Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.[CH3:8][N+:9](C)=[C:10](N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:34]([O:38][C:39]([NH:41][CH:42]([CH2:46][C:47]1[CH:48]=[N:49][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:54]=2[F:60])=[CH:51][CH:52]=1)[C:43](O)=[O:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].CNC.O1CCCC1>CN(C)C=O>[F:60][C:54]1[C:55]([F:59])=[CH:56][CH:57]=[CH:58][C:53]=1[C:50]1[N:49]=[CH:48][C:47]([CH2:46][CH:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])[C:43]([N:9]([CH3:10])[CH3:8])=[O:44])=[CH:52][CH:51]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(F)c2F)nc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (92 uL, 0.53 mmol) were added to a solution of 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoic acid (100 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL). The reaction was stirred at r.t. for 10 min, and 2 M of dimethylamine in tetrahydrofuran (0.26 mL, 0.53 mmol) was added and stirred for 1 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude tert-butyl 3-(6-(2,3-difluorophenyl)pyridin-3-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.06 g, 60%) as an oil. Analytical LCMS (M+H)+: m/z=406.0.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.6 g (0.148 mol) of magnesium filings are introduced into 8.1 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 21.8 g (0.136 mol) of diethyl malonate in 15 ml of ethanol and 58 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is subsequently continued for one hour at 60° C. A solution of 27.6 g (0.15 mol) of 2,3,4-trifluorobenzoyl chloride in 15.4 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently overnight, allowing the mixture to come to room temperature. The batch is poured into 60 ml of ice-water, treated with 9.7 ml of concentrated sulphuric acid and extracted using toluene. The toluene phase is washed with saturated sodium chloride solution and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH2:7][C:6]([F:9])(I)[CH:5]=[CH:4][C:3]=1[F:10].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13].Cl>C(NCC)C.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.[Cu]I>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[C:6]([F:9])[CH:7]=1
Reactant: FC1=C(Br)CC(F)(I)C=C1
Reactant: C#Cc1ccc(CCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2cc(F)c(Br)cc2F)cc1
Temperature: 5 °C
Yield: 80.6 %

Procedure:
2-Bromo-1,4-difluoro-4-iodobenzene (19 g) was dissolved in diethylamine (28 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.06 g) and copper(I) iodide (0.06 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (10 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (15 ml) and ice (30 g). After extraction with chloroform, the resultant was washed with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 170° to 180° C./4 mmHg) to give 4-bromo-2,5-difluoro-4'-propyltolane (16 g).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH2:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].O.ClCCl>CN(C)C=O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][C@@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:8]2)=[CH:11]1
Reactant: N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C1CN[C@H](Cc2c[nH]c3ccccc23)CN1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of (1R)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (3.30 g) in dimethylformamide (70 ml) was added potassium carbonate (3.30 g) at room temperature. The reaction mixture was stirred at 110° C. for 1 hour and 20 minutes. After cooling to room temperature, water and dichloromethane were added into the mixture, and the organic layer was separated. The aqueous layer was extracted successively with dichloromethane several times and a mixed solvent of ethyl acetate and methanol (10:1). The extracts were combined and dried over magnesium sulfate, and concentrated under reduced pressure to give (5R)-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.47 g) as an oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[NH2:17])(=O)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.C(OCC)(=O)C>O>[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][C:6]2[N:5]=[C:1]([CH2:2][CH3:3])[N:17]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH2:29][C:28]4[CH:39]=[CH:40][C:25]([F:24])=[CH:26][CH:27]=4)=[CH:32][CH:33]=3)[C:7]=2[CH:8]=1)=[O:11])[CH3:14]
Reactant: Fc1ccc(COc2ccc(CBr)cc2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)CC)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2nc(CC)n(Cc3ccc(OCc4ccc(F)cc4)cc3)c2c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
