Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:16][O:17][CH3:18])[CH:3]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CS(C)=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:16][O:17][CH3:18])[CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CO)n1
Reactant: C1CNCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCn1cc(Br)sc1=Nc1cccc(CN2CCNCC2)n1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a mixture of 330 mg (1.00 mmol) of (6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-yl)-methanol, 0.348 ml (2.00 mmol) of N,N-diisopropylethylamine and 15 ml of chloroform was added 0.116 ml (1.50 mmol) of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was washed with brine, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in 4 ml of dimethyl sulfoxide and dropped into 2 ml of a solution of 861 mg (10.0 mmol) of piperazine in dimethyl sulfoxide and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction solution was filtered and purified by a reversed phase preparative liquid chromatography to give 281 mg (0.706 mmol) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([N:13]([C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[CH3:25])[OH:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].O.Cl>CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]([C:16]2[C:15](=[O:26])[N:13]([OH:14])[C:5]3([CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]3)[C:3]=2[OH:2])=[C:22]([CH3:23])[CH:21]=1
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(Cl)cc2C)CCN(OC)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(Cl)cc1C)C(=O)N2O
Reaction time: 8 h

Procedure:
To a suspension of 4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (0.40 g, 1.04 mmol) in dimethylformamide (3 ml) at 0° C. was added potassium tert-butoxide (0.35 g, 3.12 mmol) in portions. After completion of the addition, stirring was continued at 0° C. for 30 minutes and at room temperature overnight. The reaction mixture was poured into cold water (0° C.), the pH adjusted to ca 5.5 by adding 1 N HCl and then thoroughly extracted with ethyl acetate (three times). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by column chromatography on silica gel (gradient ethyl acetate/cyclohexane 1:1→ethyl acetate). Yield: 0.14 g of 3-(4-chloro-2,6-dimethyl-phenyl)-1,4-dihydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.103) as a white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5]C=CC=1.[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]3[O:25][C:26]([C:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=4)=[CH:27][CH:28]=3)=[O:23])=[CH:16][C:15]=12.N1[CH:36]=CN2C=CC(CNC(=O)C3C=CC(C4CCNCC4)=CC=3)=CC=12>>[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]3[O:25][C:26]([C:29]4[CH2:30][CH2:31][N:32]([S:7]([CH2:1][CH:6]([CH3:5])[CH3:36])(=[O:8])=[O:9])[CH2:33][CH:34]=4)=[CH:27][CH:28]=3)=[O:23])=[CH:16][C:15]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2=CCNCC2)o1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Product: CC(C)CS(=O)(=O)N1CC=C(c2ccc(C(=O)NCc3ccn4ccnc4c3)o2)CC1

Procedure:
The title compound was prepared as described in Example 682, substituting 2-methylpropane sulfonyl chloride for benzenesulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide for N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide. 1H NMR (300 MHz, DMSO-d6). δ ppm 9.04-8.96 (m, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.89-7.87 (m, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J=3.5 Hz, 1H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.62-6.57 (m, 1H), 6.56-6.51 (m, 1H), 4.47 (d, J=6.1 Hz, 2H), 3.97-3.91 (m, 2H), 3.40 (t, J=5.7 Hz, 2H), 2.97 (d, J=6.5 Hz, 2H), 2.54-2.48 (m, 2H), 2.19-2.05 (m, 1H), 1.07-1.01 (m, 6H); MS (ESI(+)) m/e 443 (M+H)+.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C@H:7]([OH:23])[CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([F:22])[CH:11]=2)[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[C:30](C1NC=CN=1)(C1NC=CN=1)=[O:31]>C(Cl)Cl>[F:22][C:12]1[CH:11]=[C:10]([N:9]2[CH2:8][C@H:7]([CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[O:23][C:30]2=[O:31])[CH:15]=[CH:14][C:13]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 20 h
Yield: 79.1 %

