Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](C)([CH2:9][C@H:10]1[CH2:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)[C:5](OC)=O.[Na+].[Cl-].CS(C)=O>O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([CH3:5])[CH2:9][C@H:10]1[CH2:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1
Reactant: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Yield: 39.5 %

Procedure:
The ester 92 (483 mg, 1.4 mmol), NaCl (104 mg, 1.8 mmol), water (105 μL) and DMSO (5 mL) were heated to reflux for 2 hours. The solution was cooled to room temperature water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (80% to 66% hexane/acetone) of the residue gave the product as an oil (160 mg, 40%). MS m/z 290 (M+H, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN(C)[C@@H]1CCCC[C@H]1N.[CH3:41][OH:42]>[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CO
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Product: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.150 g, 0.357 mmol) in 3 mL of MeOH under an atmosphere of nitrogen was added trans-N,N-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 4 h, cooled to rt and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.03-8.99 (m, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H), 7.70-7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.39 (s, 2H), 4.01 (br s, 1H), 3.90 (s, 3H), 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1.42 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[Br:25][C:26]1[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]([C:31]([N:6]([CH2:5][C:4]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[CH2:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:32])[NH:29][CH:30]=1
Reactant: COc1ccc(CNCC#Cc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: O=C(O)c1cc(Br)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN(CC#Cc2ccc([N+](=O)[O-])cc2)C(=O)c2cc(Br)c[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23B (1 g, 3.07 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 4-bromo-1H-pyrrole-2-carboxylic acid (0.67 g, 3.53 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.77 g, 4 mmol), 1-hydroxybenzotriazole hydrate (0.61 g, 4 mmol) and triethylamine (0.4 g, 4 mmol). The reaction was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified flash chromatography (20% ethyl acetate in hexane) to afford the title compound. LC-MS (ESI): m/z 500, 498 (M+H), RT: 2.37 min; 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 3.75 (s, 3H), 3.78 (s, 3H), 4.51 (s, 2H), 4.77 (s, 2H), 6.53 (dd, J=6.4, 2.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 7.09 (dd, J=1.2, 1.6 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 8.21 (d, J=9.2 Hz, 2H), 12.02 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1)(=[O:30])=[O:29].Cl>O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([S:28]([C:31]3[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL), the pH of the medium was brought to 4 with 2 N HCl, and extracted with ethyl acetate. The extract was washed successively with water, brine, and dried (Na2SO4). The solvent was removed and the crude product was crystallized from dioxane to give the title compound (0.58 g, 63%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 2.19-2.50 (4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6 and 5.6 Hz); 7.72 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([C:31]3[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)=[O:30])[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].O1CCCC1.O>O>[CH3:54][O:53][C:49]1[CH:48]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([C:31]3[N:35]([CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)=[O:30])[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CCOC(=O)CCCn1c(C(=O)C2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4CCCC(=O)O)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 5 °C
Reaction time: 20 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(3-ethoxycarbonyl-propyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-(3,4-dichloro-phenyl)-pyrrolidine (0.32 g, 0.41 mmol) and lithium hydroxide hydrate (0.052 g, 1.23 mmol) in 4/1 tetrahydrofuran/water (20 mL). After 20 hours, dilute the reaction mixture with water and evaporate in vacuo to remove most of the tetrahydrofuran. Acidify to pH 2 using 1 M hydrochloric acid solution and cool to 5° C. to obtain a solid. Collect the solid by filtration. Suspend the solid in diethyl ether (150 mL) and stir. After 18 hours, collect the solid by filtration and dry to give the title compound: mp; 125-140° C. Elemental Analysis calculated for C39H44Cl2N4O7·HCl: C 59.43; H 5.75; N 7.11; Found: C 59.55; H 5.81; N 6.94.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:8][C:4]1[N:3]=[C:2]([NH:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC1CCCCC1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(NC2CCCCC2)n1

Procedure:
Was prepared according to Example 1 from 2,6-dichloropyrazine and cyclohexylamine.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].CNCCNC.C([Li])CCC.CC1C=CC(S(O[CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)(=O)=O)=CC=1>O1CCCC1.O>[CH3:1][C:2]1([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: CC1C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCc2cncnc2)cc1
Agent: CNCCNC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes. p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3-methyloxindole (682 mg, 4.63 mmol) and N,N′-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to −78° C. and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0° C. and stirred for 15 minutes. The mixture was recooled to −78° C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][C:10]#[N:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][C:10]#[N:11])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC#N
Product: N#CCC(O)c1cc(Br)cs1

