Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:18]([N+:19]([O-])=O)=[C:17]([N+:22]([O-])=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[ClH:25].[H][H]>CO.[Pd]>[ClH:25].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:15]3[CH:16]=[C:17]([NH2:22])[C:18]([NH2:19])=[CH:12][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc2nc(-c3ccc(C(=O)O)cc3)[nH]c2cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 5 g (16.7 mmole) of 2-[p-carboxyphenyl]-5,6-dinitrobenzimidazole (as prepared in Example I) in 200 ml of methanol at 0° C was thoroughly purged with nitrogen. To this was added 500 mg of 10% palladium on charcoal, and 30 ml of concentrated HCl. The hydrogenation flask was then pressurized with 55 lbs/in2 of hydrogen, and the flask was shaken at room temperature for 8 hours. After the reaction period had elapsed, the solution was filtered by suction, and the filtrate evaporated to dryness in vacuo. The residual yellow solid was redissolved in a minimum amount of boiling methanol (which contained a trace of HCl), and the filtered solution added to 50 ml of concentrated HCl. Removal of the methanol from the solution in vacuo and subsequent cooling in ice yielded 4.2 g (82%) of 2-[p-carboxyphenyl]-5,6-diaminobenzimidazole hydrochloride as fluffy yellow needles.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O-:15].[Na+].O>C1COCC1>[F:13][C:9]1[C:10]([CH3:12])=[N:11][C:2]([O:15][CH3:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(C)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)c(C)nc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 2-chloro-5-fluoro-6-methylnicotinate (18) (0.8 g, 3.92 mmol,) in THF (35 mL) was added sodium methanolate (0.42 g, 7.85 mmol) at 0° C. The mixture was stirred at 60° C. for 6 hours and cooled to room temperature. Then the mixture was poured into water and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexane to give methyl 5-fluoro-2-methoxy-6-methylnicotinate (19) (250 mg, 32%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:19]C(Cl)(Cl)C(Cl)(Cl)Br.O>C1COCC1>[Br:19][C:10]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncc(Br)c1Br
Temperature: -55 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
A cooled (−70° C.) solution of 5-bromonicotinic acid (12.6 g, 62.5 mmol) in THF under nitrogen was treated with 2 M lithium diisopropylamide (72 mL, 144 mmol) dropwise over 1 h. The solution stirred for 2.5 h at −55° C. The mixture was then cooled to −70° C. and treated with 1,2-dibromotetrachloroethane (25 g, 77.2 mmol) in portions over 30 min. After 1 h, the reaction mixture was allowed to warm to −20° C. over 2 h and then water (75 mL) was added slowly. The organic layer was then evaporated in vacuo and the aqueous residue was diluted with water (250 mL), then washed with ethyl acetate. The aqueous layer was then acidified to pH 3 by addition of concentrated hydrochloric acid. The precipitated solid was collected by filtration and dried at 60° C. in vacuo to afford 10 g (57%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.75 (s, 1H), 3.2 (br. s, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 91 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (5.0 g, 34.9 mmol, 1.0 eq.), 4-bromopyridine HCl (7.46 g, 38.46 mmol, 1.1 eq.) and DIPEA (18.2 ml, 104.7 mmol, 3.0 eq.) were dissolved in n-butanol (100 ml) and refluxed for 36 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 91% (7.0 g, 31.81 mmol)
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.S(Cl)([Cl:24])=O>>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([Cl:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CN1Cc2ccccc2C(c2cccc(CC(=O)O)c2)C1
Product: CN1Cc2ccccc2C(c2cccc(CC(=O)Cl)c2)C1

Procedure:
3.4 g (10.7 mmol) of 3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenylacetic acid are treated with 17.6 ml of thionyl chloride with stirring. The mixture is refluxed for one hour. The mixture is then evaporated to dryness. 3-[2-Methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenylacetyl chloride is obtained.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.Cl>O1CCCC1>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: OCCCCCCBr
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(COCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60%, 0.39 g) was added to a mixture of 6-bromohexanol (1.78 g) and 4-chlorobenzyl bromide (2.02 g) in dry tetrahydrofuran (150 ml). The mixture was stirred at 25° C. for 5 h and poured into 1M hydrochloric acid. Extraction with diethyl ether (3×), and washing the combined extracts with water and brine gave a solution that was dried over magnesium sulfate and evaporated under reduced pressure. The residue so obtained was chromatographed on silica gel using 40-60° C. petroleum ether to 10% diethyl ether in 40-60° C. petroleum ether as eluents. This gave 1-bromo-6-(4-chlorobenzyloxy)hexane (1.7 g). 1H-NMR (CDCl3) δ 1.3-1.55 (4H, m), 1.55-1.7 (2H, m), 1.75-1.95 (2H, m), 3.35-3.55 (4H, m), 4.46 (2H, s) and 7.2-7.4 (4H, m).
Reaction SMILES: C(O)C.O1CCCC1.[Cl:9][C:10]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:11]=1[CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:25][C:24]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[NH:13][CH2:12][C:11]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:10]=1[Cl:9]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Ethanol (7 ml), tetrahydrofuran (7 ml) and water (28 ml) were added to ethyl 3-(2,4-dichlorobenzylamino)-4-nitrobenzoate (1.40 g), and sodium hydrosulfite (4.50 g) was added at room temperature. The mixture was stirred at 50° C. for 20 min. The reaction mixture was extracted with chloroform and water, and the organic layer was washed with saturated brine, dried and concentrated to give the objective compound (1.4 g, as a crude product). The crude product was used in the following reaction as it was.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>CO>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc2ccc(C(=O)OC)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCn1ncc2ccc(C(=O)O)cc21
Temperature: 80 °C
Yield: 92.7 %

