:13]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:9])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:41])=[CH:54][N:55]=[CH:56]1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(=O)OCc1cncs1)OCc1cncs1
Reaction time: 18 h
Yield: 35.8 %

Procedure:
The product from Example 35 (30 mg, 0.053 mmol) in ethyl acetate (2 mL) was treated with a solution of 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (18 mg, 0.058 mmol) by extraction with aqueous NaHCO3], triethylamine (15 μl, 0.106 mmol), and N,N-dimethylaminopyridine (6 mg, 0.053 mmol) at ambient temperature. After stirring for 18 hours, the mixture was washed with aqueous 10% K2CO3 (5×2 mL), brine (2 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purify on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (13.4 mg, 36%). 1H NMR (CDCl3) δ 8.80-8.68 (m, 3H), 7.81 (m, 3H), 7.31-6.96 (m, 10H), 5.27-5.05 (m, 6H), 4.04-3.25 (m, 5H), 3.11-2.98 (m, 2H), 2.89-2.56 (m, 5H); MS (ESI+) m/z 707 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18].O>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=[N:2]1)[CH2:17][CH3:18].[CH2:16]([N:2]1[CH:3]=[C:4]2[C:5]([N:6]=[C:7]3[S:13][CH2:12][CH2:11][N:8]3[C:9]2=[O:10])=[N:1]1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: O=c1c2cn[nH]c2nc2n1CCS2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cc2c(=O)n3c(nc2n1)SCC3
Product: CCCn1ncc2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %
Yield: 64 %

Procedure:
In 50 ml of dimethylformamide was dissolved 2.50 g (12.9 mmol) of Compound 1 prepared in Example 1, and 0.93 g (23.3 mmol) of sodium hydride. (60%) and 3.77 ml (38.6 mmol) of propyl iodide were added to the solution, followed by stirring at room temperature for one hour. After addition of water and evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1). The first and second main fractions gave 1.95 g (64%) of Compound 28 and 0.75 g (25%) of Compound 29, respectively. Each compound was recrystallized from ethanol for purification.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][C:10]2=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1CNCCN1Cc1ccccc1

Procedure:
A mixture of 1,4-bis(phenylmethyl)piperazinone hydrochloride (XIII, Example 39, 15.0 g.) and 10% palladium charcoal (5.0 g.) in ethanol (200 ml.) is hydrogenated (50 lb. initial hydrogen pressure) until uptake of hydrogen ceased. The solution is filtered, the ethanol is removed under reduced pressure and the residual solid is recrystallized from methanol-isopropanol to give the title compound, m.p. 160°-161°.
Reaction SMILES: C1(N2C(=O)C3S[CH:15]=[C:16]([C:17]4C=CC=CC=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C(N)C(C)C>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:8][N:9]([CH2:10][CH:16]([CH3:17])[CH3:15])[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(C)CN
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 83.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), isobutylamine (0.076 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 101 mg (0.33 mmol, 83.5% yield) of the title compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O>[N:8]1([C:4]2[CH2:5][CH2:6][S:1][CH2:2][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: O=C1CCSCC1
Solvent: O
Solvent: c1ccccc1
Product: C1=C(N2CCCC2)CCSC1