A mixture of 0.534 g of ethyl 4-propionylamino-3-aminobenzoate, 0.374 g of potassium carbonate, 0.800 g of 4-(4-fluorobenzyloxy)benzyl bromide, 5 ml of ethyl acetate and 3 ml of water was stirred at 75° C. for 16 hours. The organic layer was concentrated, and ethanol and 0.46 g of 36% hydrochloric acid were added to the residue. The mixture was stirred for 2 hours while being heat-refluxed. The reaction mixture was neutralized with potassium carbonate, and the solvent was then concentrated under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated under reduced pressure, and was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.228 g of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (325).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])CCC.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].C1C[O:27][CH2:26]C1>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:26](=[O:27])[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11])[CH3:20]
Reactant: C1CCOC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CCNCC
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 1.5 h

Procedure:
To a stirring solution of 4-bromo-1-iodo-2-(trifluormethoxy)benzene (11600 mg, 32 mmol) in dry THF (300 mL) at −78° C. under Ar was added 2.5M n-butyllithium in hexanes (25 mL) dropwise. The reaction was stirred for 1.5 h and then quenched with crushed dry ice. The reaction was stirred for 30 min and then slowly wammed to room temperature. The reaction was partioned between 1 M hydrochloric acid in brine EtOAc. The organic layers were separated, washed with sat. aq. NaHSO3, dried over Na2SO4, and conc in vacuo to a brown oil. The oil was dissolved in dry CH2Cl2 (300 mL) with dry DMF (0.2 mL) and then treated with oxalyl chloride in CH2Cl2 (32 mL) dropwise. The reaction was stirred for 4 h and then conc in vacuo to a brown oil. The oil was dissolved in dry CH2Cl2 (300 mL) and then treated with diethylamine (5767 mg, 79 mmol) dropwise. The reaction was stirred for 48 h and then conc in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 1:2, EtOAc:hexanes) to yield 8500 mg of the product as a colorless oil. MS (ESI) 341 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[F:19][C:20]([F:28])([F:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH:21]([C:20]([F:28])([F:27])[F:19])[CH2:22][CH2:23]4)[N:7]=[CH:6][N:5]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C1CCN(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and 4-trifluoromethyl-piperidine in the presence of K2CO3 and DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0.5 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
As in Example 115, (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid (16 g) and 4-nitrophenol (6.6 g) in dichloromethane (160 mL) was treated with 1,3-dicyclohexylcarbodiimide (9.3 g). The mixture was stirred at 0.5° C. for 1 hour, then at room temperature for 18 hours. After the usual work up, the crude product was triturated with ether to give 13.2 g of (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of a portion from ether afforded the analytical sample, mp 140°-142° C. Anal. Calculated for C27H25NO8 : C, 69.60; H, 4.91; N, 3.23 Found: C, 69.19; H, 4.94; N, 3.25.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.2 g, 2.85 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (16e) (0.21 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with diethyl ether and petroleum ether-ethyl acetate (3:1) affording the title compound (0.14 g, 68%). M.p. 164° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.49 (1H, d, J=16.0 Hz); 7.16-7.89 (12H, m); 7.98 (1H, br s); 10.52 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 0.8 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C 61.94, H 4.38, N 7.60. Found, %: C 61.44, H 4.39, N 7.48.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH:50]([CH3:54])[CH2:49]2)=[N:44][CH:45]=[CH:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:49][CH:50]2[CH3:54])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCNC(C)C1
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2csc3ccccc23)C(C)C1

Procedure:
The title compound was prepared (1.39 g, 85%, mp 197°-200° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(3-methoxy-2-pyridinyl)-3-methylpiperazine.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH2:8]([O:11][C:12](=[O:28])[CH2:13][C@@H:14]([NH2:27])[C:15]([NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH:9]=[CH2:10].[C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][CH:39]2[CH2:43][CH:42](OC)O[CH:40]2OC)=[CH:33][CH:32]=1)#[N:30].FC(F)(F)C(O)=O.CC(O)=O>CCCCCCC>[CH2:8]([O:11][C:12](=[O:28])[CH2:13][C@@H:14]([N:27]1[CH:42]=[CH:43][C:39]([C:38](=[O:4])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[CH:40]1)[C:15]([NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16])[CH:9]=[CH2:10]
Reactant: COC1CC(C#Cc2ccc(C#N)cc2)C(OC)O1
