Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:30][NH:31][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH3:9])[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[C:23]=3[CH:22]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Reactant: NCC1CC1
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CC3)cc21
Yield: 86.1 %

Procedure:
By working in a manner similar to that described below in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (3.5 g) in dichloromethane (100 cc) and with cyclopropylmethylamine (3.8 g), N-(cyclopropylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (3 g) is obtained in the form of a cream-coloured product of meringue-like consistency, which is dissolved in acetonitrile (20 cc). A 2.4N solution (8 cc) of hydrochloric acid in ethyl ether is then added. The crystals are drained and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. N-(Cyclopropylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (2.6 g) is obtained in the form of white crystals, m.p. 220° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:43]=[CH:44][C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:39][CH:40]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc(N)cc2)on1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a stirred solution of 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-N-ethylisoxazole-3-carboxamide (1.45 g, 2.6 mmol) and ammonium chloride (1.4 g, 6.4 mmol, 10 eq.) in dioxane (18 mL) and water (3 mL) was added powered Zn (0.7 g, 10 mmol, 4 eq.). After heating at 100° C. for 2 hours, the solution was filtered and the filtrate was diluted with ethyl acetate and washed with 1 M NaHCO3 solution. After drying, the solvent was removed and the residue was chromatographed on silica gel eluting with hexane/ethyl acetate 3/1, to provide the title compound (0.69 g, 49% yield).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([CH:4]1[N:8]([C:18](=[O:21])[CH:19]=[CH2:20])[C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CCC(C)(C)N1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1CCC(C)(C)N1C(=O)C=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-allyl-2,2-dimethylpyrrolidine (1.5 g, 10.5 mmol) in 50 ml of anhydrous CH2Cl2, triethylamine (3 ml, 21 mmol) and acryloyl chloride (0.94 ml, 11.6 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for overnight. Analysis of the reaction mixture by LCMS indicated the completion of the reaction. Saturated aqueous NaHCO3 was added to the reaction mixture and the layers were separated. Aqueous layer was worked up twice with CH2Cl2 and the combined organic layers were dried over Na2SO4. Removal of the volatiles and purification of the crude by column chromatography gave the product in 80% yield (1.60 g) as colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:22]([OH:27])[OH:23])=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round-bottomed flask, diisopropylamine (Aldrich, 1.40 mL, 9.99 mmol) was dissolved into THF (6 mL). nBuLi (Aldrich, 2.5 M in hexanes, 3.60 mL, 8.99 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min then cooled to −78° C. 2-fluoro-5-methoxypyridine (0.520 g, 4.09 mmol) in 4 mL of THF was added slowly, and the mixture was stirred at that temperature for 40 min. Triisopropyl borate (Aldrich, 2.07 mL, 8.99 mmol) in a total of 4 mL of THF was added slowly and the mixture was stirred at −78° C. for 5 min. The cold bath was removed and the reaction mixture was stirred at room temperature for 1 h. 1 N NaOH (20 mL) was added to the mixture to quench the reaction. The layers were separated and the aqueous phase was treated with 5N HCl to adjust the pH to around 5. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.593 g of tan color solid. This material was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][C:18](Cl)=[O:19].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][C:18]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:19]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 25.0 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.0 g of 2-chloroacetic acid chloride. To the solution below 20° C., 10.7 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary post-treatment. Recrystallization from isopropyl ether gave 31.5 g of the target compound (yield 93%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:54][C:55](O)=[O:56])[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH3:53][O:52][C:50]1[CH:49]=[C:48]([CH2:54][C:55]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:56])[CH:47]=[C:46]([O:45][CH3:44])[CH:51]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc(OC)c1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-dimethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford 2-(3,5-dimethoxy-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 79%) as a white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.88 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.45 (s, 2H), 3.71 (s, 6H), 4.70 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.37 (t, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 2H), 7.51-7.67 (m, 1H), 7.72-7.81 (m, 2H), 8.61 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.83, 42.51, 48.82, 55.05, 98.34, 107.08, 121.88, 127.12, 131.51, 133.17, 134.61, 138.20, 139.18, 160.28, 166.90, 167.42, 169.77, 170.34, 172.73; Anal. Calcd. for C24H23N3O7: C, 61.93; H, 4.98; N, 9.03. Found: C, 61.62; H, 4.61; N, 8.91.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:30]([N:12]1[C:13]2[CH2:1][N:2]([C:14]3[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirred solution of Example 8 (200 mg, mmol) in DMF (mL) was added potassium t-butoxide (150 mg) at 0° C. After stirring at 0° C. for 15 min., benzyl bromide (0.1 mL, mmol) was added slowly. After completion of addition, the reaction mixture was allowed to attain room temperature and stirred for a further 3 hours. After completion of reaction, the reaction mixture was diluted with EtOAc. The organic layer was separated and washed with saturated sodium bicarbonate and water. After drying the organic layer using sodium sulfate, it was concentrated to obtain a crude product that was then purified by column chromatography to obtain methyl 2-(9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylate (200 mg, 77.0% yield), m/e=398.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 73 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.052 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:32]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 2-chlorobenzoyl chloride (1.3 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at room temperature for 4 hours.
Reaction SMILES: [CH:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>C1(C)C=CC=CC=1>[CH:1]1([NH2:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CC2CCCc3cccc1c32
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: NC1CC2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-ol and diphenylphosphoryl azide (9.31 g) in toluene (90 ml) was added DBU (diazabicycloundecene) (5.04 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with toluene. The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated. The crude product was dissolved in a mixed solvent (77 ml) of THF/water (10:1), triphenylphosphine (9.61 g) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the solvent was evaporated, 1N hydrochloric acid (100 ml) was added to the residue, and unnecessary substances were removed by extraction with ethyl acetate. The aqueous phase was alkalified with potassium carbonate, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 146-147° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.23-7.17 (m, 1H), 6.55 (t, J=5.7 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.06-3.99 (m, 2H), 3.57-3.52 (m, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.44-1.37 (m, 2H), 0.65-0.54 (m, 1H), 0.43-0.35 (m, 2H), 0.06-0.01 (m, 2H): 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.3, 153.5, 149.0, 148.6, 135.7, 134.1, 123.6, 116.7, 44.0, 42.4, 42.0, 41.2, 32.4, 17.2, 8.4, 4.3: MS (ES+) m/z 386.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[O:14][CH2:19][CH2:18][Br:17])=[CH:15][CH:16]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: OCCBr
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Yield: 8380.7 %

