Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].CN1CCCC1=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: NC(=O)[O-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol), ammonium carbamate (7.78 g, 99.6 mmol) and dry N-methylpyrrolidinone (40 ml) are placed in a glass-lined, stainless steel reactor. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (80 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to give 0.52 g (56%) picramide (Table 2, entry 2).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.C(OC1C(C(O)=O)=NC(CC2C=CC=CC=2C2C=CC=CC=2)=NC=1O)C1C=CC=CC=1>>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 48.6 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (28-02) (7.3 g, 68.6%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (27-02) (12 g, 34.24 mmol) as a white solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][Br:37])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
(4-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (8.00 g, 35.6 mmol) was dissolved in CH2Cl2 (150 mL) and treated with PPh3 (11.2 g, 42.8 mmol) under nitrogen. The reaction flask was cooled in an ice bath and CBr4 (14.2 g, 42.8 mmol) was added in small portions. The ice bath was removed after 30 min and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and acetonitrile (50 mL) was added. The reaction flask was placed in a refrigerator for 3 h and the precipitate filtered and washed with cold acetonitrile. The white solid was dried in vacuo giving (4-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (8.38 g, 82%).
Reaction SMILES: C(O[K])(C)(C)C.[C:7](=[O:14])([O:11][CH2:12][CH3:13])OCC.C1(C)C=CC=CC=1.[C:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])[CH3:23]>O>[CH2:12]([O:11][C:7](=[O:14])[CH2:23][C:22](=[O:24])[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccs1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 71.1 g (0.63 mol) portion of tert-butoxy potassium was added to 194.7 g (1.65 mol) of diethyl carbonate at 60 to 65° C. and stirred at 60 to 65° C. for 1 hour, and then 180 ml of toluene solution containing 50 g (0.40 mol) of 2-acetylthiophene was added dropwise thereto at 75 to 80° C. and stirred at 75 to 80° C. for 2 hours. The reaction solution was cooled down to room temperature, mixed with 725 g of water, extracted with 600 ml of ethyl acetate, washed with saturated brine, concentrated and then distilled under a reduced pressure to obtain 65.2 g of 3-oxo-3-(2-thienyl)propionic acid ethyl ester (yield 83%).
Reaction SMILES: [CH2:1]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BrH:18]>O>[Br:18][C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17]
Reactant: CCCCCCCCC1C(=O)NC(=O)NC1=O
Reactant: Br
Solvent: O
Product: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-octylbarbituric acid (20 g) in 120 ml of water, cooled at 0-5° C., are added 12 ml of 48% hydrobromic acid and successively are dropped 4.72 ml of brornine. After 2 hours under stirring, the white solid which separated is recovered by filtration, washed with water and partitioned between 200 ml of diethyl ether and 100 ml of water.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[C:8]([F:14])[CH:7]=1>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:11]=[C:1]=[O:2])=[C:8]([F:14])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1ccc(Br)cc1F
Solvent: Clc1ccccc1
Product: O=C=NCc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 69.1 %

Procedure:
Chlorobenzene (30 ml) is introduced into the reaction vessel at 60° C. and saturated with phosgene. A solution of 4-bromo-2-fluorobenzylamine (20.4 g, 0.10 mol) in chlorobenzene (40 ml) is added dropwise at 60° C. over 3 hours. At the same time, phosgene is passed in. Stirring of the batch is continued for 2 hours at 60° C., and the mixture is subsequently refluxed to remove the gases phosgene and hydrogen chloride. The batch is worked up by distillation. 15.9 g of 4-bromo-2-fluorobenzyl isocyanate (boiling point 109° C. at 4 mbar) are obtained. Yield: 69.1% of theory.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[N+:19]=[N-].[Na+].O>S(=O)(=O)(O)O.C(O)(=O)C>[N:8]([C:7]1[C:6]([Cl:5])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=1[Cl:17])=[N+:18]=[N-:19]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (3.2 g) in concentrated sulphuric acid (22 ml) was added dropwise with cooling to a solution of 2,6-dichloro-4-trifluoromethylaniline (9.3 g) in glacial acetic acid (48 ml). The mixture was stirred at room temperature for half an hour and then cooled to 0°-5°. A solution of sodium azide (2.6 g) in the minimum volume of water was added dropwise with cooling and the mixture stirred at 0°-5° for 1 hour and then at room temperature overnight. The mixture was poured into ice/water, extracted with dichloromethane and the extract worked up in conventional manner to give 1-azido-2,6-dichloro-4-trifluoromethylbenzene, as a red oil. A solution cf this oil (25.6 g) and 2-propyn-1-ol (40 ml) in xylene (80 ml) were stirred under nitrogen and heated under reflux overnight. The mixture was cooled and the solvent was evaporated under reduced pressure. Trituration of the residue with light petroleum (bp 30°-40°) gave a crude material which was purified by filtration through silica to give [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl]methanol, m.p.123°-125°.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a 3000 mL RB flask was added (4S)-4-(phenylmethyl)-1,3-oxazolidin-2-one (100 g, 0.564 mol) in THF (1500 mL). The solution was cooled to −78° C. and n-butyl lithium (1.6 M in hexanes, 387 mL, 0.62 mol) was added dropwise. Stirring continued for 30 min. Hexanoyl chloride (74.8 g, 0.62 mol) was then added dropwise and the reaction was monitored by TLC. The reaction was quenched by addition of NH4Cl (400 mL), and extracted with DCM (2×500 mL). The product was purified by flash column eluting with ethyl acetate/petroleum ether (1:50 to 1:20) to afford the title compound (118 g, 76%). LCMS: (M+H)+: 276.1.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
100 g of crude methyl cinnamate, 926.8 g of 2.8% caustic soda and 100 g of toluene were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. After the stop of the stirring, the solution was allowed to stand and separate at 80° C. and the resultant toluene layer was then removed. 1 g of powdery active carbon (trade name PMSX, made by Toyo Calgon Inc.) was added to the aqueous layer, and the solution was stirred for 30 minutes and then filtered at 80° C. by the use of Nutsche. The resultant filtrate was placed in a 2-liter flask equipped with a thermometer and a stirrer and then maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 84.9 g of cinnamic acid. The purity of cinnamic acid was 99.9%, and the content of each of palladium, copper and manganese was 5 ppm or less. The recovered active carbon was dried, and metallic components were then measured. As a result, the contents of palladium, copper and manganese were 960 ppm, 8.5% and 5.5%, respectively. In the filtrate and the washing solution with which cinnamic acid had been washed, metallic components of palladium, copper and manganese were each contained in an amount of 5 ppm or less.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1>CS(C)=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Dimethyl malonate (13 mL) was added dropwise to 2.7 g sodium hydride suspended in 20 mL dimethylsulfoxide. The mixture was heated to 100° C. for 10 minutes and then cooled to room temperature. 5-Bromo-2-fluoronitrobenzene (5.0 g) in 25 mL of dimethylsulfoxide was added and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and quenched with 300 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 4-bromo-2-nitrophenylmalonate as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(OC(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-Methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL). The resultant mixture was added with 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and stirred at 0° C. for 45 minutes. The reaction solution was added with ethyl acetate, a saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg, yield 6%) was obtained as a colorless oil.
Reaction SMILES: Cl.C(C1[CH:14]=[C:13]([SH:15])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)(O)=O.CI.[C:19](=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:28][CH2:29]C)(=[O:27])[CH3:26]>CN(C=O)C>[CH3:29][O:28][C:25]([C:26]1[CH:14]=[C:13]([S:15][CH3:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:27]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(S)c2ccc(Cl)cc2n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SC)c2ccc(Cl)cc2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added MeI (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)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>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77 (m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C1COCC1>[C:15]([O:14][C:12](=[O:11])[NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Temperature: 0 °C

