Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 75 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 4-[3-(1-naphthylsulfonylmethyl)-4-nitrophenoxy]piperidin-1-ylcarboxylic acid benzyl ester (3.90 g, 6.96 mmol) in ethyl acetate was treated sequentially with ethanol and tin (II) chloride dihydrate (24.0 g, 106 mmol), stirred at 75° C. under nitrogen for 3 hours and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and water. The phases were separated; the organic phase was washed with 2.5 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo for 20 minutes at 78° C. to yield 4-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-piperidine-1-carboxylic acid benzyl ester as a dark yellow film, 3.3 g (89% yield), Mass spectrum (+EI, [M+H]+) m/z 531. 1HNMR (500 MHz, DMSO-d6): δ8.57 (d, 1H, J=8.54 Hz), 8.24 (d, 1H, J=8.17 Hz), 8.03-8.06 (m, 1H), 8.00 (dd, 1H, J=7.44 Hz and 1.22 Hz), 7.58-7.69 (m, 3H), 7.27-7.38 (m, 5H), 6.53-6.58 (m, 2H), 5.97 (d, 1H, J=2.56 Hz), 5.04 (s, 2H), 4.71 (s, 2H), 4.64 (s, 2H), 3.61-3.66 (m, 1H), 3.47-3.53 (m, 2H), 2.99-3.05 (m, 2H), 1.43-1.48 (m, 2H), 1.10-1.19 ppm (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[S:24][CH2:23][C:22](=O)[CH2:21][C:20]2=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:22]2[CH2:21][C:20]3[C:19]4[C:28](=[CH:29][CH:30]=[C:17]([O:16][CH3:15])[CH:18]=4)[N:27]=[CH:26][C:25]=3[S:24][CH2:23]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc3c(c2c1)CC(=O)CS3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)OC(C)(C)C)CC1)CS3
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (2.45 g, 12.22 mmol, 2.0 eq), 6-methoxy-4H-1-thia-9-aza-phenanthren-3-one (1.50 g, 6.11 mmol, 1.0 eq) and p-toluenesulfonic acid (526 mg, 3.06 mmol, 0.5 eq) in toluene (50 mL) is heated at 120° C. for 2 hours. The resulting solution is cooled down to room temperature, solvent is removed and the crude is dissolved in dichloromethane (100 mL) and methanol (100 mL) before the addition of acetic acid (0.5 mL, 8.66 mmol, 1.4 eq) and sodium cyanoborohydride (1.24 g, 19.73 mmol, 3.2 eq). After 1 h 30 stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and a saturated sodium hydrogen carbonate aqueous solution (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:ammonia-7N solution in methanol, 1:1:0.05, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a light yellow solid (746 mg, 28% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1B(O)O>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH3:25])[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cc1cnccc1B(O)O
Product: Cc1cnccc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)sc2n1
Yield: 70 %

Procedure:
The titled compound (yield=70%) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 3-methylpyridin-4-ylboronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (s, 6H) 2.47 (s, 3H) 3.42 (s, 2H) 7.52 (d, J=8.59 Hz, 2H) 7.81-7.90 (m, 2H) 8.04 (d, J=8.59 Hz, 2H) 8.26 (d, J=8.34 Hz, 1H) 8.69 (d, J=4.29 Hz, 1H) 8.75 (br. s., 1H) 13.05 (br. s., 1H); ESI-MS: m/z 419.0 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH2:49][CH3:50])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH2:49][CH3:50])=[CH:22][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-tert-butoxyphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.47 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 54%).
Reaction SMILES: Cl[C:2]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([CH3:18])[C:2]([C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[O:3])=[CH:15][CH:14]=1
Reactant: CNc1ccc(Br)cc1
Reactant: CCOC(=O)C1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)N(C)c2ccc(Br)cc2)CC1
Yield: 50 %

