Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:8]([NH2:9])=[O:18]
Reactant: N#CC(N)c1ccc(Cl)cc1Cl
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 57 %

Procedure:
Then, 11.2 g of concentrated sulfuric acid was added to 0.54 g of water, to which 10.1 g of 2-amino-2-(2,4-dichlorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 30 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 6.14 g (yield, 57%) of 2-amino-2-(2,4-dichlorophenyl)acetamide, m.p. 113.8° C.
Reaction SMILES: [C:1]([C@:3]1([OH:21])[CH2:4][C:5]2([C:10]3[C:11](/[C:15]/1=[CH:16]\[C:17]([O:19][CH3:20])=[O:18])=[CH:12][O:13][N:14]=3)[O:9][CH2:8][CH2:7][O:6]2)#[CH:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])(=O)=O.CO>ClCCl.[Cl-].[Na+].O>[C:1]([C@:3]1([O:21][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH2:4][C:5]2([C:10]3[C:11](/[C:15]/1=[CH:16]\[C:17]([O:19][CH3:20])=[O:18])=[CH:12][O:13][N:14]=3)[O:6][CH2:7][CH2:8][O:9]2)#[CH:2]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C#C[C@]1(O)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: C#C[C@]1(O[Si](CC)(CC)CC)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A solution of Compound 60 (1.657 g, 5.69 mmol) in dichloromethane (10 mL) was treated with 2,6-lutidine (2.00 mL, 17.1 mmol) and triethylsilyl trifluoromethanesulfonate (2.58 mL, 11.4 mmol) at zero degrees C. The solution was stirred 30 minutes, anhydrous methanol (2 mL) was added, the mixture was poured into brine (50 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (20% Et2O in petroleum ether) to give Compound 61 (2.204 g, 96 percent) as a white solid, m.p. =108 °-109° C. (from CH2Cl2); Rf =0.43 (30 percent Et2O in petroleum ether); [a]D25 =-15.4° (c 2.8, CH2Cl2); IR (thin film) νmax 3307, 2116, 1721, 1646 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1 H, C=CH--O), 6.57 (s, 1 H, C=CH--CO2), 4.38-4.31 (m, 2 H, ethylene ketal), 4.18-4.10 (m, 2 H, ethylene ketal), 3.74 (s, 3 H, CO2Me), 2.66 (s, 1 H, C}C--H), 2.61 (ABq, J =14.0 Hz, Δν =34 Hz, 2 H, CH2), 0.92 (t, J =7.9 Hz, 9 H, Si(CH2CH3)3), 0.70 (q, J =7.9 Hz, 6 H, Si(CH2CH3)3); 13C NMR (125 MHz, CDCl3) δ 166.5, 161.3, 160.7, 143.8, 114.5, 111.9, 100.6, 83.2, 76.9, 70.9, 65.0, 64.8, 51.6, 49.8, 6.8, 5.9; FAB HRMS (NBA/CsI) m/e 538.0652, M+Cs+ calcd for C20H27NO6Si 538.0662.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.BrC1C=C(C(F)(F)F)C=CC=1.[Cl:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[Cl:24][CH2:25][CH2:26][CH2:27][C:28]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)=[O:29]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C(Cl)CCCCl
Agent: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(CCCCl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 417.1 %

