Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH:37]([CH3:38])[CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: NC(CO)(CO)CO.C(N(CCO)CCO)CO.[CH2:19]([C:23](O)(C(O)=O)[CH2:24][C:25]([OH:27])=[O:26])[C:20](O)=O.[OH-].[Na+].Cl.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:37]>O>[OH:37][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:35].[C:25]([OH:27])(=[O:26])[CH2:24][CH2:23][CH2:19][CH2:20][CH2:36][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCCCCCCCCC(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Solvent: OCCN(CCO)CCO
Product: CCCCCCCCCCCC(=O)O

Procedure:
We transferred approximately 60% of the required sterile water volume into a suitable container. We added the appropriate amount (as indicated in the table below) of tromethamine, trolamine, citric acid anhydrous, and sodium hydroxide pellets to the container and mixed well until dissolved. We adjusted the temperature to 21-25° C. (or room temperature) and measured the pH of the liquid. We adjusted the pH to 7.7-7.9 as necessary using 1N sodium hydroxide or 1N hydrochloric acid. We then adjusted the temperature to 45-50° C. by warming on a hotplate and maintained this temperature. We then added the capric acid to the warm solution and mixed until the capric acid was dissolved. We adjusted the temperature to 21-25° C. (or room temperature) and measured the pH of the liquid. As needed, we adjusted the pH to 7.7-7.9 using 1N sodium hydroxide or 1N hydrochloric acid. We then mixed the solution for 5 minutes. We added appropriate amount of sterile water to equal 100% of the required volume and mixed well.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.IC.[C:34](=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH3:34])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.8 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 37) (440 mg, 1.00 mmol) in anhydrous dimethylsulphoxide (10 ml) was treated with iodomethane (310 μl, 5.00 mmol) and cesium carbonate (975 mg, 3.00 mmol) and the resulting mixture was heated at 40° under a nitrogen atmosphere for 3 hours then stirred at room temperature for 17 hours. The mixture was diluted with water and extracted with diethyl ether (×3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (2:1) to afford the title compound as a colourless oil (315 mg)
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br:16]C1C=C(C=CC=1)C(Cl)=O.N1CCOCC1>>[Br:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: C1COCCN1
Product: O=C(c1cccc(Br)c1)N1CCOCC1
Yield: 71 %

Procedure:
Following the general method as outlined in Intermediate 174, starting from 3-bromobenzoyl chloride and morpholine, the title compound was obtained as a colorless sticky solid in 71% yield.
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[Na+:6].[Na+].[OH:8][P:9]([O-:12])([OH:11])=[O:10].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[OH-].[Na+]>O>[OH:3][P:2]([O-:5])([O-:4])=[O:1].[Na+:6].[Na+:6].[O-:10][P:9]([O:12][P:2]([O-:4])([O-:3])=[O:1])(=[O:11])[O-:8].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=P([O-])(O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])OP(=O)([O-])[O-]

Procedure:
Sodium phosphate dibasic (1M Catalog #S-9763 Sigma Aldrich, St. Louis, Mo.) and sodium diphosphate monobasic solutions (1M, Catalog #S-0751, Sigma Aldrich, St. Louis, Mo.) were prepared in DI water. Sodium phosphate dibasic (7.74 mL) and sodium phosphate monobasic (2.26 ml) solutions were mixed into a beaker. DI water (80.0 mL) was added to the beaker and EDTA was dissolved (186.1 mg, Sigma Aldrich, St. Louis, Mo.) in it. The pH was measured on pH meter (Symphony B70P, VWR International, Pittsburgh, Pa.) and adjusted to 7.40 using 0.1 N sodium hydroxide solution (Catalog #SS276-4, Fisher Scientific, Suwanee, Ga.). The buffer was transferred to a volumetric flask and DI water was added to adjust the final buffer volume to 100 mL.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: Cc1ccc2c(Br)c(F)ccc2n1
Temperature: 0 °C