Procedure:
Ethyl 1-chlorocarbonylcyclopropanecarboxylate (3.11 grams, 0.02 mole), prepared in Example XVIII, 4-bromo-N-methylaniline (3.00 grams, 0.02 mole) and triethylamine (1.63 grams, 0.02 mole) were reacted in a manner similar to that described in Example III to give 3.79 grams (0.01 mole) of ethyl 1-[N-(4-bromophenyl)-N-methylaminocarbonyl]cyclopropanecarboxylate isolated as a colorless oil. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[CH:4]=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].C(O)C.Cl.[NH2:16][OH:17].Cl>O>[CH3:1][C:2]1[C:3](=[N:16][OH:17])[CH:4]=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1=CC(=NO)C(C)=C(C)C1=O
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,5-trimethyl-1,4-benzoquinone (70 g, 0.51 mol) of hot ethanol (200 mL) was added a warm solution of hydroxylamine hydrochloride (35 g, 0.50 mol) and conc. hydrochloric acid (5 mL) in water (100 mL). The resulting red solution was stirred for 10 min at 60° C., stoppered and allowed to cool overnight in a refrigerator. The bright yellow precipitate was collected by vacuum filtration and dried to yield 63.9 g (83% yield) of crude product. Recrystallization from 50% aq. ethanol afforded the product as a yellow solid, mp 175° C. (dec.) (lit.: Smith, L. I.; Schubert, W. M. J. Am. Chem. Soc. 1948, 70, 2656; mp 182° C.). Spectral data: 1H NMR (CD3SOCD3): δ 1.90 (s, 3H), 1.93 (s, 3H), 2.30 (s, 3H), 7.55 (s, 1H), 12.95 (s, 1H, exchangeable with D2O); 13C NMR (CD3COCD3): δ 11.49, 12.94, 16.09, 120.53, 132.77, 137.39, 140.72, 149.04, 186.13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH:18]([CH3:21])[CH:19]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(CNCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 56 %

Procedure:
In the same way as that described in Example 4, Step 1, using tert-butyl-N-(2-aminoethyl)carbamate (1.6 g, 10 mmol), 2-phenylpropionaldehyde (1.32 mL, 10 mmol), MeOH (100 mL), acetic acid (1.72 mL, 30 mmol) and sodium cyanoborohydride (1.26 g, 20 mmol). The crude residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (90:10), to give the amine (1.56 g, 56%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.26 (3H, d, J=6.9 Hz), 1.42 (9H, s), 2.70-2.81 (4H, m), 2.90-3.00 (1H, m), 3.14-3.24 (2H, m), 4.89 (1H, br s), 7.19-7.35 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[N:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:19]3[N:20]=[N:21][CH:22]=[N:18]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 10.7 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrrolidone (100 ml), and the mixture was heated at 80° C. for 18 hours with stirring. The reaction solution was cooled, diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/acetone=1/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40; 0.494 g) as a colorless crystalline powder.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1=O
Yield: 92.9 %

Procedure:
To a solution of 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (2.27 g, 7.22 mmol) in acetic acid (75 ml) was added 48% aqueous HBr solution (75 mg), which was then heated under reflux for 1 day. The reaction mixture was extracted with diethyl ether. The organic layer was washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. Then, the residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=7:3 and 1:1) to give the title compound (1.92 g, yield 92%).
Reaction SMILES: [CH2:1]=O.[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH:9]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20].Cl>C(O)=O>[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH3:1])[CH2:10][CH:9]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(C)C2
Temperature: 80 °C

Procedure:
Formic acid (0.55 ml) and 37% formaldehyde (0.6 ml) are added at 0° C. to the compound obtained in Example 4 (1.8 g; 7.2 mmol) in the form of a base. The reaction mixture is heated at 80° C. for 24 hours with stirring. After having cooled the reaction mixture to 0° C., 10 ml of 6N HCl are added. The mixture is then washed with ether, rendered alkaline with 2N NaOH and extracted with ether. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The yellow oil so obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached). The purified oil is taken up in ether saturated with HCl(g) and stirred until a precipitate is obtained, which precipitate is then suction-filtered off and placed under a vacuum in a dessicator to yield the title product in the form of a very hygroscopic white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=2)[S:12][CH:11]=1)=[O:9].O[Li].O>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[S:12][CH:11]=1)=[O:9]
Reactant: COc1cccc(CNC(=O)c2csc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncccc34)c2)c1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CNC(=O)c2csc(-c3c[nH]c4ncccc34)c2)c1
Temperature: 150 °C
Yield: 59.3 %