Procedure:
Magnesium metal (0.6 g, 24.4 mmol) was placed into a 25 mL round bottomed flask and was vigorously stirred under nitrogen for 24 hours. To this activated magnesium was added 1 mL of tetrahydrofuran and 4-bromobenzotrifluoride (0.5 g, 2.2 mmol) and the reaction was sonicated for 30 seconds during which time a deep red color formed. The solution was cooled to 0° C. and 3-bromobenzotrifluoride (4.5 g, 20 mmol) in 9 mL of tetrahydrofuran was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1.5 hours then added to a solution of 4-chlorobutyryl chloride (9.4 g, 66.6 mmol) in 50 mL of tetrahydrofuran at −78° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Biotage) over silica gel eluting with hexane/ethyl acetate (50:1) to give 2.3 g of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ 8.08 (d, 2H, J=8.3 Hz); 7.74 (d, 2H, J=8.0 Hz); 3.69 (m, 2H); 3.21 (m, 2H); 2.25 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([CH:8]2[CH2:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=4)[C:22]#[N:23])[CH:14]=3)[O:9]2)[CH2:5][CH2:4][O:3]1.C[Si]([N:32]=[C:33]=[N:34][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:22]([C:21]1[CH:20]=[C:19]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:27])([CH3:1])[CH2:7]2)[CH2:17]/[C:16]/3=[N:34]\[C:33]#[N:32])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1(C)CC(C2CC(=O)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C2C/C(=N\C#N)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
To a solution of 3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg, 0.69 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 5 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (283 mg, 340 μL 1.52 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (20 g), It was transferred to a separating funnel after stirred for 30. The separated aqueous phase was extracted with DCM (2×20 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (276 mg), which was used for next step without further purification. MS ESI +ve m/z 386 (M+H)+.
Reaction SMILES: [P+3]=O.CS(O)(=O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[CH:13]=[CH:14][CH:15]=1>O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[CH:11]=1
Reactant: COc1cccc(CCCCC(=O)O)c1
Agent: CS(=O)(=O)O
Agent: O=[P+3]
Solvent: O
Product: COc1ccc2c(c1)CCCCC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of phosphorus(V) oxide (10 g) and methanesulfonic acid (70 mL) was stirred at 100° C. for 1 hr. The obtained solution and 5-(3-methoxyphenyl)pentanoic acid (5.28 g, 25.4 mmol) were mixed and the mixture was stirred for 1 hr. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-30% ethyl acetate/hexane) to give the title compound (4.02 g, 83%) as a red-brown oil.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.C(O)C.Cl>CO>[Cl:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)c1nc(CO)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To 300 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(3-(2-pyridyl)propyl)imidazole was added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 127 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(3-(2-pyridyl)propyl)-1H-imidazole (yield 51%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=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.C(O)C>[OH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([C:7]2[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:9][C:8]=2[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:23][CH:24]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 75.7 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (319.3 mg, 1.00 mmol, see Example 1(c) above), 4-bromobenzyl alcohol (374.1 mg, 2.00 mmol), toluene (20 mL), ethanol (4 mL), NaOH (1.0M, 4 mL, 4 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol) were mixed together under N2. The mixture was warmed to reflux for 2 hours and was then diluted with EtOAc (50 mL), washed with water and brine and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using CHCl3:MeOH (40:1) as eluent to give 289 mg of the sub-title compound (yield: 76%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:15]1[CH:29]=[CH:28][C:18]([CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:17][CH:16]=1.[C-:30]#[N:31].[Na+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][P:20](=[O:27])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[C:3]([CH2:2][C:30]#[N:31])[C:8](=[O:9])[C:7]=2[CH:10]=1
Reactant: CCOP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2CBr)cc1)OCC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2CC#N)cc1)OCC
Temperature: 25 °C

Procedure:
A 2.0 g quantity of the compound obtained in Example 23 was dissolved in a mixture of 5 ml of ethanol and 0.6 ml of water. After addition of 0.48 g of sodium cyanide with stirring at room temperature, the reaction mixture was refluxed with heating for 12 hours. After addition of 20 ml of water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed serially with 20 ml of water and 20 ml of brine and dried over Glauber's salt. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: chloroform:ethyl acetate=1:1). The resulting crude crystals were recrystallized from dichloromethane-n-hexane to provide 1.0 g of the title compound as colorless crystals. Table 1 shows the structure and physical property of the compound obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[CH3:29])[C:19]2=[O:22])=[CH:14][C:13]=1[OH:30].C1(N[S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])C=CC=CC=1.CO>C1COCC1.C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[S:38]([O:30][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[Cl:11])[C:19](=[O:22])[N:18]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:17][CH2:16]2)(=[O:40])=[O:39]
Reactant: Cc1ccncc1N1CCc2cc(O)c(Cl)cc2C1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc2C1=O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
KHMDS (0.23 mL (0.91M), 0.21 mmol) was added to a solution of 7-chloro-6-hydroxy-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (87A: 50 mg, 0.1736 mmol) in THF (5 mL) at −78° C. and stirred at −10° C. for 20 minutes, then cooled to −78° C., followed by the addition of N-phenyl trifluoromethanesulfonamide (68.2 mg, 0.190 mmol). The resulting mixture was stirred at room temperature for 60 minutes. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was quenched with saturated NH4Cl solution and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 50 mg of the product (70% yield).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: COc1cnccc1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3ccncc3OC)cnc(OC)c2o1
Yield: 86.1 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (170 mg) and 4-amino-3-methoxypyridine (120 mg). Purification by column chromatography on silica eluting with ethyl acetate gave the title compound (0.14 g) as an off white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Oc1ccccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C1CCCC1
Reaction time: 26 h
Yield: 97.7 %

Procedure:
486.7 g (3.0 mol) of 2-cyclopentylphenol, 472 g (3.9 mol) of allyl bromide and 830 g (6.0 mol) of potassium carbonate are heated under reflux in 2.5 l of acetone while stirring vigorously for 26 h. The cooled reaction mixture is filtered, and the filtrate is concentrated in vacuo. The residue is taken up in petroleum ether, and the solution is washed three times with 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo, and the residue is finally distilled in vacuo. 593 g (97% of theory) of 2-cyclopentylphenyl allyl ether are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1C(=O)N([Cl:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1Cl
Yield: 73 %

