Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:29]2[C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[CH:27][CH:28]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Yield: 70.5 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (321 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-3-hydroxyphenyl)propanoate (430 mg) and cesium carbonate (980 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1C[O:38]CC1>C(Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([CH:22]=[O:38])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(-c2ccc(CN3CCN(C4CCC4)CC3)nc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(CN3CCN(C4CCC4)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]benzonitrile (0.066 g, 0.2 mmol) was dissolved in DCM (1 mL) DIBAL 1M in THF (0.2 mL) was added. The reaction mixture was stirred at RT for 1 hour. LC-MS showed no product. Another 1.5 eq. of DIBAL (0.2 mL) was added and stirring continued 1 hour. LC-MS showed full conversion. The reaction mixture was stored at −20° C. for 3 days. The reaction mixture was added DCM (5 mL) and cold NH4Claq (5 mL). The DCM phase was washed with water (5 mL) and brine (5 mL), dried with MgSO4, filtered and evaporation afforded the title compound as the free base. 34.5 mg (51%).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])(=[O:14])[CH3:13]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (10 g, 64.04 mmol), 4-dimethylaminopyridine (9.49 g, 158.0 mmol) in dry CH2Cl2 (190 ml) was cooled to 0° C. and acetic anhydride (7.35 ml, 77.9 mmol) added dropwise in 15 min. The reaction mixture was stirred overnight at room temperature, diluted with CH2Cl2 (500 ml) and washed with 2 N HCl solution (80 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from MeOH, giving 5-acetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 1 (8.6 g, 68%).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)([CH3:4])[CH3:3].[Cl:28]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C.O>[Cl:28][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])[NH:22][CH:21]=1
Reactant: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Yield: 74.7 %

Procedure:
A solution of 4.74 g of the product of Example 9 in 43 ml of acetic acid was added with stirring under an inert atmosphere to 2.17 g of N-chlorosuccinimide over 40 minutes and the mixture was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 3.76 g of N-[2-{2-(3-[3-chloro-1H-indol-4-yl]-propyl)-phenoxy}-ethyl]-2-methyl-2-propanamine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1N
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.66, 7.08, 6.44, 5.19, 4.46, 2.82, 2.68–2.52, 2.03, 1.94, 1.78, 1.53–1.48, 1.26, 0.92; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.1993.
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:28])[C@H:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C@@H:8]([C:7]([NH:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:28])[CH2:9][CH2:10][CH2:11][NH:12][C:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:42])(=[O:16])=[O:15])=[CH:18][CH:19]=1)[C:25]#[C:26][CH3:27]
Reactant: O=C(Cl)c1cccs1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCN)C(=O)NOC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCNC(=O)c2cccs2)C(=O)NOC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
The residue from Step B (102 mg, 0.25 mmol) was dissolved in DCM (2 mL). Triethylamine (104 uL, 0.75 mmol), DMAP (0.3 mg, 0.025 mmol) and thiophene-2-carbonyl chloride (55 mg, 0.37 mmol) were added. The reaction was shaken on an orbital shaker for 16 hours then concentrated to dryness.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH3:21]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19].[NH3:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Separately, a 200-ml capacity beaker was charged with 1.44 g of granular stearic acid, 2.08 ml of aqueous ammonia having a concentration of 0.736 mole/l and 50 ml of water, and the mixture was heated at 90° C. under violent agitation by a glass rod to completely emulsify stearic acid and form an ammonia soap. The so formed ammonia soap suspension was added to and sufficiently dispersed in the above-mentioned base slurry of tribasic lead sulfate, and the mixture was heated and aged at 65° to 70° C. for 60 minutes. The solid was recovered by filtration and the cake was dried overnight in a thermostat drier maintained at 90° C. and then pulverized by an atomizer to obtain a tribasic lead sulfate powder (Sample 2-1) having a very high whiteness.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[C:12](=[N:16]O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[C:18](O)(=[O:20])[CH3:19]>C(OC(=O)C)(=O)C.[Zn]>[C:18]([NH:16][CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH:8]=2)[C:13]1=[O:15])(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CC(=O)Nc1cccc2c1C(=O)C(=NO)CC2
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 gm of zinc powder was added to a solution of 300 mg of the compound prepared in (2) above dissolved in a mixed solvent of 10 ml of acetic acid and 10 ml of acetic anhydride, and the mixture was stirred for 40 minutes at room temperature. Insoluble substances were removed by filtration and filtrate was concentrated. The residue was recrystallized in ethyl acetate and hexane to obtain 263 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][CH:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:20][CH2:21][CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCCC(N)c1ccccn1
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCCC(NC(=O)c1ccc(OC)c(C)c1)c1ccccn1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-pyridin-2-yl-butylamine. 1H NMR (500 MHz, CDCl3): δ 0.91-0.92 (t, 3H), 1.25-1.3 (m, 2H, 1.85-1.9 (m, 2H), 3.86 (s, 3H), 5.25-5.3 (m, 1H), 6.80-6.82 (d, 1H), 7.2-7.3 (m, 2H), 7.42-7.44 (d, 1H), 7.6-7.7 (m, 3H), 8.6 (d, 1H). MS (M+H, 299.1).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C(O)c2ccccc2)nc2cnc3ccccc3c21
Temperature: -78 °C

