Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16]SC[C@@H](C(O)=O)NC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NCCC1C=NC=CC=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:43]([O:42][CH2:41][CH:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:16])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) were stirred in dry DCM (0.1 M) at room temperature. 3-(2-aminoethyl)pyridine (1.2 eq) was then added followed by diisopropylethylamine (2.0 eq) and the reaction was allowed to stir at room temperature for 2 hours. The crude reaction mixture was then loaded directly onto a silica column and purified by purified by flash chromatography on a COMBIFLASH® system (ISCO) using a 100% Hex, 0-50% EtOAc/Hex, 100% EtOAc gradient to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-oxo-3-(2-pyridin-3-yl)ethylamino)propylthio)propane-1,2-diyl didodecanoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH2:10])=[N:2]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[N:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c2ccccc12
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 398.5 %

Procedure:
A 1,4-dioxane (0.5 L) solution of 1H-indazol-3-amine (3.3 g) and phthalic anhydride (14.8 g) was stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a white solid (26.0 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13]C(=O)CCCCC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(=O)OC1CCN(Cc2ccccc2)C1
Agent: O=P([O-])([O-])[O-]
Product: OC1CCN(Cc2ccccc2)C1

Procedure:
First, 10 g of (RS)-N-benzyl-3-hexanoyloxypyrrolidine and one of the commercially available enzymes listed in Table 3 were added to 100 ml of 0.1 M phosphate buffer (pH 7.0). This mixture was allowed to react at 40° C. with agitation for 22-120 hours. Then, the unreacted (RS)-N-benzyl-3-hexanoyloxypyrrolidine was recovered by three extractions from the reaction mixture with equal volumes of hexane. The aqueous phase was then adjusted to pH 13 by the addition of NaOH, and the hydrolyzed N-benzyl-3-hydroxypyrrolidine was obtained by three extractions with equal volumes of hexane. After removal of the solvent under reduced pressure, distillation yielded purified N-benzyl-3-hydroxypyrrolidine in colorless, transparent, oily form. After tosylation, the optical purity of this purified product was measured by HPLC. The results with the different enzymes used are shown in Table 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.S(=O)(=O)(O)O>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[S:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Yield: 88.7 %

Procedure:
A mixture of 5E (3.80 g) and tetrahydrofuran (12 ml) was heated to reflux in 2N sodium hydroxide (12 ml) for 12 hours. Then the mixture was poured on ice and acidified with 6N sulfuric acid (pH=1-2). The mixture is extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue is distilled under reduced pressure to yield the product as a white solid (3.22 g, 89%) with a melting point of 142-144° C.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[C-:12]#[N:13].[K+].O>CS(C)=O>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:5]1[CH2:11][CH2:10][CH:8]([CH2:9][C:12]#[N:13])[CH2:7][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCCC1=CCC(CC#N)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tosylate 1H (R=4-Methyl-3-pentenyl) (20 g) in dimethylsulfoxide (178 mL) is added potassium cyanide (19.4 g). The reaction mixture is heated to 100° C., and the reaction mixture is stirred at that temperature for three hours. The reaction mixture is cooled to room temperature, added to water (300 mL), and extracted with hexane. The combined organic layers are dried over magnesium sulfate and the solution is concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[CH2:14]Cl)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([CH2:14][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)[CH2:29][CH2:28]2)=[O:16])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)CCl)c(OC)nc1C
Product: CCc1cc(NC(=O)CN2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
N-(5-ethyl-2-methoxy-6-methylpyridine -3-yl)chloroacetamide and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 69 to obtain the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[C:3]1=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C=C2C(=O)c3ccccc3C2Br)cc1

