Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a solution of ethyl(1RS,2RS,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (0.10 g, 0.2 mmol) in ETOH (5 ml) was added a solution of sodiumhydroxide (0.10 g, 2.5 mmol) in H2O (2 ml). The resulting mixture was stirred at room temperature oveni2rht. The mixture was acidified, and the solid which formed was collected by filtration and dried under reduced pressure to afford the title compound as a tan solid (0.04 g, 86%).
Reaction SMILES: OCC(N[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])CO.COC(OC)(C)C.O>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:7]=1)[C:11]#[N:12])([O-:17])=[O:16]
Reactant: N#Cc1ccc(NC(CO)CO)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.2 %

Procedure:
A mixture of 4-[2-hydroxy-1-(hydroxymethyl)ethylamino]-3-nitrobenzonitrile (1.35 g), 2,2-dimethoxypropane (1.4 g) and p-toluenesulfonic acid (10 mg) in anhydrous dichloromethane (30 mL) was stirred at ambient temperature for 8 hours. The mixture was poured into water and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diethyl ether to give 4-[(2,2-dimethyl-1,3-dioxan-5-yl)amino[-3-nitrobenzonitrile (1.3 g) as yellow powders.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (100 mg, 0.25 mmol) is added to THF (0.5 ml) at 0° C. Sodium triacetoxyborohydride (111 mg, 0.50 mmol) is then added. The mixture is stirred for 1 h then stirred at room temperature overnight. Water (5 ml) is added and then extracted with toluene. Organic phase dried (MgSO4) and concentrated in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as for Example 23, Method 1.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:2]1([O:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[S:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=4)=[N:27][CH:26]=3)=[CH:36][CH:35]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of 1-hydroxybenzotriazole (722 mg) and 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.64 g) in dichloromethane (33 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) (1.28 g), and stirred for 2 hours at ambient temperature. To the reaction mixture was added dichloromethane (500 ml) to be clear solution, then washed with water (200 ml×2) and brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)-thiazol-5-yl]benzoic acid benzotriazol-1-yl ester (1.27 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][CH3:10].[CH2:11]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14]CC.O.CCCCCCC>C(N(CC)CC)C.[Cu]I.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][CH:19]=2)=[C:3]([CH2:9][CH3:10])[CH:4]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: C#Cc1ccc(CCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCCCc1ccc(C#Cc2ccc(Br)cc2CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g (64.3 mmol) of 1-iodo-2-ethyl-4-bromobenzene and 12 g (64.3 mmol) of 4-n-hexylphenylacetylene are initially introduced in 300 ml of triethylamine, 250 mg (1.3 mmol) of copper(I) iodide and 900 mg (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and the mixture is stirred at RT for 3 h and subsequently refluxed for 1 h. The batch is cooled, water and heptane are added, and the phases are separated. The organic phase is washed with saturated sodium chloride soln., dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane); the product is obtained as a colourless oil.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:21]([CH2:22]O)=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:9]1[C:21]([CH2:22][C:5]#[N:6])=[C:12]2[C:13]3[CH:19]=[C:18]([CH3:20])[O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: C[Si](C)(C)C#N
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCc1nn2ccc3oc(C)cc3c2c1CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, to a solution of boron trifluoride diethyl ether complex (0.563 mL, 4.44 mmol) and trimethylsilyl cyanide (0.789 mL, 5.92 mmol) in chlorobenzene (30 mL) was added a solution of (2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (340 mg, 1.48 mmol) in chlorobenzene (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (252 mg, yield 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.S1C=CC2C(N3CCN(CCCCOC4C=C5[C:57]([CH2:58][CH2:59][C:60](=[O:64])N5)=[CH:56]C=4)CC3)=CC=CC1=2.O1C=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][CH:60]5[CH2:59][CH2:58][CH2:57][CH2:56][O:64]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1COC1CCCCO1

Procedure:
A solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (0.26 g), which is a mixture with 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one, was suspended in dichloromethane (10 ml), 3,4-dihydro-2H-pyran (0.08 ml) was added, p-toluenesulfonic acid hydrate (0.11 g) was added with stirring under ice-cooling, and the mixture was stirred at room temperature overnight. With stirring under ice-cooling, aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=60:1) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tetrahydro-2H-pyran-2-yloxy)methyl-3,4-dihydro-1H-quinolin-2-one (180 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenol to give (1-phenoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 303(MH+).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:39]1([O:45][C:46]([O:48][CH:49](I)[CH3:50])=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CS(C)=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH:49]([O:48][C:46]([O:45][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH3:50])=[O:23])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)OC(=O)OC2CCCCC2)cc1

Procedure:
A solution of 504 mg (1.0 mMol) of 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, 600 mg of 1-(cyclohexyloxycarbonyloxy)-ethyliodide and 350 mg of potassium carbonate in 25 ml of dimethylsulphoxide is stirred for 14 hours at ambient temperature, then stirred into about 70 ml of saturated sodium chloride solution and extracted three times with 30 ml of ethyl acetate. The combined organic extracts are washed with water and evaporated down. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant: methylene chloride/ethanol=98:2).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)(C)(C)C.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[C:33](Cl)=[N:32][C:31]([Cl:35])=[CH:30][N:29]=1)(=[O:26])=[O:25]>>[NH2:7][C:8]1[O:9][CH:10]=[C:11]([CH2:13][O:14][C:33]2[C:28]([NH:27][S:24]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=3[Cl:16])(=[O:26])=[O:25])=[N:29][CH:30]=[C:31]([Cl:35])[N:32]=2)[N:12]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)co1
Product: Nc1nc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)co1