Procedure:
Addition of CH3CN to 4-bromothiophene-2-carbaldehyde following the method used in Example 2 gave 3-(4-bromothiophen-2-yl)-3-hydroxypropanenitrile as a light brown oil which was used in the next step without additional purification. Yield (1.95 g, 80%).
Reaction SMILES: [OH:1][P:2]([OH:5])([OH:4])=[O:3].S([O-])([O-])(=O)=O.[Zr+4:11].S([O-])([O-])(=O)=O>>[P:2]([O-:5])([O-:4])([OH:3])=[O:1].[Zr+4:11].[P:2]([O-:5])([O-:4])([OH:3])=[O:1]
Reactant: O=P(O)(O)O
Agent: [Zr+4]
Agent: O=S(=O)([O-])[O-]
Product: O=P([O-])([O-])O
Reaction time: 48 h

Procedure:
93 ml of 10.33M H3PO4 are introduced into a reactor fitted with a condenser and a paddle stirrer. The H3PO4 is then brought to the boil (stirring at 300 rev/minute) using an oil bath on a heating plate, in which the temperature is controlled by means of a contact thermometer. At this point, 0.064 mol of zirconium sulphate is introduced. The pasty product becomes pale yellow (over 1/2 h). The temperature is then lowered to 80° C. and the mixture is left for 48 hours. After cooling, the product obtained is recovered and is centrifuged for 25 minutes. The product is washed a first time with hot water (80° C.) and then with cold water until the washing waters have a pH of 4. The product is dried under vacuum for 40 hours.
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[CH2:9]([Mg]Cl)[CH:10]=[CH2:11]>C1COCC1>[CH2:11]([SiH:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH:10]=[CH2:9]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CC[SiH](C(C)C)C(C)C
Temperature: 40 °C
Yield: 86.8 %

Procedure:
Diisopropylchlorosilane (2.11 g, 14.0 mmol) was dissolved in anhydrous THF (12 mL) and treated with 1.2 equivalents of allylmagnesium chloride (8.4 mL, 2.0 M in THF, 16.8 mmol). The reaction was heated to 40° C. for 4 hours, then cooled and quenched with water (10 mL) and dilute sulfuric acid (10 mL), and extracted into pentane (2×50 mL). The organic layers were combined and washed with water (5×10 mL), then dried over MgSO4, filtered, and concentrated via rotary evaporator (carefully, product is volatile) to yield crude allyldiisopropylsilane (1.9 g). No further purification was performed.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1.[I-:25].[Na+]>C(#N)C>[I:25][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1
Reactant: [I-]
Reactant: O=c1c2c(ncn2CCCCl)c2cccnc2n1-c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=c1c2c(ncn2CCCI)c2cccnc2n1-c1ccccc1
Yield: 71.5 %

Procedure:
To 200 ml of acetonitrile were added 18 g (0.052 mol) of Compound 68 obtained in Example 68 and 12 g (0.078 mol) of sodium iodide, and the mixture was refluxed for 24 hours. In the course of refluxing, 7.8 g (0.052 mol) of sodium iodide was added to the mixture. After cooling, the solvent was evaporated under reduced pressure and water was added to the residue. Then, extraction was carried out with chloroform, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a crude product. Recrystallization from ethyl acetate-nhexane gave 16 g (yield 73%) of Compound 69.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)nc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of 1-(5-bromopyridin-2-yl)-piperazine (310 mg,1.28 mmol) (prepared in Example 3(b)) and 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (215 mg, 1.16 mmol) (prepared in Example 1(a)) in toluene (10 mL) was heated at reflux for 18 h. The heating was discontinued and the solution allowed to cool to room temperature during which time a colourless solid precipitated out of solution. The solid was collected by filtration and dried in vacuo to yield 3-[4-(5-bromopyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (420 mg, 97%). δH (300 mhz CDCl3) 2.58 (4H, m, piperazinyl), 3.51 (4H, m, piperazinyl), 3.75 (2H, s), 6.50 (1H, d, J=9.0), 7.09 (1H, dd, J=5.0 and 7.9), 7.27 (1H, s), 7.49 (1H, dd, J=2.6 and 9.0), 8.10 (1H, d, J=7.8), 8.17 (1H, d, J=2.3), 8.32 (4.5), 9.69 (1H , br s) ESMS 374 (MH+)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].ClCCCC(C1C=CC=CC=1)=O.Cl.[C:27]1([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.Cl.C1C2C(=CC=CC=2)C=CC=1OC1CCNCC1>>[ClH:1].[C:27]1([O:37][CH:38]2[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)=[O:6])[CH2:40][CH2:39]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1ccc2c(OC3CCNCC3)cccc2c1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: c1ccc2cc(OC3CCNCC3)ccc2c1
Product: O=C(CCCN1CCC(Oc2cccc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
When in the procedure of Example 13, 4-chloro-1-(4-fluorophenyl)-1-butanone is substituted for 4-chloro-1-phenyl-1-butanone and 4-(1-naphthalenyloxy)piperidine hydrochloride is substituted for 4-(2-naphthalenyloxy)piperidine hydrochloride, 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced. M.P. 220°-222.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1