Procedure:
A solution of 100.7 g (0.625 mole) of 6-fluoroquinaldine in 125 ml of 1,2-dichloroethane was added slowly over 30 minutes to 126.5 g (0.95 mole) of aluminum chloride in 125 ml of 1,2-dichloroethane. The mixture was heated to 70° to 80° C., and 32 ml of liquid bromine was added dropwise over 4 hours. The mixture was stirred and heated at 80° to 85° C. for 20 hours, and was then poured over 1.5 liters of ice. After stirring thoroughly, the mixture was acidified with 50 ml of concentrated hydrochloric acid. Zinc chloride (85 g) was added, and the mixture was stirred for 10 minutes. The mixture was cooled in an ice bath, and the solid product was separated by filtration and washed sequentially with cold 3N hydrochloric acid and dichloromethane. The solid was slurried in water and neutralized with concentrated ammonium hydroxide. Filtration provided a solid which was dissolved in toluene. The solution was dried over magnesium sulfate, and then evaporated to provide a residue which was recrystallized from hexane to provide 5-bromo-6 -fluoroquinaldine. The structure was confirmed by a nuclear magnetic resonance spectral analysis.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:21]1([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:25]=[CH:24][N:23]=[N:22]1.[I-].[K+].C[O-].[Na+]>CO>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:31][CH:32]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1

Procedure:
MS: M=304.2(API+). 1H-NMR(400 MHz, D6-DMSO): δ=4.71(s, 2H, CH2Cl), 7.21(d, 1H, ═CH), 7.40(d, 2H, Ar—H), 7.58(d, 1H, ═CH), 7.87(d, 2H, Ar—H), 8.19(s, 1H, oxazole). 0.304 g (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole, 0.217 g (1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of a 30% sodium methylate solution were added to 50.0 ml methanol and heated to reflux for 8 h. After removal of solvent, partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed with 10 ml water, 10 ml 0.1 N NaOH, 15 ml water twice and dried over sodium sulphate. The solution was concentrated until crystallisation of the product started. After leaving for 1 h at room temperature the precipitate was isolated, washed with ether and dried at 40° C. in vacuo. Yield 0.16 g (32%) 2, m.p. 138–140° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:36])([F:16])[F:35])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(C(F)(F)F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 27.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (189 mg, 0.702 mmol), 1-[4-(3-trifluoromethylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.638 mmol) and diisopropylethylamine (0.222 ml, 1.28 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 20 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 75.4 mg (27.2%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:18])=[C:8]2[CH:15]=[N:14][N:13](CC)[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].NC1N(CC)N=CC=1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:18])=[C:8]2[CH:15]=[N:14][NH:13][C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Agent: CCn1nccc1N
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2[nH]ncc2c1Cl
Yield: 54.5 %

