Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH:21]([CH3:23])[CH3:22])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C@H:11]([CH:21]([CH3:23])[CH3:22])[CH2:10]1
Reactant: CC(C)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(propan-2-yl)pyrrolidine-1-carboxylate (50 g) dissolved in tetrahydrofuran was added tetra-N-butylammonium fluoride (95 g) dissolved in tetrahydrofuran (250 mL) at 0° C. The mixture was stirred for 16 h at room temperature and then quenched with water (100 mL). The solution was washed with hydrochloric acid (6 N), extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (2/1 petroleum ether/ethyl acetate) to afford tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: CCN(CC)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCNCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.24 g, 21 mmol) was dissolved in N,N-diethylethylenediamine (15 ml, 100 mmol) under stirring at room temperature, and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with 100 ml of ethyl acetate and 100 ml of saturated brine, stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain brown oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-[3-(2-diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 h (8.2 g, yield 95%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH2:21]1[O:25][C:24]2[CH:26]=[C:27]([Cl:32])[C:28]([CH2:30]Cl)=[CH:29][C:23]=2[O:22]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:30][C:28]2[C:27]([Cl:32])=[CH:26][C:24]3[O:25][CH2:21][O:22][C:23]=3[CH:29]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: C=CCOc1ccc2[nH]c(C(=O)OCC)cc2c1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)cc(C(=O)OCC)n2Cc1cc2c(cc1Cl)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a mixture of NaH (60% suspension in mineral oil, 0.24 g, 6.12 mmol) and DMF (20 mL) was added 5-allyloxyindole-2-carboxylic acid ethyl ester (1.0 g, 4.08 mmol), from Example 1(d). After stirring at room temperature for 1 h, 6-chloropiperonyl chloride (0.84 g, 4.08 mmol) was added followed by the addition of tetrabutyl ammonium iodide (0.15 g, 0.41 mmol). The reaction was stirred at room temperature for 18 h. When the reaction was complete as indicated by TLC, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed in vacuo and the resulting crude product was purified by flash column chromatography (silica gel, EtOAc/hexanes) to yield the desired product as an oil (0.72 g, 43%). LC/MS (ES+) m/e 414.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[C:18]([Si:15]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-dichloro-phenol, (112, 4.80 g, 0.0294 mol) in N,N-dimethylformamide (100.0 mL) were added 1H-imidazole (5.21 g, 0.0766 mol) and tert-butyldimethylsilyl chloride (5.33 g, 0.0353 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 50% ethyl acetate in hexane to give a colorless oil (113, 7.10 g, 87.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([F:13])[CH:6]=1)[N:3]=[C:2]([CH2:1][Br:32])[CH:11]=[CH:10]2
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ccc2cc(F)cc(F)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c2nc(CBr)ccc2c1

Procedure:
A solution of 2-methyl-6,8-difluoroquinoline (0.147 g, 0.820 mmoles, Example 26a), benzoyl peroxide (9.93 mg, 0.0410 mmoles), and N-bromosuccinamide (0.168 g, 0.943 mmoles) in carbon tetrachloride (20 mL) is heated to reflux for 18 hours. The reaction is concentrated and the resulting residue purified by column chromatography (silica, 3:1 CH2Cl2:hexane, then CH2Cl2) to yield the title compound as a white solid. MS (ESI) 258, 260 (M+H)+, Br pattern.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][N:7]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:13]([O:12][CH2:11][CH:9]1[CH2:8][N:7]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:6][CH:5]([CH2:3][OH:2])[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(COCc2ccccc2)CN(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=S(=O)(c1ccc2ccccc2c1)N1CC(CO)CC(COCc2ccccc2)C1
Yield: 60.8 %

Procedure:
(3SR,5RS)-5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidine-3-carboxylic acid methyl ester (2.70 g) was reduced with lithium aluminium hydride as described in Example 17 to obtain (3SR,5RS)-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanol (1.54 g) as a syrup, MS: 426 (MH+).
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:20][N:3]1[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:33])([F:32])[F:21])=[C:10]2[C:5]([N:6]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH2:7][CH2:8][CH2:9]2)=[N:4]1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 200 mg of 3-bromo-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, 124 mg of 2-trifluoromethylphenylboronic acid, and 14 mg of tetrakistriphenylphosphine palladium (0) in 2 mL of dioxane was treated with a solution of 210 mg of sodium carbonate in 2 mL of water. The mixture was placed under an atmosphere of argon and heated to 100° C. for 20 h. The mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed with 20 mL of 1M HCl and 20 mL of brine, dried over magnesium sulfate, and evaporated to dryness. The residue was purified by flash silica gel column chromatography using 7% acetone/hexane as solvent yielding 87 mg of 2-methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, mp 59-63° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:30])=[C:12]([C:28]=1[CH3:29])[C:13]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[C:17]([O:24][CH3:25])[C:16]=1[O:26][CH3:27])=[O:14].Cl>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:30])=[C:12]([C:28]=1[CH3:29])[CH:13]([OH:14])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[C:17]([O:24][CH3:25])[C:16]=1[O:26][CH3:27]
Reactant: COc1cc(C)c(C(=O)c2c(O)ccc(Cl)c2C)c(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(O)ccc(Cl)c2C)c(OC)c1OC
Temperature: 25 °C

