Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1>ClCCl.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]([CH3:38])[CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][CH:26]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccco2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of dichloromethane was dissolved 0.56 g (5 m-mol) of 2-furancarboxylic acid. To this solution was added 0.7 ml of triethylamine, and the mixture was cooled to -20° C. Next, 0.65 ml of isobutyl chloroformate was added to the mixture and the whole was stirred for 30 minutes at a temperature from -10° C. to -20° C. To this mixture was added a dimethylformamide solution containing 1.0 g (4.9 m-mol) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridazinone. After removing the ice bath, the mixture was stirred for 3 hours at room temperature and the solvent was then distilled off under reduced pressure. Water was added to the residue and a solid material was collected by filtration. The solid material was washed with water and dichloromethane and then recrystallized from methanol-water whereby 570 mg of the title compound was obtained. M.P. 213°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC.O1CCOCC1>[Cl-].[Na+].O.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>[F:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccco4)sc23)c(F)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (0.300 g, 0.7768 mmol) from Example 6, Step A, PdCl2(PPh3)2 (0.02726 g, 0.03884 mmol), tributyl(furan-2-yl)stannane (0.2931 ml, 0.9322 mmol), and dioxane (8 mL). Heat to 90° C. for 6 hours under nitrogen and cool to room temperature. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (100 mL). The reaction mixture was purified by triturating with hot MeOH. The product (170 mg, 57%) was isolated as a brown solid. LRMS (APCI+) m/e 327 (M+1) detected.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: Cc1ccnc(Br)c1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and 2-bromo-4-methylpyridine. HRMS (ESI+): m/z=388.1481 [M+H]
Reaction SMILES: Cl.N[C:3]1[C:4]([O:13][CH3:14])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].N([O-])=[O:16].[Na+].F[B-](F)(F)F.[Na+]>O>[OH:16][C:3]1[C:4]([O:13][CH3:14])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=N[O-]
Reactant: COC(=O)c1cnc(OC)c(N)c1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc(OC)c(O)c1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Concentrated hydrochloric acid (9.06 mL of strength 36%) is added to a stirred suspension of methyl 5-amino-6-methoxynicotinoate (3.3 g) in water (20 mL). The mixture is cooled to 0° C. and treated dropwise with a solution of sodium nitrite (1.37 g) in water (5 mL). After 30 minutes at 0° C. a solution of sodium tetrafluoroborate (2.84 g) in water (10 mL) is added. After a further 30 minutes the precipitated diazonium salt is collected, washed with a little ice-cold water then with diethyl ether and sucked dry. Potassium carbonate (1.0 g) is added to trifluoroacetic acid (32 mL) at 0° C. followed by the addition of the diazonium salt in one portion. The mixture is stirred at reflux for 18 hours, cooled then poured into iced water and stirred for 1 hour. The aqueous mixture is neutralised with solid sodium bicarbonate and extracted with ethyl acetate. The extracts are washed with water and dried (MgSO4). Concentration afforded methyl 5-hydroxy-6-methoxynicotinoate (2.86 g) as a beige solid. This material is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+].[CH:28](I)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH:28]([N:19]1[CH:20]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10]2)[CH:16]=[CH:17][C:18]1=[O:21])([CH3:30])[CH3:29]
Reactant: COc1ccccc1C1CCN(Cc2ccc(=O)[nH]c2)C1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1CCN(Cc2ccc(=O)n(C(C)C)c2)C1
Reaction time: 8 h