Procedure:
To a mixture of methyl 1-butyl-1H-indazole-6-carboxylate (0.356 g) in methanol (10 mL) was added saturated sodium bicarbonate (5 mL). The mixture was heated at 60° C. for 2 h at which time 1N NaOH (5 mL) was added and the mixture heated to 80° C. for 18 h. The mixture was cooled to room temperature, poured into 1N HCl (50 mL), and extracted with ethyl acetate. The ethyl acetate extract dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.310 g of the title compound: 1H NMR (CDCl3) δ 0.964, 1.96, 4.48, 7.81, 7.89, 8.29, 8.46.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:16][NH:17][C:18]([CH3:31])([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH2:40][OH:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:42]1([CH2:49][NH2:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:16][NH:17][C:18]([CH3:31])([CH3:30])[CH2:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27]([NH:50][CH2:49][CH:42]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH2:40][OH:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: NCC1CCCCCC1
Product: CC(C)(Cc1cccc(CC(=O)NCC2CCCCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Yield: 97 %

Procedure:
The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl propyl}phenyl)acetic acid (preparation 148) and cycloheptane methylamine, using a similar method to that of preparation 38, as a white solid in 97% yield. 1H NMR (400 MHz, CD3OD) δ: 7.72 (1H, dd), 7.44 (1H, d), 7.42 (2H, m), 7.38-7.21 (5H, m), 7.19 (1H, d), 7.07 (1H, d), 7.02 (1H, m), 5.08 (2H, d), 5.03 (1H, m), 4.71 (2H, d), 3.51 (2H, d), 3.03-2.96 (4H, m), 1.77-1.34 (13H, m), 1.28 (6H, m), 1.07 (2H, m), 0.93 (9H, s), 0.07 (3H, s), −0.92 (3H, s) ppm; LRMS ESI m/z 688 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([OH:22])=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[S:25](O)(=[O:27])=[O:26].N1C=CC=CC=1>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=1[O:22][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Cc1ccc(C=O)c(O)c1OCCCOCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 6 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-Benzyloxy-propoxy)-2-hydroxy-4-methyl-benzaldehyde (0.3 g, 1.0 mmol), trifluoromethanesulfonic acid (0.34 mL, 2.0 mmol), pyridine (0.25 mL, 3.1 mmol), dichloromethane (15 mL). Purification: flash column chromatography (10-15% EtOAc/hexane): yield 0.25 g (59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.14 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.42-7.29 (m, 6H), 4.53 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.40 (s, 3H), 2.07-2.22 (m, 2H). 19F NMR (400 MHz, CDCl3) δ (ppm): −73.63 (s).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:25])C>C(O)C>[C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCOc1cc(-c2ccccc2)nc2ccccc12
Reactant: CC(=O)O
Solvent: CCO
Product: O=C(O)CCCOc1cc(-c2ccccc2)nc2ccccc12
Reaction time: 1 h

