Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.O1CCCC1.Cl.[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[CH:42][C:41]=1[C:53]([F:56])([F:55])[F:54])([O-:39])=[O:38]>CN(C)C=O.ClCCl>[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][CH:47]2[CH2:48][CH2:49][N:50]([C:17](=[O:19])[CH2:16][O:15][CH:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:1])[F:20])=[CH:4][CH:5]=4)[CH2:10][CH2:11]3)[CH2:51][CH2:52]2)=[CH:42][C:41]=1[C:53]([F:56])([F:54])[F:55])([O-:39])=[O:38]
Reactant: O=C(O)COC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(COC1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 59 %

Procedure:
[1-(4-Trifluoromethyl-phenyl)-piperidin-4-yloxy]-acetic acid (186 mg; 0.61 mmol, prepared according to Example 11), diisopropylethyl amine (220 μL; 1.22 mmol) and tetramethyl-β-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (232 mg; 0.61 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (18 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (200 mg; 0.61 mmol, prepared in accordance with Example 8) in dimethylformamide (6 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (50 mL), the organic layer is sequentially washed with water (15 mL), aq. sat. sodium hydrogen carbonate (15 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The desired product (209 mg; 0.36 mmol) is isolated in pure form following purification by column chromatography on silica gel (dichloromethane:methanol from 100:0 to 95:5). The structure was confirmed using Protocol II-E. Calculated mass=575; observed mass=576; HPLC retention time=11.52 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]([CH2:38][CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][N:30]([CH2:38][CH3:39])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CCCl)c1cccc(C)c1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCOc1ccc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1OC)c1cccc(C)c1
Temperature: 75 °C
Yield: 42 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added N-(2-chloroethyl)-N-ethyl-3-methylaniline (99 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (58 mg, 42%). 1H NMR (DMSO-D6) δ 1.13 (3H, t, J=7.0 Hz), 2.24 (3H, s), 3.45 (2H, q, J=7.0 Hz), 3.70 (2H, d, J=5.8 Hz), 3.79 (3H, s), 4.16 (2H, d, J=5.8 Hz), 6.43 (1H, t, J=7.3 Hz), 6.57 (2H, m), 7.02-7.20 (4H, m), 7.60 (2H, d, J=8.6 Hz), 7.96 (3H, m), 8.39 (1H, s). LCMS m/z=546 (m+H+).
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[H-].[Na+].Cl[CH2:11][CH2:12][CH2:13][OH:14]>CN(C=O)C>[OH:14][CH2:13][CH2:12][CH2:11][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]=[O:2]
Reactant: O=Cc1ccc[nH]1
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccn1CCCO
Yield: 91.9 %

Procedure:
The starting material may be prepared as follows. A solution of 2-formylpyrrole (1.0 g.) and a 50% w/w dispersion of sodium hydride in oil (0.72 g.) in DMF (20 ml.) was treated with 3-chloropropanol (1.03 g.) and the mixture heated at 90° for 18 hours and then evaporated to dryness. The residue was partitioned between water and ether, and the ether phase was dried and evaporated to dryness to give 1-(3-hydroxypropyl)-2-formylpyrrole (1.48 g.) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7](Br)=[CH:6][CH:5]=2.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1

Procedure:
3-(2-Methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXVII (1.25 g, 57%) was prepared from 2-methyl-5-bromoindole using the procedure described above for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (see Example 14).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[S:24][C:23]3[C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:21][C:20]([C:31]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:32]=4[CH:33]=[CH:34][NH:35]5)=[N:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>>[NH:35]1[C:36]2[C:32](=[C:31]([C:20]3[N:21]=[C:22]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[C:23]4[S:24][C:16]([CH2:15][N:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)=[CH:17][C:18]=4[N:19]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c2cc[nH]c2c1

Procedure:
Via ethereal HCl-mediated BOC-group cleavage of 4-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2](=[NH:1])[N:3]([CH3:19])[C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=N)c(F)cn(S(=O)(=O)c2ccccc2)c1=O
Temperature: 60 °C
Yield: 50.6 %

Procedure:
4-Amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidine-2-one (200 mg, 0.74 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 1.5 mmol). Iodomethane (210 mg, 1.5 mmol) was added and the mixture was heated at 60° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water. The organic phase was dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by chromatography on silica gel (gradient, 20 to 80% EtOAc in petroleum ether) to isolate 1-benzenesulfonyl-5-fluoro-4-imino-3-methyl-3,4-dihydro-1H-pyrimidin-2-one (106 mg, 50%) as a white solid: mp 144° C.; 1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.03-8.00 (m, 2H), 7.97 (d, J=5.9 Hz, 1H), 7.80-7.76 (m, 1H), 7.67-7.63 (m, 2H), 3.09 (s, 3H); ESIMS m/z 284 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(C)C(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using isobutyryl chloride (58 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylpropanamide (0.026 g).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:26][CH2:25]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCC1CC1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 46.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (158 mg, yield: 46.4%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1.[H-].[Na+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:22]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)nc(NCCCCN(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(CCCCN(C)C)C(=O)N(C)C)c1
Reaction time: 2 h