Procedure:
9.75 g of (+)-5-[3-(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridin-2-one (example 2) are dissolved in 170 ml of toluene. 14.2 g of Na2CO3, followed by 6.9 ml of isopropyl-iodide are added to the solution which is stirred at 100° overnight. Subsequently, another 3.4 g of isopropyliodide are added and stirring continued for additional 17 hours. The reaction solution is extracted with water and the combined organic phases dried and evaporated resulting in an oily residue which is purified by flash chromatography on silica gel using CH2Cl2/MeOH/conc. aqueous NH4OH 95/4.5/0.5 as solvent system which provides (+)-1-Isopropyl-5-[3-(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridin-2-one {[αD25]=+19.7° (c=1.0, EtOH); MS (Cl): MH+=327; NMR (DMSO, 120°): 1.3 (6H, d), 1.95 (1H, m), 2.3 (1H, m), 2.7-3.4 (4H, m), 3.6-3.8 (3H, m), 3.8 (3H, s), 5.0 (1H, q), 6.35 (1H, d) 6.9-7.0 (2H, m), 7.2 (1H, t), 7.3 (1H, m), 7.4 (1H, m), 7.6 (1H, m)} and (+)-2-Isopropoxy-5-[3-2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridine {[αD25]=+22.8° (c=1.0, EtOH); MS (EI): M+=326; NMR (DMSO): 1.3 (6H, d), 1.75 (1H, m), 2.15 (1H, m), 2.4 (1H, t), 2.65 (2H, m), 2.8 (1H, t), 3.5-3.65 (3H, m), 3.75 (3H, s), 5.2 (1H, m), 6.7 (1H, d), 6.85-6.95 (2H, m), 7.15 (1H, t), 7.3 (1H, d), 7.6 (1H, m), 8.05 (1H, s)}
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[C:15]([CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:12][C:13]1[N:20]2[C:16]([S:17][C:18]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19]2)=[C:15]([CH3:21])[N:14]=1
Reactant: Cc1nc(C)n2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C)c2s1
Temperature: -30 °C
Reaction time: 1.33 h

Procedure:
To 50 ml of anhydrous THF cooled to −65° C. under the atmosphere of argon was added 10.9 ml of a 1.63 N n-butyl lithium/n-hexane solution, and a solution of 2.564 g of 5,7-dimethylimidazo[5,1-b]thiazole in 17 ml of anhydrous THF was further added dropwise at −64-−60° C. over a period of 15 minutes. The reaction mixture was then stirred at the same temperature for 80 minutes. After 5.0 ml of tri-n-butylstannyl chloride was added dropwise to the mixture at a temperature of −63-−58° C. over a period of 10 minutes, it was warmed to −30° C., and further stirred for 110 minutes. The reaction mixture was diluted with 100 ml of semi-saturated aqueous saline, extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The oil thus obtained was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1-−1:2) to give the title compound as a light orange oil in a yield of 6.164 g.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.Cl>O.CS(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:32])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: Oc1ccccc1OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCCCCCCCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 250 mL Erlenmeyer flask was added freshly ground potassium hydroxide (4.2 g, 74.91 mmol) and 100 mL dimethyl sulfoxide. 2-benzyloxy-phenol (5 g, 24.97 mmol) and 11-bromoundecanoic acid methyl ester (7 g, 25.07 mmol) was added and the mixture was allowed to stir at room temperature overnight. Water (75 mL) was added and the solution was heated to 85° C., with stirring, for 3 hours. The reaction was cooled to room temperature and acidified with concentrated hydrochloric acid to pH 2. The acidified solution was cooled to 4° C. for 2 hours, and the precipitate then collect by suction filtration. The product was recrystallized form ethanol/water. The product (8.88 g, 93%) was isolated as a light brown solid, mp 62-63° C. Combustion analysis: Found: C, 74.71; H, 8.08%; C24H32O4 requires C, 74.97; H, 8.39%;
Reaction SMILES: O.[OH-].[Li+].[C:4]1([CH:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([O:23]C)=[O:22])=[N:13]2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[C:4]1([CH:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([OH:23])=[O:22])=[N:13]2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1nn(C(C)c2ccccc2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)n1nc(C(=O)O)c2ccccc21
Temperature: 45 °C
Reaction time: 12 h
Yield: 58.1 %