Procedure:
N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline (57 gm) is dissolved in methylene dichloride (600 ml), carbonyl diimidazole (32 gm) is added at ambient temperature and the reaction mixture is stirred for 20 hours. The reaction mass is washed with water and methylene dichloride is distilled to give 48 gm of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide as solid.
Reaction SMILES: [CH3:1][C:2]12[C:10]([CH3:12])([CH3:11])[CH:6]([NH:7][CH2:8][CH2:9]1)[CH2:5][C:4]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:3]2=1>CC(C)=O>[CH3:1][C:2]12[C:10]([CH3:11])([CH3:12])[CH:6]([NH:7][CH2:8][CH2:9]1)[CH2:5][C:4]1[CH:3]=[CH:16][CH:15]=[C:14]([OH:17])[C:13]2=1.[CH3:12][C:10]1([CH3:11])[CH2:6][NH:7][CH:8]2[CH2:5][C:4]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:3]=3[CH:9]2[CH:2]1[CH3:1]
Reactant: CC12CCNC(Cc3cc(O)ccc31)C2(C)C
Solvent: CC(C)=O
Product: CC12CCNC(Cc3cccc(O)c31)C2(C)C
Product: CC1C2c3ccc(O)cc3CC2NCC1(C)C

Procedure:
2-(3-Methoxy-benzyl)-3,3-dimethyl-4-methylene-piperidine-1-carbaldehyde (for preparation see J. Med. Chem. 1997, 40, 2928-2939; 47.5 g) is combined with 48% HBr in water (300 mL). The mixture is heated to reflux temperature and stirred at this temperature for 24 h. After cooling to ambient temperature, the precipitate is separated by filtration, washed with water, and triturated with acetone. Then, the precipitate is taken up in a mixture of 1 N aqueous NaOH solution and CH2Cl2. The CH2Cl2 phase is separated, dried (Na2SO4), and concentrated. The residue is recrystallized from EtOAc to afford 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol. The filtrate of the reaction mixture is combined with the water and acetone phases (from washing and triturating the precipitate) and basified using concentrated aqueous ammonia solution. The resulting mixture is extracted with CH2Cl2, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is purified by chromatography on silica gel (EtOAc/MeOH/NH4OH 90:10:1->70:30:3) to afford 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-ol and 3,3,4-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol separated.
Reaction SMILES: ClS(O)(=O)=O.[CH3:6][O:7][C:8](=[O:23])[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=2)[CH2:11]1.[CH3:24][O:25][C:26](=[O:41])[CH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[S:37](Cl)(=[O:39])=[O:38])[CH2:29]1.[F:42][C:43]([F:57])([F:56])[C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:46][CH:45]=1.C(N(CC)CC)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:6][O:7][C:8](=[O:23])[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:19]([N:53]3[CH2:52][CH2:51][N:50]([C:47]4[CH:46]=[CH:45][C:44]([C:43]([F:56])([F:57])[F:42])=[CH:49][CH:48]=4)[CH2:55][CH2:54]3)(=[O:21])=[O:20])[CH:16]=2)[CH2:11]1.[CH3:24][O:25][C:26](=[O:41])[CH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[S:37]([N:53]2[CH2:52][CH2:51][N:50]([C:47]3[CH:46]=[CH:45][C:44]([C:43]([F:56])([F:57])[F:42])=[CH:49][CH:48]=3)[CH2:55][CH2:54]2)(=[O:39])=[O:38])[CH2:29]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CC1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: COC(=O)CC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC1Cc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2C1
Product: COC(=O)CC1Cc2cccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19 %
Yield: 6 %