Procedure:
A mixture of 10.0 g (37.4 mM) of 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, prepared according to Examples 1b. and 1c. from 5-amino-1-ethylpyrazole in place of 5-amino-1-pentylpyrazole, and 7.65 g (43.0 mM) of N-bromosuccinimide in 75 ml of carbon tetrachloride was illuminated with a sunlamp and stirred under N2 at gentle reflux for 2 hours. The cooled reaction mixture was filtered and the filtrate concentrated to leave an orange residue which was dissolved in 50 ml of THF. 35 ml of saturated aqueous sodium carbonate were added, and the mixture was stirred vigorously at room temperature for 18 hours and then diluted with water and extracted with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to leave a white solid which was chromatographed over silica gel using the solvent system of ethyl acetate:hexane (1:3) as the eluant. The fractions containing the desired product were combined and concentrated to leave a white solid. Recrystallization of the solid from toluene/hexane gave 4.88 g of the desired ester as white needles, mp=156°-157.5° C.; tlc, Rf =0.2, silica gel, ethyl acetate:hexane (1:3).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24](=[O:31])(=[O:30])[NH:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=2)[N:12]=1)=[O:10].Cl>C1COCC1>[NH2:17][C:16]1[N:15]=[CH:14][C:13]([C:18]2[CH:19]=[C:20]([S:24]([NH:25][CH2:26][CH2:27][O:28][CH3:29])(=[O:30])=[O:31])[CH:21]=[CH:22][CH:23]=2)=[N:12][C:11]=1[C:9]([CH:1]1[CH2:2][CH2:3]1)=[O:10]
Reactant: COCCNS(=O)(=O)c1cccc(-c2cnc(N)c(C(=O)N(C)OC)n2)c1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(-c2cnc(N)c(C(=O)C3CC3)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of cyclopropyl magnesium bromide in THF (1.3 ml, 1.3 mmol) is added to a solution of 3-amino-6-[3-(2-methoxy-ethylsulfamoyl)-phenyl]-pyrazine-2-carboxylic acid methoxy-methyl-amide (Intermediate CB) (0.49 g, 1.24 mmol) in anhydrous THF (15 ml) under N2. The orange solution is stirred at room temperature for 18 hours after which time a 1M solution of cyclopropyl magnesium bromide in THF (1.3 ml, 1.3 mmol) is added. The orange solution is stirred at room temperature for 1 hour. 1M HCl (45 ml) is added and the product extracted into EtOAc (120 ml), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, 50-100% EtOAc in iso-hexane) yields the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (1H, s), 8.51 (1H, m), 8.39 (1H, d), 8.22-7.90 (2H, br), 7.88 (2H, m), 7.76 (1H, t), 3.73 (1H, m) 3.37 (2H, t), 3.21 (3H, s), 3.02 (2H, q), 1.19 (2H, m), 1.14 (2H, m); MS m/z 377 [M+H]+
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39](Cl)=[O:40]>C1COCC1>[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]3[N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[N:8]=[N:9][N:10]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27])=[O:40]
Reactant: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Reactant: O=C(Cl)CC(CBr)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1C(=O)CC(CBr)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one (cilostazol, 1, A=H, 2.0 g, 3.50 mmol), N,N-dimethylaminopyridine (0.043 g, 0.35 mmol) and triethylamine (0.5 ml, 0.35 mmol) in THF (100 mL) at 0° C. and under nitrogen, a solution of 4-bromo-3-(bromomethyl)butanoyl chloride (0.97 g, 3.50 mmol) in THF (5 mL) is slowly added and the reaction mixture stirred at room temperature for 2 hours. Then it is partitioned between ethyl acetate and phosphate buffer (pH=3) and extracted with ethyl acetate (3×25 mL). The organic phase is dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography (CH2Cl2/acetone 7:3).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])[CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-3-furancarboxylic acid (0.302;1.58 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.22 ml; 1.58 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.35 g;1.58 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a tan solid after trituration with Et2O (0.3 g;48%), mp=185°-187° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[CH2:10][C:9]3[S:16][CH:17]=[CH:18][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC1.C(OCC)(=[O:27])C>>[C:1]1([CH:7]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10](=[O:27])[C:9]3[S:16][CH:17]=[CH:18][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)N1Cc2sccc2C(c2ccccc2)C1
Solvent: C1CCCCC1
Product: CC(=O)N1CC(c2ccccc2)c2ccsc2C1=O
Yield: 20 %

Procedure:
The compound is prepared according to the procedure of Example 1, from 4-phenyl-6-acetyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, to give white crystals, M.p.=132° C. (cyclohexane-ethyl acetate), Yield: 20%.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].[Br:28]N1C(=O)CCC1=O.ClCC(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([Br:28])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: COC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)C(Br)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
A mixture of methyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.400 g, 0.00100 mol), N-bromosuccinimide (0.370 g, 0.00210 mol), benzoyl peroxide (0.0100 g) and tetrachloroethane is stirred 2.5 hours at reflux, cooled to room temperature, and chromatographed on silica gel with methylene chloride to afford the title compound as an off-white solid (0.430 g, 90.0%, mp 84-87° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH:10]=O)[C:6]=2[CH:12]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:12]=1
Reactant: O=Cc1csc2ccc(Br)cc12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield 5-bromo-benzo[b]thiophene-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(OCC)(=O)C.C(Cl)Cl>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:18])[CH2:53][CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following was added to DCM (5 mL): 1-(4-chlorobenzyl)-1H-indole-2-carboxylic acid (70 mg, 0.245 mmol), DIPEA (0.130 mL, 0.735 mmol), EDC (57 mg, 0.294 mmol), HOBT (45 mg, 0.294 mmol), and 1-benzylpiperazine (0.085 mL, 0.490 mmol). The solution was stirred at rt for 16 h, at which time the solution was diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with water (1×), 10% aq. sodium carbonate (1×), and brine (1×). The organic phase was then dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel flash chromatography (30 g silica, 10% EtOAc/hexanes) and triturated with ethyl acetate and hexanes to afford the title compound as a white powder. (Yield: 52 mg, 0.117 mmol, 48%) 1H NMR (400 MHz, CDCl3) δ 7.62, 7.36-7.19, 7.14, 7.02, 6.60, 5.48, 3.62, 3.42, 2.32, 2.03