Procedure:
To 2-(4-dimethylaminobutylamino)-4,6-dimethylpyridine (3.7 g. 0.00168 mole) dissolved in toluene (150 ml) is added sodium hydride in mineral oil (50%) (0.96 g., 0.002 mole. The mixture is refluxed with stirring under nitrogen for 31/2 hours, cooled to 35°, and dimethylcarbamoyl chloride (2.15 g., 0.002 mole) in toluene (25 ml) is added. The mixture is then refluxed for 18 hours, cooled and extracted with dilute hydrochloric acid. The aqueous extracts are made alkaline with 10 N sodium hydroxide and extracted with diethyl ether then methylene chloride. The combined organic extracts are washed with brine, dried (sodium sulfate) and concentrated under vacuum. The residue is taken up in diethyl ether, filtered from insoluble matter and the filtrate concentrated. The residue is distilled and the product, a hygroscopic oil, is collected at 138°-141°/0.3 mm.
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C:15](=[CH2:17])[S:14]/[C:13]/3=[N:18]\[C:19](N3C=C[N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH3:28][CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[F:27][C:3]1([F:2])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C:15](=[CH2:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:30]3[CH2:31][CH2:32][CH2:33][CH:29]3[CH3:28])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2cc[n+](C)c2)S1
Reactant: CC1CCCN1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)N2CCCC2C)S1
Temperature: 60 °C

Procedure:
To a solution of 1-({[(2Z)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-methylene-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (Example 116, 0.1 g, 0.19 mmol) and 2-methylpyrrolidine (0.018 g, 0.19 mmol) in anhydrous acetonitrile (5 mL) was added Hunig's base (0.025 g), and then the solution was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction was diluted with 50 mL of CH2Cl2, washed water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was choromatographed over silica using CH2Cl2 to give the titled compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:18][C:17]2=[O:31])=[N:13][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:18][C:17]2=[O:31])=[N:13][CH:14]=1
Reactant: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=CCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Yield: 69.1 %

Procedure:
Compound B (0.5 g) and NaOH (0.5 g) were dissolved in 100 mL of methanol. The mixture was hydrogenated in the presence of 0.5 g of palladium/charcoal under 1 atmospheric pressure. After the completion of the reaction as monitored by TLC, the catalyst was removed by filtration and the filtrate was evaporated in vacuo to produce a residue, which was dissolved with 50 mL of water. The obtained aqueous solution was adjusted to PH=7. A precipitate was formed and collected to give a 0.27 g (70%) of 3-[(5-hydroxypyrid-in-2-yl)methylidene]-6-(benzylmethylidene)piperazine-2,5-dione (Compound C). 1H-NMR (400 MHz, CDCl3): 6.758 (s, 1H), 7.087 (s, 1H), 7.290-7.580 (m, 7H, aromatic), 8.328 (s, 1H), and 12.289 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH2:23][CH2:24][C@@H:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:11])=[O:10].[CH2:32]([N:34]([CH2:51][CH3:52])[CH2:35]/[CH:36]=[CH:37]\[Sn](CCCC)(CCCC)CCCC)[CH3:33]>O1CCOCC1.CS(C)=O>[CH2:32]([N:34]([CH2:51][CH3:52])[CH2:35]/[CH:36]=[CH:37]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH2:23][CH2:24][C@@H:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:11])=[O:10])[CH3:33]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCN21
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC(C)(C)C)OC[C@H]1CCN21
Temperature: 95 °C
Reaction time: 17 h
Yield: 26.2 %

Procedure:
A mixture of tert-butyl (R)-6-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 43, 0.061 g) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.096 g) in dioxane (3 mL) and DMSO (0.3 mL) was purged with nitrogen and tris-(dibenzylideneacetone)dipalladium (0) (0.006 g) and tri-tert-butylphosphonium tetrafluoroborate (0.004 g) were added. The reaction mixture was heated at 95° C., under an atmosphere of nitrogen for 1.5 hours. Further N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.096 g), tris-(dibenzylidene-acetone)dipalladium (0) (0.006 g) and tri-tert-butylphosphonium tetrafluoroborate (0.004 g) were added and heating was continued for a further 17 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give tert-butyl (R)-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (0.017 g) as a light brown foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]([C:15]([OH:17])=[O:16])[CH2:10][CH2:9][CH2:8][C:7]2=1>C1(C(C)C)C=CC=CC=1.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=[CH:8][C:7]2=1
Reactant: Cc1cccc2c3c([nH]c12)C(C(=O)O)CCC3
Agent: [Pd]
Solvent: CC(C)c1ccccc1
Product: Cc1cccc2c1[nH]c1c(C(=O)O)cccc12
Yield: 75 %