Procedure:
4-(1-Oxoindan-2-ylidenemethyl)benzonitrile (2.18 g, 8.9 mmol) was dissolved in carbon tetrachloride (40 mL). N-bromosuccinimide (1.58 g, 8.9 mmol) and benzoyl peroxide (100 mg) were added in one portion. Reaction mixture was reflux for 9 h, cooled down; precipitate was filtered off and washed with diethyl ether (10×30 mL) for removal of N-hydroxysuccinimide Precipitate was dried under vacuum, provided pure 15a.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.CCOC(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=Cc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Sc2ccncc2)nc1
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a solution of 4-mercaptopyridine (5.59 g, 50.3 mmol) in DMF (100 mL) was added NaH (60% dispersion in oil, 1.99 g, 49.7 mmol) in portions and the mixture was stirred for 20 min. 6-Bromo-3-pyridine carboxaldehyde (9.22 g, 49.6 mmol) was added and the resultant mixture was stirred for 1 h. Water was added followed by the addition of EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by recrystallization from EtOAc. The resultant colored solid was filtered through a silica gel column (eluent: MTBE). Evaporation of the filtrate and further recrystallization from MTBE gave the product as a white solid (8.1 g, 76% yield).
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=O)[CH2:4][OH:5].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:35][O:34][CH2:33][C@H:32]([CH3:36])[O:31][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]([C:7]3[O:5][CH2:4][C@@H:3]([C@H:2]([OH:1])[CH3:37])[N:6]=3)=[CH:13][CH:12]=2)[CH:19]=[C:18]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
N-[(1S,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.42 g, 2.66 mmol) synthesized in Example (95a) was dissolved in tetrahydrofuran (25 mL), and anhydrous methanesulfonic acid (0.72 g, 3.99 mmol) and triethylamine (1.11 mL, 7.98 mmol) were added at 0° C., followed by stirring for 1 hour under nitrogen atmosphere. The temperature was raised naturally, and stirring was carried out at room temperature for 1 hour, followed by stirring at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (758 mg, yield 55%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C([N:16](CC)CC)C.[OH-].[NH4+].O>O1CCCC1>[NH2:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=S)c1cnc(C)nc1N
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (25.4 g, 106 mmol, Aldrich Chemical Co., Milwaukee, Wis., USA) in 300 mL of tetrahydrofuran was treated with 50 mL of triethylamine and 40 mL of aqueous ammonium hydroxide. After stirring for 4 hours, 300 mL of water was added and the phases were separated. The organic layer was washed with 300 mL of brine, concentrated in vacuo, dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 16.5 g (95%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:15][C:3]=12.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.CCN(C(C)C)C(C)C>C(O)CCC>[C:34]([O:33][C:32]([NH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:3]=23)[CH2:26]1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 140 °C
Yield: 86.7 %

Procedure:
A mixture of ethyl 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.5 g, 4.3 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (1.0 g, 5.0 mmol) and DIPEA (0.84 g, 6.5 mmol) in 1-butanol (10 mL) was heated to 140° C. for 14 h, then allowed to cool. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with EtOAc and washed with aq. NaHCO3. The organic extract was washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 20-100% EtOAc in hexanes, to give the sub-title compound (1.9 g, 86%). LCMS calc. for C27H36N5O5 (M+H)+: m/z=510.3. Found: 510.2.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N+](C)=CCl.[Cl-].[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O)[N:19]=1)=[O:13].Cl.[NH2:28][CH:29]1[C:50](=[O:51])[N:31]2[C:32]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=[C:33]([Cl:36])[CH2:34][S:35][C@H:30]12>C(OCC)(=O)C.C[Si](CC(N)=O)(C)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([NH:28][CH:29]2[C:50](=[O:51])[N:31]3[C:32]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[C:33]([Cl:36])[CH2:34][S:35][C@H:30]23)=[O:23])[N:19]=1)=[O:13]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 51.8 %

Procedure:
N,N-Dimethylformamide (0.16 g.) and phosphorous oxychloride (0.34 g.) were mixed to prepare Vilsmeier reagent in a usual manner, and the resultant Vilsmeier reagent was suspended in dry ethyl acetate. To the suspension was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer, 0.46 g.) under ice-cooling with stirring, and then the solution was stirred at the same temperature for 30 minutes to prepare the activated acid solution. p-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (0.81 g.) was dissolved in a solution of trimethylsilylacetamide (2.10 g.) in ethyl acetate (200 ml.). To the solution was added the activated acid solution obtained above all at once at -20° C., and the solution was stirred at -20°~-5° C. for 1.5 hours. After water and ethyl acetate (100 ml.) were added to the resultant solution at -20° C., the insoluble product was separated by filtration, washed with water and acetone in turn and then dried to give p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.6 g.). After ethyl acetate was removed from the above filtrate, the aqueous layer was extracted with ethyl acetate (50 ml.) twice. The ethyl acetate layer and the extract were combined together, washed with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After removing ethyl acetate from the solution, diethyl ether was added to the residue. The insoluble product was collected by filtration to give the same object compound (0.25 g.), m.p. 226° to 228° C. (dec.), Total yield 0.85 g.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)=[O:34]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:2]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:33]=[O:34])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCn1c(-c2ccccc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 40 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in dioxane (0.15 M) were added Na2CO3 (6 eq, 2 M aqueous solution), 1.6 eq of (2-formylphenyl)boronic acid and 0.2 eq of bis(triphenylphosphine)-palladium(II) dichloride. The mixture was heated at reflux for 1 h. The reaction mixture was filtered and the filtrate diluted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si25M, 1:9 EtOAc/PE) to afford the title compound (40%); MS (ES+) m/z 448 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN1CCCN(C)C1=O.[CH3:22][C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1.[C:39](=O)([O:42]C)[O:40][CH3:41]>C1COCC1>[CH3:41][O:40][C:39](=[O:42])[CH2:22][C:23]1[C:24]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)OC
Reactant: Cc1cccnc1-c1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1cccnc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of diisopropylamine (4.8 ml, 34 mmol) in dry THF (20 ml) was cooled to 0° C. and n-butyllithium (1.6M in hexanes, 21.3 ml, 34 mmol) was added dropwise. After stirring at 0° C. for 30 mins, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.1 ml, 34 mmol) was added. After 15 mins a solution of the pyridine (Step 1, 4.033 g, 17 mmol) in dry THF (10 ml) was added. The reaction was stirred for 15 mins at 0° C. then cooled to −78° C. and dimethyl carbonate (3.4 ml, 40 mmol) in dry THF (10 ml) was added. The reaction was allowed to warm to −5° C. and stirred for 1 hr then quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (×3), the combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-30% EtOAc/hexanes) to give the ester (0.621 g, 12%). 1H NMR (500 MHz, CDCl3) δ: 3.65 (2H, s), 3.67 (3H, s), 7.31-7.34 (1H, m), 7.61-7.62 (2H, m), 7.71-7.75 (3H, m), 8.63-8.64 (1H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH:19]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:24](=[O:26])[CH3:25])=[CH:22][CH:21]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(OCCCCCCCCCCCCO)cc1
Solvent: O
Product: CC(=O)OCCCCCCCCCCCCOc1ccc(C=O)cc1