Procedure:
Ethyl 1H-indole-2-carboxylate (26.45 mmol, 1.0 equiv.) was dissolved in CCl4 (26 ml); NCS (29.10 mmol, 1.1 equiv.) was added and the mixture was heated for 16 h at boiling temperature. The resulting solid was filtered out, and the filtrate was washed with water (2×50 ml) and sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 73%
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.N1C=CC=C1.[H-].[Na+].C1(S(OC)=O)C=CC=CC=1.[OH-].[Li+]>O1CCCC1.O1CCOCC1.O.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: Clc1cccc(CBr)c1
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCCc2c1ccn2Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(3-chlorobenzyl)-4-oxo-4,5,6,7-tetrahydroindole was prepared from 1,5,6,7-tetrahydro-4H-indol-4-one and 3-chlorobenzylbromide using methodology common to the art. The pyrrole (0.5 g, 1.9 mmol) was dissolved in tetrahydrofuran (2.5 mL). Sodium hydride (0.18 g, 4.4 mmol) was added. After 5 minutes, methyl benzenesulfinate (0.48 g, 3.1 mmol) was added. The color of the mixture darkened to red as gas evolution was observed. The mixture was stirred for 1 hour. Thin layer chromatography indicated complete consumption of starting material (sulfoxides, Rf 0.11; 1/1 hexane/ethyl acetate). The reaction mixture was quenched with water, stirred for 10 minutes, and diluted with chloroform. The solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to give an orange oil. The oil was dissolved in dioxane (5 mL) and refluxed for 3 hours at which time the sulfoxides were no longer observed by thin layer chromatography. The reaction mixture was cooled to room temperature and a solution of lithium hydroxide (85 mg) in water (2 mL) was added. The solvent was evaporated and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to give an orange oil. Column chromatography with 20% ethyl acetate in hexane provided 0.41 g of a yellow solid. (81% yield) TLC Rf 0.28 (20% EtOAc in hexane); 1H NMR (CDCl3): d 7.30 (d, J=8.2, 1 H), 7.24 (t, J=7.8, 1 H), 7.18 (s, 1 H), 7.11 (t, J=7.9, 1 H), 7.07 (d, J=3.2, 1 H), 6.98 (d, J=7.6, 1 H), 6.92 (d, J=8.3, 1 H), 6.75 (d, J=3.3, 1 H), 6.63 (d, J=7.6, 1 H), 6.01 (s, 1 H), 5.24 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(SC2CCCC2)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(Br)cc(SC2CCCC2)c1

Procedure:
A solution of 3-bromo-5-(cyclopentylthio)benzoic acid (1.49 g, 4.95 mmol) in methanol (40 mL) was treated with acetyl chloride (3.87 mL, 54.4 mmol) at 0° C. The reaction mixture was heated to reflux overnight, and then concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:12]3[S:16][C:15](=[S:17])[NH:14][C:13]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.IC.[CH:21](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:21][S:17][C:15]1[S:16][C:12](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[CH:4]3)[C:13](=[O:18])[N:14]=1
Reactant: O=C1NC(=S)SC1=Cc1ccc2ncncc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
The suspension of 5-quinazolin-6-ylmethylene-2-thioxo-thiazolidin-4-one (example 1b, 2.6 g, 9.52 mmol), iodomethane (1.2 mL, 19.0 mmol) and diisopropylethylamine (DIEA) (2.4 mL, 14.3 mmol) in anhydrous ethanol (100 mL) was stirred at room temperature for 12 h. After adding water (200 mL), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (2.5 g, 92%) as a black solid. LC-MS m/e 288 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][OH:31])([CH3:7])[CH3:6])[CH3:2].[CH3:33]I.[H-].[Na+].S(=O)(=O)(O)O>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:33])([CH3:7])[CH3:6])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1COC
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a 15 mL round bottom flask under a nitrogen atmosphere were charged 0.075 g (0.17 mmol) of 2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester, dissolved in 1 mL of anhydrous DMF, followed by the addition of 0.16 mL (1.7 mmol) of methyl iodide. The reaction solution was cooled down in an ice bath and was treated with 0.014 g (0.34 mmol) of NaH. The reaction was stirred cold for 2 h. Next the reaction was poured into 6 mL of EtOAc and 10 mL of brine, and then acidified using dilute sulfuric acid. The organic layer was separated away, dried over Na2SO4, and removed in vacuo to give a crude oil. This crude residue was purified using radial chromatography with a 1 mm normal phase silica gel plate, eluting with 15:85 EtOAc:Hex to give a colorless oil (0.039 g, 51%). MS (ES) m/e 454 (M+1).