Procedure:
The ethyl ester of 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid is dissolved in cumene and, after adding 10% palladium-carbon, dehydrogenated as set forth in Example 1(b). After recrystallization from methanol, the ethyl ester of 8-methylcarbazole-1-carboxylic acid is obtained in a 75% yield, m.p. 68° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.[O:18]=[C:19]1[N:23](CO)[C:22](=[O:26])[CH2:21][N:20]1[CH2:27][C:28]#[CH:29]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:12]([CH:13]([CH3:14])[CH3:15])[C:11]([O:10][CH2:9][N:23]2[C:22](=[O:26])[CH2:21][N:20]([CH2:27][C:28]#[CH:29])[C:19]2=[O:18])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2C(=O)OC(=O)C2C(C)C)cc1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C)cc2)C(C)C)C1=O

Procedure:
Following the above procedure, 3-(4-methylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-methylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:18]1=[O:33])[CH3:16].[H-].[Na+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=4[N:4]=3)=[CH:30][CH:31]=2)[C:18]1=[O:33])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4c(n3C)CCCC4)cc2)c2ncccc21
Yield: 5.8 %

Procedure:
1-Methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (84 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (18.8 mg) (60% in mineral oil) in DMA (3 ml) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 120° C. set by IR sensor, fixed hold time: on, Absorption level: High) for 1 h in a Biotage Initiator 60EXP. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-100% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8.90 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[C:3]=12.[Cl:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([S:26]([NH:29][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[S:8][CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C:3]=23)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(-c2csc3nccc(Cl)c23)c1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cccc(-c2csc3nccc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 150 °C
Yield: 46 %

Procedure:
A mixture of 4-chloro-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine (Description 43) (100 mg, 0.363 mmol), 3-chlorobenzensulfonamide (90 mg, 0.471 mmol), palladium(II) acetate (8.14 mg, 0.036 mmol), xantphos (42.0 mg, 0.073 mmol), and Cs2CO3 (236 mg, 0.725 mmol) in 1,4-dioxane (3.6 mL) was degassed with nitrogen for 5 min. The mixture was heated at 150° C. for 45 min in a microwave and then poured into water (50 mL) and extracted with DCM (30 mL×4). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethanol in toluene, followed by further purification by MDAP (basic conditions), to give the title compound (72 mg). LCMS (A) m/z: 431 [M+1]+, Rt 1.34 min (acidic).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].P(Cl)(Cl)([Cl:33])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([Cl:33])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(O)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
Into a solution of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4,6-dihydroxypyrimidin-2-yl]piperidine-1-carboxylate (45 g, 105.02 mmol, 1.00 equiv) in toluene (500 ml) was added phosphoryl trichloride (16.1 g, 105.00 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (27 g, 209.30 mmol, 1.99 equiv). The resulting solution was stirred for 20 mins at 120° C. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to give 30 g of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as a light yellow solid. MS m/z [M+H]+ (ESI): 447.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]=2[CH:20](O)[CH3:21])[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:25]>C(Cl)Cl>[Br:25][CH:20]([C:10]1[O:11][C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:23])[CH3:1])[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:21]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Yield: 125.9 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 4-(3-(dimethylamino)phenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B8, 200 mg, 0.64 mmol), 1M PBr3 (1.1 ml, 1.1 mmol) in DCM (2 ml) at RT. The crude was purified with Biotage Silica SNAP 50 g with a gradient of DCM and MeOH to give the title compound (300 mg).
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:41])([CH3:40])[CH2:24]1>C1(C)C(C)=CC=CC=1>[OH:21][C:10]1[CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH:18]2[CH2:30][C:27]([CH3:28])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]2)=[O:16])[CH:19]=[CH:20][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Solvent: Cc1ccccc1C
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)COc2ccc(C(=O)c3ccccc3)c(O)c2)CC1(C)C
Temperature: 80 °C
Yield: 78.7 %

Procedure:
A mixture of 22.0 g (76.8 mmol) of methyl 4-benzoyl-3-hydroxyphenoxyacetate, 32.9 g (0.115 mol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine, and 100 ml of xylene is heated at reflux. Water is removed by fractional distillation. The reaction mixture is cooled to 80° C., treated with 2.1 g of lithium amide, and diluted with 50 ml of xylene. The reaction mixture is heated at reflux for 2 hours, and methanol is removed by fractional distillation. The reaction mixture is cooled, then diluted with diethyl ether (250 ml). The organic solution is washed with 1N hydrochloric acid (200 ml), and solids are removed by filtration. The solution is washed with saturated sodium bicarbonate solution (100 ml), dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (85:15 heptane: ethyl acetate) affords 32.6 g (79% yield) of the title compound, a yellow syrup.