Procedure:
4-(12-Hydroxyl-dodecyloxy)-benzaldehyde (1.1 g, 3.6 mmol, see Example 2 above) was heated at reflux in acetic anhydride (15 ml) for 90 minutes. After cooling, the solution was poured into water with stirring. The title compound formed as a precipitate which was collected by filtration, washed with water and dried.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>O>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(N2CCC(N)CC2)cc1
Reactant: O=C(O)CCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCC(NC(=O)CCc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A mixture of 3-phenyl propionic acid (360 mg, 2.4 mmol), CDI (410 mg, 2.5 mmol) and DMF (20 ml) was stirred at 50° for 1 h. After cooling to 0°, 1-(4-methoxy-phenyl)-piperidin-4-ylamine (500 mg, 2.4 mmol) was added and stirring continued for 1 h. After the addition of H2O (60 ml) the white precipitate was collected to give N-[1-(4-methoxy-phenyl)-piperidin-4-yl]-3-phenyl-propionamide (618 mg, 76%, MS: m/e=339.3 (M+H+)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1.BrC1C=CC(Br)=CN=1.O1C2C=CC=CC=2C=C1B(O)O.[C:37]1(B(O)O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:45]2[C:46]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:42]=[CH:43][CH:44]=2)=[CH:12][N:11]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccc(-c2cc3ccccc3o2)nc1
Agent: Brc1ccc(Br)nc1
Agent: OB(O)c1cc2ccccc2o1
Product: c1ccc2oc(-c3ccc(-c4cccc5ccccc45)cn3)cc2c1

Procedure:
It is easy to synthesis the following compound in the same manner as in Example 1 except that 2-(benzofuran-2-yl)-5-bromopyridine was synthesized from 2,5-dibromopyridine (made by Tokyo Kasei Kogyo K.K.) and 2-benzofuranboronic acid (made by Aldrich Co.) and is reacted with 1-naphthylboronic acid (made by Tokyo Kasei Kogyo) to obtain 2-(benzofuran-2-yl)-5-(naphthalene-1-yl)pyridine, which is used instead of 2-(5-trifluoromethylpyridine-2-yl)benzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]=[N:7]O)([O-])=O.C(O)(=O)C.[H][H].[OH-].[Na+]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH2:7]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1C=NO
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NCc1ccccc1N
Reaction time: 7 h
Yield: 79.4 %

Procedure:
16.6 g (0.1 mol) of this o-nitrobenzaldoxime, 0.83 g of a 5% Pd-C catalyst, 12 g (0.2 mol) of glacial acetic acid and 100 ml of tetrahydrofurane were charged into a hermetically sealed glass container and stirred vigorously while charging hydrogen. Reaction was continued at temperatures of 25°-35° C. for 7 hours. After the reaction, the resulting mixture was filtered to remove the catalyst, was added with 8 g (0.2 mol) of sodium hydroxide and was subject to distillation. Thus, 9.7 g of o-aminobenzylamine was obtained. Yield 79.4%; Purity 99.4%; B.P. 91°-93° C./1 mmHg. M.P. 58°-61° C.