Procedure:
A solution of 103 g (0.89 mole) of tetrahydrothiopyran-4-one, 95 g (1.33 moles) of pyrrolidine, and one l. of anhydrous benzene is heated under reflux in a nitrogen atmosphere for 2 hours until the theoretical amount of water has collected in a Dean-Stark trap. The solvent is distilled, and the residue is fractionated under reduced pressure to provide 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran as a colorless liquid, b.p. 124° (0.01 mm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=C(C#N)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[K+].Cl.[CH2:28]([OH:31])[CH2:29]O>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:29]([C:28]([OH:31])=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCn1c(C)nc2cc(C#N)cc(OCc3ccccc3)c21
Reactant: OCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carbonitrile (549 mg, 1.71 mmol, Step 4) and potassium hydroxide (85%, 564 mg, 8.54 mmol) in ethylene glycol (10 mL) was stirred at 135° C. for 5 hours. After cooling to room temperature, 2 mol/L hydrochloric acid was added until pH of the solution became about 3. The formed precipitate was collected by filtration to afford the title compound as a gray solid (530 mg, 91%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.C(S(N1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=O)=O)CC.C(N(CC)C(C)C)(C)C.CN([CH:50]=[O:51])C>CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][CH2:50][O:51][CH2:33][CH2:34]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CCCS(=O)(=O)N1CCNCC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCOCC3)n2n1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 1-(propylsulfonyl)piperazine hydrochloride (144 mg, 0.75 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (111.6 mg, 89%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.15 (s, 1H), 6.16 (s, 1H), 4.27 (t, J=4.9 Hz, 2H), 4.00 (t, J=6.2 Hz, 2H), 3.79-3.85 (m, 2H), 3.72-3.78 (m, 2H), 2.36 (s, 3H), 2.05 (quin, J=5.8 Hz, 2H), 1.46 (s, 6H); ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:26](Cl)(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:13]([N:25]([CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4])[C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
Preparation from D-mannose, dodecylamine and stearoyl chloride in analogy to Example 11.
Reaction SMILES: C[C:2]1([CH3:26])[O:6][C:5](=[O:7])/[C:4](=[C:8](\[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=O)=O)=[CH:11][CH:10]=2)/[CH2:3]1.Cl[C:28]1C=C(/C(=C2\C(=O)OCC\2)/C2C=CC(S(C)(=O)=O)=CC=2)C=CC=1>>[CH2:26]([CH:2]1[O:6][C:5](=[O:7])[C:4](=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:12]([S:15][CH3:18])=[CH:13][CH:14]=2)[CH2:3]1)[CH3:28]
Reactant: CC1(C)C/C(=C(/c2ccc(F)cc2)c2ccc(S(C)(=O)=O)cc2)C(=O)O1
Reactant: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(Cl)c2)cc1
Product: CCC1CC(=C(c2ccc(F)cc2)c2ccc(SC)cc2)C(=O)O1

Procedure:
Prepared by the procedure of Example 4 from the derivative of Example 32. The mixture of the two isomers, (E) and (Z), is used as such in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20]CC)=[O:19])[CH:14]=1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([OH:20])=[O:19])[CH:14]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2nc3ccccc3o2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.482 g, 1.23 mmol) in THF/H2O (20 mL:10 mL) was added lithium hydroxide (0.295 g, 12.3 mmol, 10 eq). The mixture was allowed to stir at RT overnight. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.420 g, 94% yield) as a white solid. LC-MS M+H+364.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5](=O)[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=1.P(Cl)(Cl)([Cl:21])=O>ClCCl>[Cl:21][C:5]1[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reaction time: 18 h

Procedure:
A stirred suspension of 2-chloromethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (1.5 g, 5.42 mmol) and phosphoryl chloride (23 ml) was heated under reflux for 7 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100 ml) and then washed with water (2×100 ml) followed by saturated sodium hydrogen carbonate solution (100 ml). The organic extract was dried (MgSO4) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d]pyrimidine as a pale-yellow solid (1.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[CH3:14].[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)(C)C>[C:13]([C:12]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:18]([C:17]([O:23][CH3:24])=[O:22])=[C:19]([CH3:21])[NH:10][C:11]=1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)C=C(C)N
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(Cl)cc1

Procedure:
5.64 g (40 mmol) of 4-chlorobenzaldehyde, 4.0 g (40 mmol) of 4-aminopent-3-en-2-one and 4.6 g (40 mmol) of methyl acetoacetate are heated to reflux for 12 h in 100 ml of isopropanol. The reaction mixture is allowed to cool and is concentrated. 1.85 g of the title compound crystallize from Et2O.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:11])[CH:9]=O.[CH3:12][N:13]([CH3:18])/[CH:14]=[CH:15]/[C:16]#[N:17].O.O.[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23]>ClCCCl.CC(O)C>[C:21]([O-:26])(=[O:25])[C:22]([O-:24])=[O:23].[C:16]([C:15](=[CH:14][N:13]([CH3:18])[CH3:12])[CH:9]=[N+:8]([CH3:11])[CH3:7])#[N:17].[C:16]([C:15](=[CH:14][N:13]([CH3:18])[CH3:12])[CH:9]=[N+:8]([CH3:11])[CH3:7])#[N:17]
Reactant: CN(C)/C=C/C#N
Reactant: O=C(O)C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: O
Solvent: CC(C)O
Product: CN(C)C=C(C#N)C=[N+](C)C
Product: O=C([O-])C(=O)[O-]
Reaction time: 0.75 h
Yield: 97.2 %

