Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.Cl[CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH:23]=[C:22]([CH3:24])[S:21][C:19]=2[N:20]=1.CC(C)([O-])C.[K+]>C1COCC1>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:14][C:15]2[NH:16][C:17](=[O:25])[C:18]3[CH:23]=[C:22]([CH3:24])[S:21][C:19]=3[N:20]=2)[CH:6]=1
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CCO)c(C(F)(F)F)n3)nc2s1
Temperature: 75 °C
Yield: 32 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol (50 mg, 0.278 mmol), 2-(chloromethyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (60 mg, 0.278 mmol) and potassium tert-butoxide (62 mg, 0.07 mL, 0.555 mmol) in THF (3 mL) was heated to 75° C. for 4 h. The reaction mixture was allowed to cool to RT before being filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound as a white solid (32 mg, 0.089 mmol, 32%).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[OH-:22].[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:4]2[NH:3][C:2](=[O:22])[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: COc1ccc(OCc2nc(N)c3nccnc3n2)cc1
Agent: [Na+]
Product: COc1ccc(OCc2nc3nccnc3c(=O)[nH]2)cc1

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 5.5 g (0.0194 mole) of 4-amino-2-[(4-methoxyphenoxy)methyl]pteridine in 150 ml of 5% aqueous sodium hydroxide. The solid obtained is taken up in dilute sodium hydroxide for purification. The insoluble portion is removed by filtration. The filtrate is acidified with acetic acid to pH 5.5. The precipitate formed is isolated by filtration; it is finally recrystallized from a mixture of ethanol and N,N-dimethylformamaide. Yld: 1.7 g (31%), m.p. 233°-234° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(N(C)c2ccccc2)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.5 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (66.3 mg, 0.18 mmol) in methanol (0.5 mL, 0.37M) was treated with a 4N aqueous sodium hydroxide solution (0.05 mL, 0.2 mmol) and was stirred at 25° C. overnight. After this time, the reaction was diluted with water (10 mL), acidified with a 1N aqueous hydrochloric acid solution and then was extracted into methylene chloride (3×25 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid (67.3 mg) as a viscous, yellow oil. This material was used without further purification.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[C:4]([OH:6])=[O:5])#[N:2].C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO>[C:1]([CH:3]([CH2:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CC(=Cc1c(Cl)cccc1Cl)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC(Cc1c(Cl)cccc1Cl)C(=O)O
Temperature: 18 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
92 g of 2-cyano 3-(2,6-dichlorophenyl)propenoic acid (Tetrahedron Lett., 1975, p.3643-4) are put into 860 ml of methanol and 285 ml of a 10% sodium hydrogen carbonate solution. This is cooled to 18° C. and the necessary quantity of sodium borohydride is introduced over a two and one-half hour period. The mixture is left for 2 hours at ambient temperature, then concentrated and acidified by adding 1N hydrochloric acid until a pH of 2.3. The solution is then extracted with ether and the organic layer is washed with water, dried on magnesium sulphate, filtered and evaporated. 82.4 g of 2-cyano 3-(2,6-dichlorophenyl)propanoic acid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:6]([O:5][C:1]([NH:2][NH:3][C:16](=[O:18])[CH3:17])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl carbazate (1.0 g, 7.6 mmol) and pyridine (3.1 ml) in methylene chloride (5 ml) was slowly added acetic acid anhydride (1.5 ml) and the mixture was stirred overnight. The mixture was added to methylene chloride (50 ml) and washed with water (2×10 ml) and brine (10 ml) and dried (MgSO4), filtered and concentrated in vacuo to give 0.95 g of N'-acetylhydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.Cl>CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared according to procedure G using potassium carbonate (94.23 g, 681.8 mmol), dimethyl malonate (39.1 mL, 340.9 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (28 mL, 227.27 mmol) in DMF (227 mL). After pouring over 200 mL of 2N aqueous HCl the precipitate was collected by filtration and washed with water (4 L) to give dimethyl 2-(4-bromo-2-nitrophenyl)malonate. Mass Spectrum (ESI) m/e=332 [(M+1) (79Br)] and 334 [(M+1) (81Br)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#Cc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#Cc1cccc(NC(=O)[C@H](C)NC)c1
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl (1-((3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (G2, 265 mg) in 1,4-dioxane (4 mL), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (4 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was evaporated under reduced pressure. To the obtained residue, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then the solvent was evaporated under reduced pressure. The obtained solid matter was recrystallized from a mixed solvent of ethyl acetate and methanol to obtain (S)—N-(3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)phenyl)-2-(methylamino)propanamide (G3, 105 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.[F-].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1I
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1-c1cccnc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-benzyl (1-(6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-yl)ethyl)carbamate (100 mg, 0.22 mmol) and pyridine 3-yl-boronic acid (30.7 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added cesium fluoride (66.8 mg, 0.440 mmol) at 25° C. The reaction mixture was degassed with nitrogen for 30 min and then tetrakis triphenylphosphine palladium(0) (13 mg, 0.011 mmol) was added at 25° C. The reaction mixture was stirred overnight at 100° C. After completion of the reaction water was added and the mixture extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide (S)-Benzyl (1-(6-fluoro-3-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)ethyl)carbamate: LC-MS (ESI)] m/z 391.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:18](Cl)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>CO.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][N:12]([CH:13]([CH2:14][OH:15])[CH2:16][OH:17])[C:18](=[O:19])[O:20][CH2:21][CH:22]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c(CNC(CO)CO)c[nH]c12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
Amine 6 (330 mg, 1.4 mmol) was suspended in methanol (35 mL) and 10% aqueous NaHCO3 (3.5 mL). Fmoc chloride (432 mg, 1.7 mmol) was added and the solution stirred for 15 min. The suspension was concentrated under reduced pressure. Chromatography of the residue on a column of silica gel eluted with 7.5-20% methanol in dichloromethane gave the title compound 7 (150 mg, 0.33 mmol, 48% allowing for recovered starting material). Subsequent elution with 50% methanolic ammonia (3.5M) in dichloromethane returned the starting amine 6 (170 mg, 51%). 7, colourless amorphous solid, ESI-MS+, found 460.1975, calc. for C25H26N5O5 [M+H]+ 460.1985.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C[Si]([N:12]=[N+:13]=[N-:14])(C)C>CO>[N:12]1[NH:13][N:14]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cn[nH]n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-propynoate (4.13 ml) and trimethylsilyl azide (13.5 ml) was heated to 100° C. for 24 h. The cooled mixture was cautiously decomposed with methanol (50 ml) and evaporated in vacuo to give the title compound (5.7 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]1([CH3:1])[CH3:14]
Reactant: CCOC(=O)CN1C(=O)CCC1(C)C
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Product: C[C@@H]1CCC[C@H](C)N1CCCNC(=O)CN1C(=O)CCC1(C)C