Procedure:
1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinoline (4 g; 0.017 mole) was dissolved in 50 mL of tetrahydrofuran then cooled to -78° C. A 7.75 mL portion of n-butyl lithium (2.5M in hexanes) was added dropwise to the cooled solution. At 15 minutes post addition, benzaldehyde (2.7 mL; 0.027 mole) was added and the reaction mixture was allowed to warm slightly. The reaction was quenched with water then diluted with ethyl ether. The ether was separated, dried with magnesium sulfate then concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 5% methanol in methylene chloride as the eluent to give an oily yellow solid. This material was recrystallized from methylene chloride/hexane to provide 1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol as a white crystalline solid, m.p. 160°-166° C. Analysis: Calc'd: C, 76.1; H, 6.4; N, 12.7; Found: C, 75.9; H, 6.3; N, 12.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:32]\[OH:33])=[C:4]([F:30])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(4-(methylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=463.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29](#[N:31])[CH3:30]>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.O>[O:14]1[CH2:15][CH2:16][N:11]([C:9]2[S:10][C:5]3[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:3][C:2]([C:30]4[CH:29]=[N:31][C:2]([NH2:7])=[N:3][CH:4]=4)=[N:7][C:6]=3[N:8]=2)[CH2:12][CH2:13]1
Reactant: CC#N
Reactant: Clc1nc(N2CCOCC2)c2sc(N3CCOCC3)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(N4CCOCC4)nc3n2)cn1

Procedure:
5-Chloro-2,7-dimorpholinothiazolo[4,5-d]pyrimidine 79, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 150° C. for 10 minutes. An additionally 0.1 equivalents of trans-dichlorobis(triphenylphosphine)palladium(II) was added and the solution was microwaved an additional 10 minutes at 150° C. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to give 139.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[C:13]([F:34])[CH:12]=2)=[O:9])[C:4](=[O:35])[N:3]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH2:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[F:34][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:5]2[C:4](=[O:35])[N:3]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])[CH:33]=[CH:32][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][CH2:43][CH2:44][OH:45])=[O:31])[CH:17]=1
Reactant: NCCO
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)NCCO)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 69.4 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and 2-aminoethanol (3.0 mg, 0.22 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and diluted with EtOAc (20 mL). The precipitate was collected by filtration, and then washed with EtOAc (3 mL) to give the title compound as a white solid (65 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:38](=[O:40])[CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (58 mg, 0.132 mmol) in dichloromethane (1.3 ml) was added pyridine (64 ul, 0.789 mmol), followed by acetic anhydride (50 ul, 0.526 mmol) and a catalytic amount of DMAP. The resulting solution was stirred for 18 hours at room temperature and then quenched with a saturated solution of NaHCO3 (5 ml). The aqueous phase was separated and washed with ethyl acetate (2×5 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was then purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 50 mg (78%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH:12]=O.C([O-])(=O)C.[Na+]>CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=S)SC1=Cc1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 1.75 h