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: C=CCOC(=O)C[C@H](C(=O)N[C@H](C(=O)NC)C(C)(C)C)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt and 3-[2-(4-cyanophenyl)-ethynyl]-2,5-dimethoxy-tetrahydrofuran were heated with trifluoroacetic acid (1 equiv) at 70° C. for 4 hours. Flash column chromatography twice with 0.5% HOAc/15% EtOAc/CH2Cl2 as eluant and azeotrope with n-heptane afforded 800 mg (36%, 43% based on recovered furan) of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid allyl ester as a brown oil. 1H NMR (CDCl3): δ 7.58 (d, 2H, J=8.1 Hz), 7.47 (dd, 1H, J=1.9, 1.9 Hz), 7.36 (d, 2H, J=8.1 Hz), 6.84 (d, 1H, J=9.0 Hz), 6.74 (dd, 1H, J=2.8, 2.8 Hz), 6.63 (dd, 1H, J=1.6, 2.8 Hz), 6.08 (dd, J=2.8, 6.8 Hz), 5.82 (ddt, 1H, J=5.9, 10.3, 17.1 Hz), 5.26 (ddd, 1H, J=1.2, 2.8, 17.1 Hz), 5.19 (q, 1H, J=7.2 Hz), 4.56 (dddd, 2H, J=1.6, 2.8, 4.4, 15.9 Hz), 4.18 (d, 1H, J=9.0 Hz), 4.05 (s, 2H), 3.34 (dd, 1H, J=7.2, 16.8 Hz), 2.99 (dd, 1H, J=7.2, 16.8 Hz), 2.72 (d, 3H, J=5.0 Hz), 0.90 (s, 9H). 13C NMR (CDCl3): δ 191.2, 170.2, 169.4, 168.0, 140.6, 132.2, 131.3, 130.3, 125.7, 125.7, 122.0, 119.0, 118.9, 110.5, 110.4, 66.0, 61.0, 59.4, 46.1, 37.5, 34.8, 31.9, 29.0, 26.5, 26.0. IR (KBr): 3320, 2965, 229, 1736, 1648, 1531, 1173 cm−1. HRFABMS: Calculated for C27H33N4O5 (M+H+): 493.2451. Found 493.2462. Anal. Calculated for C27H32N4O5•0.2 H2O•0.2 CH2Cl2: C, 63.66; H, 6.44; N, 10.92. Found: C, 63.86; H, 6.56; N, 10.58.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=O)[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=O)[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH2:35]([N:42]1[CH:1]([CH3:2])[C:4]2[C:5](=[O:34])[N:6]([CH3:33])[C:7]3[N:8]=[C:9]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])[C:10]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:11][C:12]=3[C:13]=2[N:14]=[C:15]1[CH3:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1=Nc2c(c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc23)C(C)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Example 1 (80 mg) in 1,2-dichlorethane (1.5 mL) was combined with benzyl amine (16 μL), sodium triacetoxyborohydride (32 mg) and acetic acid (8.5 μL). The reaction was stirred for two days at room temperature. The reaction mixture was diluted with CH2Cl2 and washed with aqueous NaOH (1 M) and brine. The concentrated residue was purified by preparative TLC on silica gel eluted with 30% EtOAc in CH2Cl2 affording the title compound. HPLC/MS: 587.1 (M+1), 589.1 (M+3); Rt=3.86 min.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.I[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]2[CH2:20][C:21]([O:23][CH3:24])=[O:22].CNC1C=CC(I)=CC=1.C1(C)C=CC=CC=1>C(N(CC)CC)C.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>[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]2[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)Cc1cc(=O)n(C)c2ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CNc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(=O)n(C)c2ccc(C#N)cc12
Temperature: 25 °C

Procedure:
1.1 ml of trimethylsilyl cyanide (8.4 mmol) followed by 0.15 g (0.13 mmol) of tetrakistriphenylphosphinepalladium are added to a solution of 0.50 g (1.4 mmol) of methyl 6-iodo-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetate (prepared from N-methyl-4-iodoaniline according to the method described in Example 1) in 6 ml of anhydrous triethylamine. The reaction medium is then heated to reflux for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the medium is poured into 60 ml of toluene and 60 ml of water. The organic phase is washed with water and the initial aqueous phase is re-extracted with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. The residue is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)(N1C=CN=C1)=O.O1CCC[CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:30]([CH2:31][CH2:32][N:28]([CH3:21])[CH3:34])[CH3:29])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: CN(C)CCN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it, during which time a solution was formed. A solution of N,N,N'-trimethylenediamine (3.56 g, 0.0348 mole) in tetrahydrofuran (4.5 ml) was added and the solution was refluxed overnight under a nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting oil was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated, the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed once with water, twice with 5% potassium hydroxide solution and twice with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether to give 3.5 g of product. A 1.0-g portion was dried at high vacuum overnight to give 0.63 g of title compound, mp 120°-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:20]([O:38][CH:39]1[CH:44]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:43]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH2:42][CH:41]([C:83](O)=[O:84])[CH2:40]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:83]([CH:41]2[CH2:42][CH:43]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH:44]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:39]([O:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:40]2)=[O:84])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(CO)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
4-Aminobenzyl alcohol (282 mg, 2.29 mmol) was dissolved in chloroform (40 ml), and HOBt (32 mg, 0.23 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (1.11 g, 1.19 mmol) were added. EDC.HCl (356 mg, 1.86 mmol) and pure water (120 μl) were added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml), and isolated by silica gel column chromatography (chloroform/ethyl acetate=10:1) to give N-(4-hydroxymethylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (556 mg, 0.54 mmol, yield 45%).