Procedure:
From 10 g. of ethyl 2,2-dimethyl-5-oxopyrrolidineacetate, (British Pat. No. 1,309,692) and 10.5 g. of cis-3-(2,6-dimethyl-1-piperidinyl)propylamine, following the procedure of Example 9, there is obtained cis-N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-2,2-dimethyl-5-oxo-1-pyrrolidineacetamide; m.p. 86°-87° C. after crystallization from isooctane.
Reaction SMILES: [CH2:1]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[Mg]Br.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].[Cl-].[NH4+]>CCOCC>[CH2:1]([C:15]1[NH:16][C:17]([C:23]([O:24][CH2:25][CH3:26])=[O:27])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc[nH]1
Reactant: CCOC(=O)Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
Into 20 ml of anhydrous ether was dissolved 4.00 g (15 mmol) of 2-tetradecylpyrrole obtained in Synthetic Example 2, and then 7 ml (21 mmol) of ca. 3M ethereal solution of methylmagnesium bromide was added thereto at room temerature. The resulting mixture was heated under reflux for 30 minutes. Under cooling with ice water, 2 ml (21 mmol) of ethyl chlorocarbonate was added to the mixture. After heating under reflux for 10 hours, the resulting mixture was cooled to room temperature, poured into ice water containing ammonium chloride, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous megnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain 1.89 g (37% yield) of ethyl 5-tetradecylpyrrole-2-carboxylate, m.p. 60°-63° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[NH2:41][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(=O)O)cc23)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}butanoic acid (0.8 g, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g, 2.0 mmol), 1-hydroxy-1H-benzotriazole ammonium salt (0.24 g, 1.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (2:1). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give tert-butyl {[6-(4-amino-4-oxobutoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.68 g, yield (84%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: Oc1cc(F)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2cc(F)cc(Cl)c2)cc1
Yield: 88.9 %