Procedure:
At −20° C., under an atmosphere of protective gas, 3 mmol of a 1-molar solution of LiAlH4 in tetrahydrofuran (THF) were added dropwise to a solution of 0.86 g of 5-chloro-2-hydroxy-6,6′-dimethyl-2′, 3′, 4′-trimethoxybenzophenone in 10 ml of anhydrous THF. The reaction mixture was warmed to room temperature and then admixed with ice water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with sat. NaCl solution, dried and purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 3:7). This gave 0.46 mg of the title compound as a white solid of m.p. 140-142° C.
Reaction SMILES: [OH-].[K+].C1(=O)CCCC(=O)C1.ClCC(=O)C.Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C([O-])(=O)C.[Na+].O=[C:30]([CH3:40])[CH2:31][CH:32]1[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][C:33]1=O>O.C(O)C>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][N:22]1[C:33]2[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:32]=2[CH:31]=[C:30]1[CH3:40])[CH3:18]
Reactant: CCOC(=O)CN
Reactant: CC(=O)CC1C(=O)CCCC1=O
Agent: CC(=O)CCl
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(C)cc2c1CCCC2=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
In reaction vessel 1, potassium hydroxide (11.78 g, 10.0 g corrected for assay, 178 mmol)) was dissolved in water (72 mL) with stirring (highly exothermic) then the solution was cooled back to 20° C. 1,3-cyclohexanedione (20.0 g, 178 mmol) was added (exothermic addition) and the resulting dark red solution was stirred at 20° C. for 5 mins. Redistilled chloroacetone (18.9 g, 17.0 g corrected for assay, 184 mmol) was added in one portion, rinsing in with ethanol (18 mL) and the reaction mixture was stirred overnight at 20° C. The resulting solution of 2-(2-oxopropyl)cyclohexane-1,3-dione, volume 124 mL, was split into 4 equal portions. Glycine ethyl ester hydrochloride (6.85 g, 49.0 mmol), anhydrous sodium acetate (4.02 g, 49.0 mmol), water (26.5 mL) and ethanol (5.0 mL) were charged to reaction vessel 2 and stirring started. One portion of the solution of 2-(2-oxopropyl)cyclohexane-1,3-dione prepared above (31 mL) was then added to the contents of reaction vessel 2 with stirring and the resulting mixture was heated to 75° C., held at this temperature for 2 h, then cooled to 20° C. over 55 mins. After stirring overnight at 20° C., the solid was collected by filtration, washed with water (10 mL), tert-butyl methyl ether (2×10 mL) and then dried in vacuo 40° C. for 20 h to provide (2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid ethyl ester as a beige solid, 5.88 g (56.0% yield). MP 101.2 to 103.5° C. Assay by 1H-NMR 95.3% w/w. Purity by GC 99.25 area %.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](COC[C@H](Cc1ccc(C)cc1)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@@H](COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methylbenzyl)pentyl)oxy)propanoate (2.06 g, 4.28 mmol) in aqueous THF (16 THF:5H2O; 21 mL total volume) was added LiOH—H2O (0.54 g, 12.83 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was diluted with H2O (50 mL) and the majority of the THF was removed on the rotovap. The aqueous residue was acidified with 2 N HCl and extracted with CH2Cl2 (6×50 mL) until the aqueous phase was nearly clear. The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil (1.96 g). The oil was purified by RP flash chromatography (C18; 0→85% CH3CN/H2O) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methyl-benzyl)pentyl)oxy)-propanoic acid (1.71 g, 85%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 4H), 6.57 (s, 2H), 5.47 (d, J=8.1 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 3.41 (d, J=7.2 Hz, 1H), 3.24 (m, 4H), 2.91 (dd, J=13.7, 4.0 Hz, 1H), 2.46 (dd, J=13.7, 10.8 Hz, 1H), 2.31 (s, 3H), 2.10 (dd, J=6.8, 3.3 Hz, 1H), 1.81 (dp, J=13.2, 6.6 Hz, 1H), 1.44 (s, 9H), 1.25 (d, J=6.2 Hz, 3H), 0.91 (dd, J=6.7, 2.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.72, 153.71, 135.81, 133.44, 127.15, 127.02, 81.61, 78.33, 76.81, 69.13, 68.31, 67.08, 51.93, 40.98, 31.48, 27.16, 26.42, 19.12, 17.65, 17.58, 17.38; ESIMS m/z 491 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([Cl:22])[CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=2[CH3:8])=[C:17]([Cl:22])[CH:16]=1
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reactant: Nc1ccc(Br)cc1Cl
Product: Cc1c(Nc2ccc(Br)cc2Cl)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 4-bromo-2-chloroaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH2:32][CH3:33])[CH2:30][OH:31]>>[CH2:32]([C@@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH2:30][OH:31])[CH3:33]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 83 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-1-butanol. Then, the product was recrystallized with ethanol and petroleum ether to give a desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]C(=O)C(F)(F)F)#[N:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:9][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: N#Cc1ccccc1NC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)c1[nH]c2ccccc2c1N