Procedure:
A 50 mL flask was charged with 899 mg rhodanine (6.75 mmol, 1.0 equiv), 1.77 g 3,4-dichlorobenzaldehyde (10.1 mmol, 1.5 equiv), 1.66 g sodium acetate (20.25 mmol, 3.0 equiv) and 20 mL methanol. The mixture was heated to 65° C. with stirring for 1.75 h. The yellow solid was then filtered and washed (4×MeOH) to give the product 5-(3,4-dichlorophenylmethylene)-4-oxo-2-thionothiazolidine as a yellow solid (1.059 g 3.67 mmol, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C[N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:12])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc(Br)cc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)cc1C(N)=O
Yield: 46 %

Procedure:
4-Bromo-1-methyl-1H-pyrrole-2-carboxylic acid (122 mg, 0.60 mmol), HATU (274 mg, 0.72 mmol) and DIEA (194 mg, 1.50 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature with ammonia gas bubbled through continuously overnight. The reaction mixture was diluted with 100 mL of DCM, and then washed with water (50 mL). The aqueous layer was extracted with DCM (20 mL×2). All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6/1) to give 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (56 mg, yield 46%). 1H NMR (300 MHz, CDCl3): δ 6.74 (d, J=1.8 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.92 (s, 3H). LC-MS calcd for C6H7BrN2O (m/e) 201.97, obsd 203 and 205 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[N:19]([CH3:33])[C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)NC2=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)N(C)C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
5-[3-(3-Bromo-4-ethoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl-methylene]-thiazolidine-2,4-dione (Compound No. 77, 0.10 g, 0.21 mmol) was dissolved in 1.00 mL of anhydrous dimethylformamide. Sodium hydride (12.74 mg, 0.32 mmol) was added under nitrogen atmosphere and iodomethane (19.78 μL, 0.32 mmol) was added 5 minutes later. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, 10 mL of water was added and the solution was extracted with dichloromethane (10 mL×2 times). The organic layer was washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The product was purified with silica gel chromatography (n-hexane/ethyl acetate=4:1) to obtain 48 mg (46.7%) of the target product in yellow solid form.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2C(OCC)=O)(=O)=O)C=CC=CC=1.[Br:24]Br.O>CN(C=O)C>[Br:24][C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: BrBr
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 1-phenylsulfonylindole-2-carboxylate (1 eq.) in DMF (2.5 ml/mmol) under N2, was added a solution of bromine (4 eq.) in DMF (0.5 ml/mmol). This reaction mixture was stirred at room temperature for about 4 hours, following which water was added and the mixture was extracted with dichloromethane (×3). The organic layer was washed with a saturated solution of Na2SO5, dried and evaporated to give a crude yellow oil. Purification by chromatography on silica gel (eluent:C6H12/EtOAc 9/1) afforded 3-brominated indole 11.
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[Na+].Cl>O>[CH3:17][C:11]1[N:10]=[C:9]2[C:14]([C:15]([OH:16])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(O)ccnc2n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of the product from Example 1b (1.30 g, 5.59 mmol) and NaOH (233 mg, 5.82 mmol) in 20 mL of water was heated in a sealed metal reactor at 180° C. for 16 h. Cooled to room temperature and adjusted to pH 6 with 1N HCl. The resulting precipitates was filtered and dried under vacuum giving the title compound as a black solid (743 mg, 82%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13]>C(OC)(C)(C)C>[F:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Solvent: COC(C)(C)C
Product: OC(c1ccccc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C

Procedure:
Phenylmagnesium bromide (1.83 mL, 5.5 mmol) was added dropwise to a tirring solution of 2,4′-difluorobenzophenone (1.09 g, 5.0 mmol) in t-butylmethyl ether (12 mL) at room temperature (“rt,”˜25° C.). After the addition was complete the reaction was heated at reflux for 3 h. The solution was cooled to rt and was poured in to ice cold 1.0 M HCl (aq) (20 mL). The organics were extracted with EtOAc (3×10 mL) and dried (Na2SO4). Concentration under reduced pressure gave the desired product (2-fluorophenyl)-(4-fluorophenyl)phenylmethanol as a pale brown oil which was used in the next reaction without any further purification.