Procedure:
Suspend tyramine (10.0 g, 73.0 mmol) in THF (200 mL). Cool to 0° C. Add a solution of (BOC)2O (31.8 g, 145 mmol) in THF (43 mL). Allow reaction mixture to warm to room temperature overnight. After 20 hours concentrate. Purification through two Waters 500A columns on a Prep LC system 500A to give the title compound: MS FAB ES+ 238.3 (M+H)+, base peak 182.2 (M+2H—C(CH3)3)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm. S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min. 30-99% over 19 min], tR=8.5 min, 100% purity.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].C1(=O)OC(=O)C2CCCCC12>>[CH:1](=[C:19]([C@@H:17]([C@H:15]([C@@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18])[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=Cc1ccccc1
Agent: O=C1OC(=O)C2CCCCC12
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Reaction time: 0.75 h

Procedure:
A reactor was charged with 106 g (1 mole) of benzaldehyde, 270 g (1 mole) of a 70% aqueous solution of D-sorbitol and 15 g of hexahydrophthalic anhydride, and they were reacted at 20° C. with stirring. In 45 minutes after the formation of fine crystals in the mixture within the reactor, the torque of the stirrer became about 3 times as high as that at the start of the reaction. At this time, the amount of monobenzylidene sorbitol formed was 40% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of (5,6-Dichloro-pyridin-3-yl)-methanol (1.8 g, 10 mmol) in CH2Cl2 (20 ml) was added manganese dioxide (4.4 g, 50 mmol). The reaction was stirred for 16 h after which time it was filtered through a pad of Hyflo and a fresh portion of manganese dioxide (1.8 g, 20 mmol) added and the reaction stirred for a further 4 h. The manganese dioxide was removed by filtration through Hyflo and the reaction concentrated affording crude 5,6-dichloro-pyridine-3-carbaldehyde (1.4 g, 81%). This was then dissolved in toluene (20 ml) and (methoxycarbonylmethylene)triphenylphosphorane (4.1 g, 12 mmol) added and the mixture heated to reflux for 1 h after which time the mixture was diluted with CH2Cl2, silica gel added and the mixture concentrated to dryness. The absorbed product was then purified by flash column chromatography (EtOAc:Heptane 1:1) furnishing the title compound (1.5 g, 81%) as a white solid.
Reaction SMILES: C([Cl:4])(=O)C.[CH:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:14])=[CH:9][CH:10]=1>C(O)C>[ClH:4].[ClH:4].[ClH:4].[O:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:18]=[CH:17][C:16]([CH2:15][C:13]([NH:12][CH2:11][C:8]4[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=4)=[O:14])=[N:21][CH:20]=3)=[CH:23][CH:24]=2)[CH2:36][CH2:35]1
Reactant: CC(=O)Cl
Agent: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Solvent: CCO
Product: Cl

Procedure:
The resulting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate (7) and benzyl amine were coupled in anisole at high temperature to afford 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (KX2-391). An HCl solution formed by adding acetyl chloride to absolute ethanol was added to KX2-391 to form the bis-HCl salt, 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride, (KX2-di-HCl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Yield: 100.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) and methanol (5 mL) was treated with 10% palladium on activated carbon (30 mg). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 16 h. The catalyst was then removed by filtration through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (277.4 mg, quant) as a pale yellow glass: mp 65-68° C.; EI-HRMS m/e calcd for C21H25N3O3 (M+) 367.1893, found 367.1899.