Procedure:
Follow the procedure of Example 3 (Steps B3–B5) but start with N-(2-cyano-phenyl)-2,2,2-trifluoroacetamide (synthesis described in J. Fluorine Chem. 1981, 18, (2), 185–95) and tert-butyl bromoacetate to obtain the title compound: MS 310(M+H), TLC (silica gel, dichloromethane/methanol, 7:1) Rf=0.38.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: OCc1ccncc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirring solution of methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol), 4-pyridylcarbinol (1.1 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) in THF (25 mL) at 0° C. was added diisopropyl azodicarboxylate (2.0 g, 9.87 mmol) dropwise. After stirring at room temperature for 16 h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.599 g, 37%). MS(ESI): 244.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.C([Cu])#N.[Li+].[Cl-].[CH3:25][O:26][C:27](=[O:40])[CH:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([O:26][CH3:25])=[O:40])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCC(I)C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
All glassware was dried prior to use. THF was dried over molecular sieves. LiCl was dried at 150° C. for 1 h, then stored in a closed bottle. All reaction solutions were made under nitrogen, and the solutions were transferred via syringe. 4-Iodobenzoic acid tert-butyl ester (3 g, 9.9 mmol) was dissolved in THF (7.5 ml), and cooled to −20 to −30° C. Isopropyl magnesium chloride (10.9 mmol, 2M in THF) was added over 5 min, and the solution was stirred for 30 min. A solution of CuCN (0.97 g, 10.9 mmol) and LiCl (0.92 g, 21.7 mmol) in 7.5 ml THF was added. The reaction was removed from the cold bath and allowed to warm to rt. After 15 min, trimethylphosphite (0.62 ml) was added. After stirring for 5 min—iodododecanoic acid methyl ester (2.69 g, 7.89 mmol) was added in a solution of THF (5 ml). After stirring for 16 h, the reaction was quenched with sat. NH4Cl (6 ml). Water (100 ml) was added and the solution was extracted with AcOEt (3×100 ml). The organic extracts were pooled ant washed with water (100 ml) (some sat. NaCl and MeOH was added to aid phase separation) and sat. NaCl (100 ml), dried over MgSO4 and concentrated under vacuum to yield a two-phased residue (5.85 g). The residue was dissolved in AcOEt and added drop wise to a bed of silica in a glass filter (7.5 cm dia×3 cm). 200 ml of AcOEt was washed through the silica, and the filtrate was concentrated to yield a residue. This was dissolved in DCM (10 ml) and purified by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt). The relevant fractions were pooled and concentrated under vacuum. This was dissolved in 9:1 heptane/AcOEt (7 ml) and purified again by flash chromatography (15 cm×40 mm, eluant 9:1 heptane/AcOEt) to yield a colorless oil (185 mg).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:12]([F:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N+:8]=1[O-:17].[OH-].[Na+]>ClCCl>[CH3:6][C:7]1[C:12]([F:13])=[C:11]([Cl:3])[CH:10]=[CH:9][N+:8]=1[O-:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(F)c([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(F)c(Cl)cc[n+]1[O-]

Procedure:
Phosphoryl chloride (19 ml) in dichloromethane (50 ml) was added dropwise to a stirred solution of 2-methyl-3-fluoro-4-nitropyridine-N-oxide (12 g) in dichloromethane (50 ml). The reaction mixture was heated under reflux for a total of 8 hours. After cooling and pouring onto ice, the mixture was basified (NaOH) to pH 9 and extracted with dichloromethane. After drying (K2CO3) and removal of solvent, the crude product was purified by column chromatography (silica gel; 1% MeOH/CHCl3) to give 2-methyl-3-fluoro-4-chloro-pyridine-N-oxide (6.78 g) m.p. 63°-65°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:19][OH:20])[N:4]=1.I[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COCCOCCOCCI
Reactant: COC(=O)CCNCCOc1cc(CO)nc(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a solution of 284 mg of methyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate in 28 ml of acetonitrile was added 356 mg of 1-iodo-2-[2-(2-methoxy-ethoxy)-ethoxy]-ethane and 330 μl of diisopropylethylamine. The mixture was heated at 80° C. for 3 days and then concentrated under reduced pressure and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40g), using a gradient of 5 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 165 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=0.44 min; [M+H]+: m/z 431.