Procedure:
Indanyl-2-acetic acid methyl ester (1.0 g, 5.26 mmol) was added to a stirring solution of chlorosulfonic acid (5 mL) at 0° C. The solution was stirred at 0° C. for 0.5 h, then room temperature for 3 h. The resulting solution was poured slowly over ice and extracted with diethyl ether (3×100 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford a mixture of 5-chlorosulfonyl-indan-2-acetic acid methyl ester and 4-chlorosulfonyl-indan-2-acetic acid methyl ester (1.38 g, 4.78 mmol. 91%). The sulfonyl chloride mixture was taken on to the next step without further purification. The mixture of sulfonyl chlorides (370 mg, 1.28 mmol) were dissolved in dry THF (10 mL). To this solution was added 1-(4-trifluoromethylphenyl)piperazine (315 mg, 1.37 mmol), triethylamine (600 μL, 4.3 mmol) and DMAP (catalytic amount). The reaction was stirred at room temperature for 1 h, concentrated and directly purified by silica gel flash column chromatography to separate the regioisomers (25% ethyl acetate in hexanes) affording {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (118 mg, 19%) and {4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (40 mg, 6%) as clear colorless oils. {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) 7.57 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.33 (d, 1H), 6.87 (d, 2H), 3.69 (s, 3H), 3.33 (m, 4H), 3.21 (dd, 2H), 3.14 (m, 4H), 2.95 (m, 1H), 2.71 (dd, 2H), 2.52 (d, 2H).
Reaction SMILES: [OH-:1].[Na+].Cl.[C:4]1([C:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[C:13](=[O:19])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:26]([O:29]CC)(=[O:28])[CH3:27]>>[C:26]([OH:29])(=[O:28])[C@@H:27]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:1].[C:20]1([C:10]2([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C@@H:18]3[C@@H:14]([CH2:15][NH:16][CH2:17]3)[C:13](=[O:19])[CH2:12][CH2:11]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)[C@H](O)c1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@@H]12

Procedure:
50 cm3 of aqueous 4N sodium hydroxide are slowly added to a suspension of 20 g of (3aRS,7aRS)-7,7-diphenyl-perhydroisoindol-4-one hydrochloride in 250 cm3 of ethyl acetate, while stirring; stirring is continued until the starting substance has disappeared. The organic solution is washed with 100 cm3 of distilled water and with 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. A solution of 9.3 g of D-(-)mandelic acid in 50 cm3 of ethyl acetate is added to the solution thus obtained, while stirring. The crystals formed are filtered off, drained, washed with 50 cm3 of ethyl acetate (twice) and dried. The crystals are taken up in a solution of 220 cm3 of acetonitrile and 60 cm3 of distilled water and the mixture is refluxed for 15 minutes, while stirring; the crystals formed are filtered off and recrystallised in a mixture of 100 cm3 of acetonitrile and 35 cm3 of distilled water. 6.4 g of (3aS,7aS)-7,7-diphenyl-perhydroisoindol-4-one D-mandelate are obtained.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:20][NH:21][CH3:22]>CO>[CH3:20][N:21]([CH3:22])[CH2:3][CH2:2][C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Reactant: CNC
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN(C)C)CC2
Temperature: 65 °C
Yield: 70.5 %

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.8 g, 3 mmol) in methanol (10 mL) was treated with dimethyl amine (10 mL, 2 M in THF, 20 mmol, Aldrich) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 20% methanol/dichloromethane) to give N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1 H)-isoquinolinyl]-3-oxo-1-propanamine (0.65 g, 71%). ESIMS (M+H)+=308.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]=[O:25]>O1CCCC1>[F:20][C:21]([F:27])([F:26])[CH2:22][CH2:23][CH:24]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[OH:25]
Reactant: O=CCCC(F)(F)F
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of the ethyl 4-iodobenzoate (1.21 ml, 7.24 mmol) in tetrahydrofuran (12 ml) at −40° C. was added isopropylmagnesium chloride lithium chloride complex (6.13 ml, 7.97 mmol, 1.3 M in tetrahydrofuran) dropwise. The mixture was stirred for approximately 1 hour whereupon 4,4,4-trifluorobutanal (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred at −40° C. for 15 minutes and slowly warmed to ambient temperature over 12 hours. The reaction was quenched with aqueous 1.0 M hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl (+/−)-4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate, which was used without further purification.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH2:11][C@H:12]1[CH2:16][C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13]1)=[CH2:10])[CH3:6].C(N(CC)CC)C>>[CH2:5]([O:7][C:8](=[O:25])[CH:9]([CH2:10][S:3][C:1](=[O:4])[CH3:2])[CH2:11][C@H:12]1[CH2:16][C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13]1)[CH3:6]
Reactant: CC(O)=S
Reactant: C=C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
Thioacetic acid (4 mL), which had been cooled to 0° C., was added to a mixture of 2-(cis4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-acrylic acid ethyl ester (0.56 g, 1.9 mmol) and triethyl amine (0.28 mL, 2.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 19 h and then poured onto ice-water (400 mL). The aqueous layer was extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3, dried and concentrated under reduced pressure to give 1.7 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded 2-acetylsulfanylmethyl-3-(cis4-tert-butoxycarbonylamino-cyclopent-2-enyl)-propionic acid ethyl ester (0.46 g, 65%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccc(-n3cnc4ccccc43)n2)CC1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) (115 mg, 0.42 mnmol) and 1-Benzyloxycarbonyl-4-(aminomethyl)piperidine (122 mg, 0.49 mmol) were dissolved in DMF-toluene (1:1, 5 mL), and the mixture was heated at 100° C. for 5 h. After cooling, the mixture was diluted with EtOAc and washed with H2O to remove DMF followed by brine. The organic extract was dried over Na2SO4, and the solvent was removed under reduced pressure to give 105 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.38 (br s, 1H); 8.18 (m, 1H); 7.85 (m, 1H); 7.4-7.28 (m, 7H); 6.79 (d, J=5.5 Hz); 5.12 (s, 2H); 4.22 (br s, 2H); 3.43 (m, 1H); 2.78 (br s, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>O1CCCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=4)=[O:11])[CH2:26]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Reactant: O=C=Nc1ccc(CCl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of 4-(chloromethyl)phenylisocyanate (0.38 g) in tetrahydrofuran was added dropwise under ice cooling into a solution of 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (0.5 g) in tetrahydrofuran. The resulting mixture was stirred for one hour and was then evaporated to remove the solvent to obtain 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)benzyl chloride (0.82 g) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:16][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:6][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCO1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: O=C(CCCCO)OCc1ccccc1
Temperature: 65 °C
Yield: 15 %