Procedure:
N-(3-Methoxybenzyl)-5-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-3-carboxamide (70 mg, 0.14 mmol) was dissolved in THF (4 mL) and LiOH hydrate (42 mg, 1 mmol) was added in water (1 mL). The reaction mixture was heated to 150° C. in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with 10% citric acid, saturated sodium bicarbonate, and then dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (50 to 100% EtOAc/hexanes) to give the product as a white solid 30 mg, 0.083 mmol, 59%. 1H NMR 500 MHz (DMSO-d6) 12.00 (1H, s), 8.88 (1H, t), 8.32 (2H, m), 8.01 (1H, s), 7.87 (1H, s), 7.83 (1H, s), 7.26 (2H, m), 6.92 (2H, m), 6.93 (2H, m), 6.82 (1H, d), 4.43 (2H, d), 3.70 (3H, s). MH+ 364.10
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC3C=CC=CC=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)C=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1.C1CCN2[C:46](=[N:47]CCC2)CC1>O1CCCC1>[N:47]1[CH:46]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]1[CH:16]=[C:15]([NH:17][C:18]([N:40]2[CH2:39][CH2:38][N:37]([C:31]3[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:42][CH2:41]2)=[O:26])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: O=C(Nc1cc(-c2cccnc2)nc2ccccc12)Oc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(-c4ccccn4)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(111 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography (dichloromethane:methanol=20:1) to obtain the titled compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]3[CH:48]=[CH:47][C:46](B4OC(C)(C)C(C)(C)O4)=[CH:45][C:39]=3[C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.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.O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]3[CH:48]=[CH:47][C:46]([C:2]4[CH:19]=[C:6]([C:7](=[O:8])[NH:9][C:10]5([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=6)[CH2:12][CH2:11]5)[C:5]([O:20][CH3:21])=[CH:4][C:3]=4[CH3:22])=[CH:45][C:39]=3[C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[CH:32][CH:31]=1
Reactant: COc1cc(C)c(Br)cc1C(=O)NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc12
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: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)c(OC)cc3C)cc12
Temperature: 85 °C
Yield: 57 %

Procedure:
Alternative synthesis. To a sealed tube was added 5-bromo-2-methoxy-4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)benzamide (1.9024 g, 5.27 mmol), dioxane (70 mL), 2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (2.529 g, 6.40 mmol), cesium carbonate (2.57 g, 7.90 mmol), water (14.00 mL) and finally tetrakis(triphenylphosphine)palladium(0) (0.304 g, 0.263 mmol). The vessel was sealed and heated for 16 hours at 85° C. in an oil bath. The mixture was cooled to room temperature, diluted with 20 ml of DCM and pushed through a plug of celite. The resulting dark solution was concentrated to a grey oil. To this residue was added 20 ml of 0.5N HCl, followed by 20 ml of water. The flask was cooled in an ice bath for 30 minutes and the resulting solids were collected by filtration and washed with 10 ml of water and dried under vacuum. The crude product was taken up in 1:1 ethyl acetate/hexane and pushed through a plug of silica gel. Solvent was removed giving 1.65 grams of the product as a light tan solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[Br:13]Br>CCOCC>[CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH:10]([Br:13])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)C1CCCC(Br)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 31 g. of ethyl cyclohexanone-2-carboxylate in 25 ml. of ether, cooled to -10° C., was added dropwise 35 g. of bromine. Stirring was continued one hour while the solution was allowed to come to room temperature. The solution was poured into ice water containing 20 g. sodium carbonate and was extracted with ether. The ether extract was washed with water, dried and evaporated to dryness to give 23 g. of the title compound; b.p. 88°-91°C. (0.2 mm).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[OH:42][C:35]1[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])=[CH:14][CH:13]=2)=[C:39]([CH3:40])[CH:38]=[C:37]([CH3:41])[N:36]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(CCO)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A mixture of 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 1.5 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (432 mg, 2.25 mmol), N-hydroxybenzotriazole (3.4 mg, 2.25 mmol) and triethylamine (455 mg, 4.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (228 mg, 1.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloro methane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (41 mg, 8.3%). LRMS (M+H+) m/z: calcd 328.18 found 328; 1H. NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.11 (s, 1H), 4.49 (s, 2H), 3.44-3.42 (m, 2H), 2.94 (q, J=7.2 Hz, 1H), 2.36 (s, 3H), 2.42 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl>O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[NH4+:1]
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: O
Product: NCCCCCCCCCCCC(=O)[O-]
Product: [NH4+]
Reaction time: 0.08 h

Procedure:
100 g of montmorillonite having an average thickness of the silicate layer unit of 0.95 nm and a size of about 0.1 μm was dispersed in 10 liter of water, to which 51.2 g of 12-aminododecanoic acid and 24 ml of a concentrated hydrochloric acid were added. The mixture was stirred for 5 minutes, and dried under vacuum to obtain a composite of ammonium 12-aminododecanoate ions and montmorillonite. The layer distance of the layered silicate particles (the weight center distance of the particles) in the obtained composite was measured by an X-ray diffraction to be 1.8 nm.