Procedure:
5-(3-Nitrophenyl)-1H-tetrazole (4.41 g) was hydrogenated in ethanol (50 ml) over 10% palladium on carbon (0.4 g) under 3 atmospheric pressure of hydrogen at ambient temperature. The reaction mixture was filtered through Celite® (Johns Manville) and washed with ethanol. The filtrate and the washings were combined and evaporated to give 5-(3-aminophenyl)-1H-tetrazole as a crystalline powder, which was triturated in diisopropyl ether and collected by filtration to afford the desired product as a white powder (3.19 g, 85.8%). This was used in a following reaction without further purification.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[S:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.C1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: c1ccsc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (150 mg, 0.39 mmol, prepared in example 1), thiophene-3-benzene boronic acid (74 mg, 0.56 mmol), potassium carbonate (80 mg, 0.56 mmol) and tetrakis(triphenyl phosphine)palladium(0) (31 mg, 0.027 mmol) were combined in dioxane/water (15 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (236 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 7:3 to yield the title compound (107 mg, 81%) as a white solid. Ion spray M.S. 340.0 (M*−1).
Reaction SMILES: [CH3:1][CH:2]([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:37][CH3:38])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]3[C:35](=[CH:36][C:6]=2[N:5]=1)[CH:34]=[CH:33][CH:32]=[CH:31]3
Reactant: CCC(C)Cc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)Cc1nc2cc3ccccc3cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylbutyl)-naphtho[2,3-d]imidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15](O)=O)[CH2:11][CH2:10]1.[OH-].[Na+]>Cl>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: J. Heterocyclic Chem., 1989, 26, 54. A mixture of benzene-1,2-diamine (12.6 g, 116 mmol), piperidine-4-carboxylic acid (15 g, 116 mmol) and 4M aqueous HCl (250 mL) is stirred and heated under reflux for 48 h. The reaction mixture is cooled to room temperature and is made basic by addition of 5M aqueous NaOH. The precipitate formed is collected by suction filtration, washed with water and dried in the vacuum oven to afford 8.8 g (38%) of 2-(piperidin-4-yl)-1H-benzimidazole. m/z=202 [M++H].
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CCN=C=NCCCN(C)C.Cl.[NH2:34][C:35]1[CH:59]=[CH:58][C:57]([N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:56][C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=2)=[N:44][CH:45]=1)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=[O:4])[C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:34][C:35]2[CH:59]=[CH:58][C:57]([N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:56][C:36]=2[C:37](=[O:38])[NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)=[N:42][CH:41]=2)=[O:10])[CH:6]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (186 mg, 0.64 mmol, 2.00 equiv) in dichloromethane (10 mL), EDC.HCl (92 mg, 0.48 mmol, 1.50 equiv), 4-dimethylaminopyridine (59 mg, 0.48 mmol, 1.50 equiv), and 2-amino-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (140 mg, 0.32 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 191 mg (71%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.97 (m, 2H), 9.66 (s, 1H), 9.25 (s, 2H), 8.63 (m, 2H), 7.99 (m, 4H), 7.79 (m, 1H), 7.63 (m, 2H), 7.42 (s, 1H), 7.26 (m, 1H), 3.99 (m, 2H), 3.83 (m, 2H), 3.61 (m, 4H), 3.43 (m, 2H), 3.24 (m, 6H), 2.95 (s, 3H), 1.59 (m, 6H). MS (ES, m/z): 716 [M+H]+.