Procedure:
To a mixed solution of lithium hydroxide monohydrate (0.68 g, 16.8 mmol) in tetrahydrofuran (20 mL) and water (10 mL), methyl 1-(1-phenylethyl)-1H-indazole-3-carboxylate (2.3 g, 8.4 mmol) was added. The mixture was stirred at 45° C. for 12 hours. Then the organic solvent was removed under reduced pressure. To the residue, 1 N hydrochloride aqueous solution was added to adjust the pH to 3-4, and then the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to afford 1-(1-phenylethyl)-1H-indazole-3-carboxylic acid (1.3 g, 60%) as a white solid, which was directly used in next step. LRMS (M+H+) m/z: calcd 266.29. found 266.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrBr.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[C:15]1([CH2:14][N:21]2[CH2:2][C:1](=[O:3])[C:4]3([CH2:5][CH2:6]3)[C:7]2=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: NCc1ccccc1
Agent: BrBr
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
Ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 41.153 mmol) was dissolved in 46 mL of EtOH. Bromine (2.32 mL, 45.2683 mmol) was slowly added to the solution. The resulting reaction mixture was stirred for 2 h, then concentrated in vacuo. The crude residue was dissolved in 46 mL of EtOH and the mixture was cooled to 0° C. with an ice water bath. To this solution was slowly added benzyl amine (11.2 mL 102.8825 mmol) and the reaction mixture was stirred at room temperature overnight, then concentrated in vacuo to dryness. The residue was dissolved in CH2Cl2 (200 mL) and 1N aq HCl (100 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (100 mL), the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel using an eluting system of hexane/EtOAc (60:40) provided 5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (2.4283 g 27%) as an orange solid. LCMS: (M+H)+: not detected.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:26](O)=[O:27])[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl-].[NH4+].C([N:34](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:26]([NH2:34])=[O:27])[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)O)C2=O)cnc1OCC(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(N)=O)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a mixture of 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (20 mg, 0.051 mmol, Intermediate-47, single enantiomer), ammonium chloride (8.1 mg, 0.15 mmol), and N,N-diisopropylethylamine in MeCN (2.0 mL) is added HBTU (23 mg, 0.061 mmol) at rt. The reaction mixture is stirred at rt for 1 hour. After removal of the solvent, the residue is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is purified by preparative LC-MS to give 10.2 mg (50% yield) of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1.CO>C1CCCCC1.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:12]2[CH2:13][CH2:14][N:10]([CH3:9])[C:11]2=[O:15])=[CH:19][N:18]=1
Reactant: CN1CCCC1=O
Reactant: ClCc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(Cc2ccc(Cl)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere at a temperature of from −78° C. to −60° C., 150 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise in the course of one hour to 20 g of N-methylpyrrolid-2-one in 50 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.0 g of 2-chloro-5-(chloromethyl)-pyridine in 40 ml of THF are added, and the mixture is stirred for a further 6 hours at that temperature and then for a further 6 hours at 0° C. 15 ml of methanol are added and the reaction mixture is then poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over magnesium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant The title compound (compound 1.4) is obtained in the form of a colourless oil.
Reaction SMILES: FC1C=C[C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1.CC1N=C(N2CCN(CC(=O)N3CCCC3)C2=O)SC=1C(OCC)=O>>[CH3:20][C:18]1[N:19]=[C:15]([N:12]2[CH2:13][CH2:14][N:10]([CH2:9][C:8](=[O:27])[N:7]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]2=[O:26])[S:16][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC(=O)N3CCCC3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC(=O)N3CCCC3)C2=O)sc1C(=O)O
Yield: 85 %

Procedure:
Following the procedure as described in Preparation 9, making variations as required to replace ethyl 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)imidazolidin-1-yl)thiazole-5-carboxylate, the crude title compound was obtained as a colorless solid in 85% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.84 (br s, 1H), 4.09-4.00 (m, 4H), 3.84 (s, 2H), 3.65-3.57 (m, 2H), 3.42 (t, J=6.7 Hz, 2H), 3.30 (t, J=6.7 Hz, 2H), 2.51 (s, 3H), 1.95-1.84 (m, 2H), 1.83-1.71 (m, 2H); MS (ES+) m/z 339.3 (M+1).
Reaction SMILES: [BrH:1].[S:2]1[C:6]([CH2:7]O)=[CH:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]1=2.C(Cl)(Cl)Cl>C(O)(=O)C.ClCCl>[Br:1][CH2:7][C:6]1[S:2][C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[CH:5]=1
Reactant: OCc1cc2ccccc2s1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: BrCc1cc2ccccc2s1
Reaction time: 3 h