Procedure:
Prepared by the method of Example 112 using (4-hydroxymethyl-2-oxazolyl)carbamic acid tert-butyl ester (Example 212a) (0.12 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.21 g). Purification was by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures to give the title compound with the BOC (tert-butyl carbonyl) attached (0.11 g). This compound was dissolved in trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL). After 2 h, the solution was evaporated. Purification was by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures to give the title compound. Yield 0.08 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]3)[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCCC1CCN(c2cccc(Br)n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: OCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1

Procedure:
Under an inert atmosphere, 3.6 g (12.62 mmol) of 2-(6′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)ethanol (WO2004/099176), 3.53 g (25.25 mmol) of 4-fluorophenylboronic acid, 5.23 g (37.87 mmol) of potassium carbonate and 4.88 g (15.15 mmol) of tetrabutylammonium bromide in suspension in 20 ml of water are introduced. Subsequently 0.142 g (0.63 mmol) of Pd(OAc)2 is added. The reaction mixture is subsequently heated at reflux for 24 hours.
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Na+:1].[CH:17]1([CH2:16][O:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=S(=O)([O-])c1ccc(OCC2CC2)cc1
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a suspension of 75 g (323 mmol) of 4-hydroxybenzenesulfonic acid sodium salt in 1350 ml of DMF, 20.67 g (517 mmol) of 60% oil suspended NaH are carefully added portionwise at r.t. To the mixture, 11.93 g (32.3 mmol) of tetrabutylammonium iodide and 50.13 ml (517 mmol) of (bromomethyl)-cyclopropane are added successively. After stirring for 25 h at 60° C., the reaction mixture is cooled to r.t. Precipitates are collected and washed with CH2Cl2 several times, and then recrystalized with mixed solvent (EtOH:H2O=2:1) to give the title compound as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:27]=3)[C:23]([O:25]C)=[O:24])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:27]=3)[C:23]([OH:25])=[O:24])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3ccccc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cncc(OC(=O)N2CCC(CCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Methyl 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate (3.95 g) was dissolved in THF (32 ml) and methanol (16 ml), and under ice cooling, aqueous 1 M sodium hydroxide solution (16 ml) was dropwise added thereto. This was stirred at room temperature for 30 minutes, and under ice cooling, this was neutralized with 1 M hydrochloric acid (16 ml). The colorless solid precipitated was collected by filtration, and recrystallized from methanol/water to obtain 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid (3.70 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1.[CH3:16]O>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
Thionyl chloride (1.23 mL, 17.0 mmol) was added dropwise into a solution of 4-bromo-2-chlorobenzoic acid (Combi-Blocks CA-4187, 1.0 g, 4.25 mmol) in MeOH (20 mL) at 0° C. The reaction mixture was then stirred at RT until completion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound (871 mg, 82%). 1H NMR (CDCl3, 300 MHz) δ 7.72 (d, J=8.4 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.46 (dd, J=8.4, 1.9 Hz, 1H), 3.93 (s, 3H). HPLC (Method A) Rt 4.22 min (Purity: 98.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]([C:23]1[CH:40]=[CH:39][CH:38]=[CH:37][C:24]=1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)=[O:22].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:12]([N:11]([CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:34](=[O:35])[CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:24]2[CH:37]=[CH:38][CH:39]=[CH:40][C:23]=2[C:21]([O:20][CH3:19])=[O:22])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNCCc1ccccc1OC
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccccc1OC)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-[2-(2-Methoxyphenyl)ethyl]heptan-1-amine (0.091 g, 0.366 mmol) was dissolved in DMF (5 ml), (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.094 g of methyl 2-{[4-(2-{heptyl[2-(2-methoxyphenyl)ethyl]amino}-2-oxoethyl)phenoxy]methyl}benzoate (yield 53.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5](=[O:7])[N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[N:3]1[CH2:18][C:19]#[CH:20].[BH4-].[Na+].OS(O)(=O)=O>C1COCC1.CCO>[OH:7][CH:5]1[N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[N:3]([CH2:18][C:19]#[CH:20])[C:2]([CH3:21])([CH3:1])[CH2:6]1
Reactant: C#CCN1N(C(=O)OCc2ccccc2)C(=O)CC1(C)C
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C#CCN1N(C(=O)OCc2ccccc2)C(O)CC1(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
To a stirred solution of 104 (3.0 g, 10.48 mmol) in THF (75 mL) and EtOH (50 mL), sodium borohydride (2.6 g, 68.1 mmol) was added at −20° C. followed by few drops of conc. H2SO4 and stirred for 3 h at −20° C. The reaction mixture was quenched with sat. NaHCO3 solution at −20° C. and allowed to reach room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to get crude compound which was purified through silica gel column chromatography, eluted with 15% EtOAc/hexanes to get 105 (2.3 g, 76%). 1H NMR (CDCl3) δ 7.26-7.37 (m, 5H), 5.76 (m, 1H), 5.25 (s, 2H), 3.80-3.60 (m, 3H), 2.48-2.38 (m, 1H), 2.22 (m, 2H), 1.38 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:1])[CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 70 °C
Yield: 17.4 %

Procedure:
DABCO (111 mg) was added to a solution of 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E13) (100 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in THF (3 mL) and water (3 mL). Sodium hydroxide (40 mg) was added to the mixture. The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E14) (18 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 5.44 (1H, m), 7.17 (1H, t), 7.19 (1H, s), 7.43 (1H, d), 7.80 (1H, d), 8.57 (1H, d), 8.95 (1H, d), 12.10 (1H, br s). MS (ES): C22H21ClN4O4 requires 440; found 441.1 (M+H+).