Procedure:
To a solution of 3-chloro-5-fluorophenol (1.46 g, 10 mmol) and 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was heated to reflux for 4 hours. After filtration, the solvent was removed. The residue obtained was washed with n-hexane (2 times 15 mL) and dried to afford the title compound (2.38 g) which was directly used in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.Cl[CH2:31][C:32](=O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]2[S:21][CH:31]=[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:22]=2)=[CH:17][CH:18]=1
Reactant: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.5 g (0.0037 mol) of the compound from Example III and 1.5 ml=1.83 g (0.011 mol) of ethyl chloroacetoacetate were heated together with 30 ml of toluene and 10 ml of water at 100° C. for 1 hour. The mixture was neutralised with 10% strength sodium bicarbonate solution, the organic phase was separated off, dried with sodium sulphate and concentrated to a small volume in vacuo, and the residue was separated by column chromatography. A yellow oil was obtained.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]2)=[N:10][C:11]=1[NH2:12].Cl.[Cl:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34](=N)OCC)[CH2:33][CH2:32]2)[CH:30]=1>>[Cl:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34]3[NH:12][C:11]4=[N:10][C:9]([N:13]5[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]5)=[CH:8][CH:7]=[C:6]4[N:5]=3)[CH2:33][CH2:32]2)[CH:30]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1

Procedure:
Acetic acid (2.5 mL, 41.66 mmol) was added to a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate, prepared in step 2, followed by ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate hydrochloride salt, prepared in step 3). The mixture was heated at reflux for 18 h, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 silica gel, 25-70% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (900 mg). MS (ES+) (M+H) 415.2; LCMS retention time 2.506 min (Method N1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2>C(O)(=O)C.S(=O)(=O)(O)O.[Pt]=O>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: Nc1cccc2cnccc12
Agent: O=[Pt]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1cccc2c1CCNC2
Yield: 63.1 %

Procedure:
A solution of 5-aminoisoquinoline (10 g, 69 mmol) in glacial acetic acid (150 ml) and concentrated sulfuric acid (1 ml) was hydrogenated over platinum oxide (1 g) at 55 psi for 20h. The acetic acid was then removed in vacuo and the residue treated with saturated aqueous potassium carbonate (100 ml) and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the title compound (6.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:9]([C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)[CH:10]=[CH:11][C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:39]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[C:9]([C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)[CH:10]=[CH:11][C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([O-:18])=[O:17])=[CH:6][CH:7]=1.[Na+:39]
Reactant: Cn1nnnc1C(C=C[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1C(C=C[C@@H](O)C[C@@H](O)CC(=O)[O-])=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
A solution of the dihydroxyester prepared in Step D (35 mg; 0.068 mmole) in ethanol (2 mL) was treated with 1N NaOH solution (68 l; 0.068 mmole) and the mixture stirred for 30 minutes at 23° C. The solvent was removed by evaporation in vacuo and the residue dissolved in water (2 mL) and lyophilized to afford 36 mg (100%) of the title compound; m.p.>110° C. decomp. [α]D25 =-22.2° (c=0.32, H2O). The 1H NMR and 13C NMR are identical to the (±)-erythro product prepared in Example 12.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6](/[CH:8]=[N:9]/[O:10][CH3:11])=[N:5][NH:4][C:3]1=[O:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CCO.Cl>[CH3:11][O:10]/[N:9]=[CH:8]/[C:6]1[CH2:7][N:2](/[N:1]=[CH:19]/[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:12])[NH:4][N:5]=1
Reactant: CO/N=C/C1=NNC(=O)N(N)C1
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: CO/N=C/C1=NNC(=O)N(/N=C/c2cccnc2)C1
Temperature: 60 °C

Procedure:
To a solution of 4-amino-6-[(E)-methoxyiminomethyl]-2,5-dihydro-1,2,4-triazin-3-one (2.57 g, 15.0 mmol) in EtOH was added pyridine-3-carbaldehyde (1.41 mL, 15.0 mmol), followed by addition of 1 drop conc. HCl. The mixture was heated to 60° C. for 3 h and then allowed to cool to room temperature. After addition of silica gel, the reaction mixture was evaporated and purified by flash chromatography (5% MeOH/CH2Cl2) to give compound I-001 as a white solid. LCMS (Method H) RT 0.97 min. [M+H]+ 261. M.p. 237-238° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH2:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:22][C:23]1[CH:24]=[C:25]([C:29]2[N:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][N:30]=2)[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH:21][C:35]([C:32]2[CH:33]=[N:34][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)=[N:30][CH:31]=2)=[O:36])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium carbonate (13.94 mmol) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (4.65 mmol) in ethyl acetate (30 mL) and water (20 mL) is added a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (4.65 mmol) in ethyl acetate (20 mL). The mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated in vacuo to give 3-({[2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a solid. MS 415 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.47 (s, 9H), 1.55-2.22 (m, 5H), 2.90-4.90 (m, 6H), 7.15-7.25 (m, H), 7.41-7.53 (m, H), 7.56 (bs, NH), 8.18 (d, H), 8.29 (d, H), 9.21 (s, 2H).