Procedure:
A solution of 4-[(2-phenyl-4-quinolyl)oxy]butanol (2.20 g) in glacial aceic acid (10 cc) is added slowly to a solution, cooled to 5° C., of chromic anhydride (2.25 g) in 90% strength acetic acid (5 cc). The temperature is allowed to rise to approximately 20° C., and the mixture is then stirred for one hour at this temperature. Ethanol (50 cc) is then added, the solvents are evaporated off under reduced pressure, the residue is taken up with water (100 cc) and the insoluble material is drained and washed several times with water. This insoluble material is taken up with normal sodium hydroxide solution (15 cc) and heated under reflux for two hours. The insoluble material is removed by filtration and the filtrate acidified by adding glacial acetic acid. The precipitate obtained is drained. 4-[(2-Phenyl-4-quinolyl)oxy]butanoic acid (0.740 g), m.p. 264° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[C:9]1=C=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].C1C[O:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH3:15])[N:11]([CH2:28][CH2:29][OH:30])[CH:12]([CH3:14])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC1CN(C(=O)OC(C)(C)C)C(=C=O)C(C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
3,5-Dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester derived from the above reaction was dissolved in THF (300 mL) and lithium aluminium hydride (3.31 g) was added thereto under ice-cooling. After stirring at 0° C. for 1 hour, water and 2N aqueous sodium hydroxide solution was sequentially added. After filtration of the insoluble material, the filtrate was concentrated under reduced pressure to give the title compound (20.3 g). Yield: 90%.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH2:29]([O:36][C:37]1[CH:47]=[CH:46][CH:45]=[C:39]2[C:40]([O:42][C:43](=O)[C:38]=12)=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:43](=[O:42])[C:38]2=[C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:47]=[CH:46][CH:45]=[C:39]2[C:40]1=[O:41])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: O=C1OC(=O)c2c(OCc3ccccc3)cccc21
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc(OCc3ccccc3)c2C1=O)OC
Yield: 38.3 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.64 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.4 g of 3-(benzyloxy)phthalic anhydride, there was obtained 0.347 g of [[3-(benzyloxy)phthalimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)[CH3:25])[CH3:21]
Reactant: Oc1cccc(-c2cccnc2)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-hydroxyphenyl)pyridine (40.91 g, 0.239 mol) in 500 mL dimethylformamide was added potassium carbonate (148.62 g, 1.075 mol) and ethyl-2-bromoisobutyrate (157.8 mL, 1.075 mol). The mixture was heated to reflux under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 1 L water and extracted with diethyl ether (3×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1 L. The organic solution was diluted with 1 L water and made acidic with 6N HCl. The layers were separated and the organic phase extracted with 500 mL water. The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (4×500 mL) and the extracts were combined, washed with 500 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield crude 2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester as a pale yellow oil which was taken on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH3:11][O:12][C:13]1[CH:57]=[CH:56][C:16]([CH2:17][N:18]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[CH:29]=[N:30][C:31]=3F)[N:20]=2)=[CH:15][CH:14]=1>>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:18]([CH2:17][C:16]2[CH:56]=[CH:57][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[CH:29]=[N:30][C:31]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:20]=2)=[CH:53][CH:52]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 155, Step 2, using 5-fluoro-6-methoxypyridin-3-amine and tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate. tert-Butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate was isolated (90%) as a yellow solid. m/z (ESI, +ve ion) 765.8 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[N:2]1.CN1CCOCC1.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:16])=[N:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
A solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (30 mg, 0.11 mmol) obtained in Step 1 of Example 47 in THF (0.50 mL), was sequentially added with 4-methylmorpholine (25 μL, 0.23 mmol), 2-aminothiazole (17 mg, 0.17 mmol), EDC (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (20 mg, 0.15 mmol), followed by stirring at room temperature for 2.0 hours. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) and the obtained compound was crystallized from 4.0 mol/L hydrogen chloride-ethyl acetate solution (1.0 mL)/ethyl acetate (1.0 mL). The obtained solid was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=15/1) to obtain Compound 138 (8.5 mg, 22%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[C:12](Cl)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[O:30]=[C:12]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with octadecanoyl chloride gave 3,4-bis [(1-oxooctadecyl)oxy]nitrobenzene (mp 68°-70°) The structure was confirmed by the nmr spectrum.
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[NH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[N:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cncc(F)c1
Agent: N#N
Solvent: CN(C)C=O
Product: Nc1cnc(Br)c(F)c1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-amino-5-fluoropyridine (900 mg, 8.03 mmol) in dry DMF (13 mL) was treated at 0° C. with N-bromo-succinimide (1.43 g, 8.03 mmol). The reaction mixture was stirred at rt until completion of the reaction. The mixture was then partitioned between Et2O and water. The layers were separated and the org. layer successively washed with water, sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 9:1 to 1:1) and the title compound obtained as an orange solid. LC-MS-conditions 07: tR=0.52 min; [M+H]+=191.30.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=1.[ClH:22].[CH3:23]O>O=[Pt]=O>[ClH:22].[CH3:23][CH:4]([CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1)[C:3]([OH:2])=[O:21]
Reactant: CO
Reactant: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Product: CC(C(=O)O)C1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h

Procedure:
A mixture of methyl{2-[4-(trifluoromethyl)phenyl]pyridin-4-yl}acetate (6.2 g, 21 mmol), PtO2 (200 mg, 0.9 mmol) and HCl solution (4N in dioxane, 5.8 ml, 23 mmol) in MeOH (100 ml) was hydrogenated at 20 psi on a Parr® apparatus for 5 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give the desired piperidine as white solid (7.1 g, quant). 1H NMR (400 MHz, CD3OD) δ: 1.58-1.72 (1H, m), 1.75-1.85 (1H, m), 2.08 (1H, d, J 14.2), 2.19 (1H, t, J 14.2), 2.28-2.38 (1H, m), 2.45 (2H, d, J 6.9), 3.24-3.32 (1H, m), 3.51-3.57 (1H, m), 3.67 (3H, s), 4.46 (1H, d, J 10.2), 7.72 (2H, d, J 8.3), 7.79 (2H, d, J 8.4).