Procedure:
A mixture of 4,4′-dichlorobenzhydrol (4.40 g, 0.17 mmol) and 2-bromoethanol (3.0 g, 24.0 mmol) in benzene (50 ml) was treated with sulfuric acid (0.25 ml) and the resulting mixture was heated under reflux for 1 h. The cooled mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and hexane (1:1) as eluent to give the title compound as a clear oil (5.13 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1C
Product: COC(=O)c1nc(C)sc1-c1cccc(C)c1C

Procedure:
prepared by reaction of 3-chloro-3-(2,3-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=262.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]>[Cl:14][C:15]1[CH:16]=[C:17]([N:1]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)[C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Clc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1cccc(N(c2ccc(-c3ccccc3)cc2)c2cccc(Cl)c2)c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 5.3 grams of 4-aminobiphenyl, 25.0 grams of m-chloroiodobenzene and 16.5 grams of potassium carbonate in 150 milliliters of dimethyl sulfoxide was mechanically stirred and heated to 110° C. in a round-bottomed flask fitted with a reflux condenser under a nitrogen atmosphere. Subsequently, 9.5 grams of copper bronze powder was added, and the temperature of the reaction mixture was raised to 170° C. After 48 hours, the reaction mixture was filtered while still hot, and the filtrate was evaporated under reduced pressure to provide a viscous oil. Purification by column chromatography on neutral alumina using a mixture of methylene chloride and hexane (1:10) as the eluent afforded 7.9 grams of analytically pure bis(m-chlorophenyl)-4-biphenylylamine.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.O[CH:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:29]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(O)Cc1ccccc1
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Yield: 55.2 %

Procedure:
Following the procedure described in Step 2 of Example 4, 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (2.38 g, 5.62 mmol) was coupled to ethyl 2-hydroxy-3-phenylpropanoate (1.65 g, 8.50 mmol) in presence of triphenylphosphine (2.23 g, 8.50 mmol) and diisopropylazodicarboxylate (1.7 mL, 8.5 mmol) in benzene (62 mL). Purification by HPLC, using 95% acetonitrile in water as the mobile phase, yielded ethyl 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a yellow gum (1.86 g). 1HNMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.25 (d, 1H, J=7.7 Hz), 8.1 (d, 1H, J=7.7 Hz), 7.95-8.1 (m, 2H), 7.85 (d, 1H, J=7.7 Hz), 7.4-7.5 (m, 5H), 7.2-7.4 (m, 3H), 5.5 (t, 1H, J=6.0 Hz), 4.1 (q, 2H, J=7.0 Hz), 2.75 (t, 2H, J=7.0 Hz), 1.45-1.6 (m, 2H), 1.05-1.25 (m, 6H), and 0.7 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1/[CH:21]=[CH:22]/[C:23](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: O=C(Cl)/C=C/c1cccs1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.