Procedure:
A solution of oxalyl chloride (13.1 mL, 0.15 mol) in 1,2-dichloroethane is added dropwise to a solution of N,N-dimethylformamide (11.6 mL, 0.15 mol) in 1,2-dichloroethane while maintaining the reaction mixture temperature below 0° C. The reaction mixture is stirred for 45 minutes, treated with a solution of trans-3-dimethylaminoacrylonitrile (16.4 mL, 0.15 mol) in 1,2-dichloroethane, stirred at room temperature for 16 hours, refluxed for two hours and concentrated in vacuo to obtain a semi-solid residue. A solution of the residue in 2-propanol is treated with a solution of oxalic acid dihydrate (18.9 g, 0.15 mol) in 2-propanol and warmed until a clear solution is obtained. The clear solution is cooled to and held at room temperature for several hours, cooled in a freezer for two hours and filtered. The filter cake is washed sequentially with 2-propanol and ether and dried in a vacuum desiccator at 50° to give the title product (28.6 g, 79%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].F[C:10]1[CH:11]=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[C:14]([NH2:16])[CH:15]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[C:14]([NH2:16])[CH:15]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
A mixture of 1-ethyl-piperazine (1.2 mL, 9.6 mmol), 5-fluoro-2-nitro-phenylamine (1 g, 6.4 mmol), DIPEA (1.24 g, 9.6 mmol) in DMF (15 mL) was heated at 80° C. overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extract was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by flash chromatography on silica to afford the title compound (1 g, yield: 63%). ESI-MS: 251 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl.FC1C=CC(C(Cl)=O)=CC=1.N1C=CC=CC=1>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a suspension of 30.0 gm (0.217 mole) 4-nitroaniline in 225 mL dichloromethane were added 17.57 mL (0.217 mole) pyridine. The suspension was cooled to 0° C. and then 25.66 mL (0.217 mole) 4-fluorobenzoyl chloride were added slowly. Within 15 minutes the reaction mixture became homogeneous and was allowed to warm to room temperature. After an hour an additional 2.56 mL (21.7 mMol) 4-fluorobenzoyl chloride and 1.75 mL (21.7 mMol) pyridine were added and the reaction continued at room temperature for an additional hour. The reaction mixture was then washed with 200 mL water at which point a precipitate formed. The solid was filtered, washed with 100 mL hexane, washed with 200 mL water and dried under reduced pressure at 60° C. to give 56.6 gm (100%) of the desired compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.O>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:24]1
Reactant: COc1ccc(C(C)C)cc1CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)C)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
Phenylsulfonyl chloride (0.24 ml) was added to a solution of the product from step (b) (396 ml) and triethylamine (0.44 ml) in dichloromethane (3 ml) and the mixture was stirred for 3 h. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4), evaporated in vacuo and purified by chromatography (silica, petrol—ether as eluent) to give the sub-title compound (431 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
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: C1COCCO1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 4-methoxyphenylboronic acid (185 mg, 1.2 mmol), Na2CO3 (256 mg, 3.04 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (117 mg, 0.1 mmol) was added. Stirring was continued at 80° C. for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (30 mg, 7%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.20-8.01 (m, 2H), 7.87-7.62 (m, 2H), 7.61-7.51 (m, 2H), 7.38-7.30 (m, 2H), 7.16-7.09 (m, 2H), 6.91 6.80 (m, 4H), 5.96 (bs, 1H), 5.39 (s, 2H), 3.81 (s, 3H), 1.43 (s, 6H). MS: M+H: m/z=451.2 and HPLC: 94%, (Condition-I).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[CH2:10]([N:12](CC)CC)C.CN>ClCCl.C1COCC1>[CH3:10][NH:12][C:7]([C:5]1[N:6]=[C:2]([Cl:1])[S:3][CH:4]=1)=[O:8]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1csc(Cl)n1
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1csc(Cl)n1

Procedure:
To 445 mg (2.44 mmol) 2-chloro-thiazole-4-carbonyl chloride in 8.0 mL dichloromethane is added a mixture of 0.38 mL (2.69 mmol) triethylamine and 1.35 mL (2.69 mmol) 2 molars solution of methylamine in THF. The mixture is stirred over night, concentrated and the residue is treated with water and NaHCO3 solution. After extraction with ethylacetate the organic phases are combined, dried (Na2SO4) and concentrated to yield the desired product