Procedure:
HBr in acetic acid (6 mL) was added to a suspension of benzo[b]thiophen-2-ylmethanol (1 g, 6.1 mmol) in dichloromethane (6 mL) at room temperature. The reaction mixture was stirred for 3 hours then diluted by addition of chloroform (20 mL). The organic phase was washed with a saturated solution of hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated to dryness. The title product was obtained as a yellow oil (1.3 g, quantitative).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:8][C:9]([NH2:13])=[N:10][C:11]=1[CH3:12].[CH:20]([C:22]1[CH:23]=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][CH:27]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:13][C:9]1[N:10]=[C:11]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:20][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[C:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:8]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCNc1nc(N)nc(C)c1CCCCNCc1cccc(CC(=O)OC)c1
Reaction time: 72 h
Yield: 6.2 %

Procedure:
To the product of step (ii) (0.06 g), methyl 2-(3-formylphenyl)acetate (0.0403 g) and acetic acid (0.0136 g) in THF (10 mL) was added sodium triacetoxyborohydride (0.1102 g). The reaction mixture was stirred for 72 h, the solvents were evaporated and the residue dissolved in MeOH, acidified and purified via SCX resin, then RPHPLC to give the title compound 6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].[CH2:18]([NH:20][C:21]([NH2:23])=[O:22])[CH3:19].CC(C)([O-])C.[K+].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>O1CCOCC1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][C:21](=[O:22])[NH:20][CH2:18][CH3:19])[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: CCNC(N)=O
Reactant: O=C(Nc1cccnc1)c1cnc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Cl)c(C(=O)Nc2cccnc2)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Compound ii (1.0 g, 3.7 mmol) and N-ethylurea (362 mg, 4.1 mmol) were dissolved in degassed dioxane (50 mL) under an atmosphere of argon. Potassium tert-butoxide (628 mg, 5.6 mmol), Xantphos (129 mg, 0.22 mmol) and palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) were added sequentially. The mixture was heated at 100° C. with stirring under argon for 16 h. Additional palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) and N-ethylurea (560 mg, 6.4 mmol) were added and the mixture heated at reflux for 5 h. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and then adsorbed on to silica by concentration in vacuo. The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc) to afford iii as a light brown solid (244 mg, 20%). [M+H]+ m/z=320.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
A mixture of 4,4-bis(4-fluoro-phenyl)-1-chloro-butane (39.0 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (15.9 mg, 25.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.41 (s, 1H), 7.3-7.15 (m, 4H), 7.10 (m, 3H), 6.89 (apparent t, 5H), 3.81 (t, 1H, J=7.8 Hz), 3.30 (s, 1H), 2.91 (d, 1H, J=12,5 Hz), 2.80 (m, 1H), 2.40 (m, 2H), 2.31 (t, 1H, J=8.0 Hz), 1.93 (apparent q, 3H, J=8.0 Hz), 1.72 (m, 3H), 1.40 (m, 2H), 1.20 (m, 2H), 1.15 (d, 6H, J=8.1 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: BrCCCCCCCCCCCCBr
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: BrCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Yield: 50.1 %

Procedure:
A mixture of 6.56 g of 1,12-dibromododecane, 3.24 g of N-phenylpiperazine, 2.53 g of triethylamine, and 50 ml of toluene was heated under reflux for 2 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a 1:2 mixture of ethyl acetate and hexane as a developing solvent to yield 4.1 g of 1-bromo-12-(4-phenylpiperazinyl)dodecane (m.p.=26.0°-28.0° C.).