Procedure:
A solution of δ-valerolactone (10 g, 100 mmol) in 1M aqueous sodium hydroxide (100 mL) was heated overnight with stirring at 65° C. The solution was concentrated in vacuo to dryness and any residual water removed under high vacuum at −190° C. The resulting white powder was broken up and suspended in acetone (40 mL). With stirring, benzyl bromide (17 g, 101.4 mmol) and tetrabutylammonium bromide (0.82 g, 2.539 mmol) were added. The mixture was heated at 45° C. with stirring for 72 hours, cooled, and concentrated. The resulting white oily powder was dissolved in ethyl acetate (300 mL) and washed twice each with saturated NaHCO3 and brine. The organic portion was dried over anhydrous MgSO4, filtered, and then concentrated. The result was a yellow oil, which was purified by column chromatography (column 10″L×2″W; eluted with a gradient of 100% hexanes→30%→50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.11 g, 15%).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc2nccc(O)n2n1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nccc(Cl)n2n1
Yield: 60.1 %

Procedure:
To a suspension of the product obtained in Step 1 (35 g) in 400 ml phosphorus oxychloride 24 g of N,N-dimethylaniline was dropwise added at room temperature. The mixture was refluxed for two hours, excess phosphorus oxychloride was removed by distillation under normal pressure, and the reddish brown oil left was dissolved in 1.5 liters of chloroform. This solution was slowly poured into 800 ml of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after thorough mixing, and the aqueous layer was again extracted with one liter of fresh chloroform. The organic layers were joined together, washed with 500 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to about 100 ml, and 200 ml of n-hexane was added to this concentrate, giving 20 g of the objective compound as faint yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.[Cu]I>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[O:28][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(c1ccncc1Br)N1CCCc2ccccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccncc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 180 °C
Yield: 9.6 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (41.2 mg, 0.13 mmol, 1.0 equiv) and 2,5-dichloro-phenol (21.2 mg, 0.13 mmol, 1.0 equiv; [CAS RN 583-78-8]) in DMAc (1 mL) was added potassium carbonate (35.9 mg, 0.26 mmol, 2.0 equiv; [CAS RN 584-08-7]) and copper(I) iodide (5.0 mg, 0.026 mmol, 0.2 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 180° C. for 8 h. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 5 mg (10%) of the title compound. MS (ISP): 399.1 [M+H]+.
Reaction SMILES: [CH:1]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][CH:15]([NH:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
The crude 2-{2-[4-(benzhydryl-amino)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (2.70 g) was dissolved in ethanol (5 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×15 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product [1-(2-amino-ethyl)-piperidin-4-yl]-benzhydryl-amine was obtained (0.150 g, 7.9% yield).