Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1.CO>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]2[NH:4][CH2:1][CH2:2][CH3:3])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]2[NH:4][CH2:1][CH2:2][CH3:3])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCCN
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCCN[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Product: CCCN[C@@H]1CNCC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 70 °C
Reaction time: 12 h
Yield: 12 %

Procedure:
Propylamine (226 μL, 2.75 mmol) was added to a mixed solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (102 mg, 0.275 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) under ice-cooling, and the mixture was heated under reflux at 70° C. for three hours. The reaction solution was concentrated under reduced pressure, and then the residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). Acetic acid (315 μL, 5.50 mmol) and sodium cyanoborohydride (69 mg, 1.10 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and a 1 N aqueous hydrochloric acid solution was added. The aqueous layer was washed with diethyl ether. The aqueous layer was concentrated under reduced pressure with heating, and then saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 17 mg of the cis isomer of the title compound (20%) as a colorless oily substance and 10.0 mg of the trans isomer of the title compound (12%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C([SiH2][O:15][C:16](C)(C)[C:17]([CH2:23]C)([CH2:21]C)[CH2:18][CH:19]=O)(C)(C)C.[CH2:27](Cl)Cl>>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:19]/[CH2:18][C:17]([CH3:23])([CH3:21])[CH2:16][O:15][CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)(CC=O)C(C)(C)O[SiH2]C(C)(C)C
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)CN
Product: COCC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.78 g, 5.8 mmol) was reacted with 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal (1.5 g, 5.8 mmol) in CH2Cl2 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.2 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]([CH3:10])=O.C(O)(=O)C.C(O[BH3-])(=O)C.[Na+]>ClC(Cl)C>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:8]([CH3:10])[CH3:7]
Reactant: CC(C)=O
Reactant: NCCCCO
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)NCCCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-aminobutanol (2.0 mg, 22.4 mmol) in 110 ml of dichloroethane were added acetone (3.3 ml, 44.8 mmol), acetic acid (5 eq.), and sodium acetoxyborohydride (11.9 g, 56.09 mmol). The cloudy mixture was stirred at ambient temperature for about 18 hours. The reaction was quenched with saturated sodium bicarbonate. Sodium hydroxide (1 M) was added to adjust the pH to about 10. The aqueous layer was extracted with a mixture of isopropyl alcohol and methylene chloride (1:3). The organic fractions were combined and dried over sodium sulfate, filtered, and concentrated. The desired intermediate was further purified by bulb to bulb distillation to yield 1.4 grams as a dear oil. If desired, additional yield may be recovered by extracting the aqueous fraction with 3:1 toluene:butanol.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([F:12])[C:4]=1O)C.C(C1C=C(C)C=C([C:25]([CH3:28])(C)C)N=1)(C)(C)C.[F:29][C:30]([F:43])([F:42])[S:31]([O:34]S(C(F)(F)F)(=O)=O)(=[O:33])=[O:32].C(OCC)(=O)C>ClCCl.CCCCCC>[CH2:25]([O:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:34][S:31]([C:30]([F:43])([F:42])[F:29])(=[O:33])=[O:32])=[CH:4][C:5]=1[F:12])[CH3:28]
Reactant: CCc1ccc(C(=O)[O-])c(F)c1O
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A stirred, cooled (ice bath) solution of ethyl-2-fluoro-hydroxy-benzoate (Intermediate 5, 0.368 g, 2 mmol) and 2,6-di-tertbutyl-4-methyl-pyridine (0.81 g, 8 mmol) in 8 mL of dichloromethane was treated with trifluoromethanesulfonic anhydride (0.1 g, 4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (0.53 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[NH2:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:25])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(N)=O)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 14.7 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-aminocarbonylphenyl)boronic acid (0.603 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 64 hours and allowed to cool to room temperature. A precipitate formed and was isolated by filtration, washed with water and DME, and recrystallized from methanol (100 mL/900 mg). The crystals were isolated by filtration, washed with methanol, and dried in a vacuum oven at 65° C. to provide 191 mg of 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]benzamide as an off-white solid, mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[CH3:25][O:26]C1C=C(C=CC=1)C(CC#N)=O.[CH3:38][O:39]C1C=CC(C#C)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:26][CH3:25])=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:39][CH3:38])[CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: COc1cccc(C(=O)CC#N)c1
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(-c2nnc3c(c(-c4cccc(OC)c4)nn3C)c2Cl)cc1

Procedure:
Compound 15 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-methoxybenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1 and 4-methoxyphenyl acetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1.O.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1.CO>C(=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[S:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=4)[C:7]4[C:8](=[O:9])[NH:10][CH:38]([CH3:39])[NH:1][C:2]=4[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N)c(C(N)=O)c1-c1ccc(OCCO)cc1
Agent: CC=O
Solvent: CO
Solvent: O
Product: CC1NC(=O)c2c(nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c2-c2ccc(OCCO)cc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 138 mg (0.256 mmol) of the compound from Example 22A were initially charged in 3 ml of acetaldehyde, a spatula tip of 4-toluenesulfonic acid monohydrate was added and the mixture was stirred at RT for 1 h. 2.5 ml of methanol were then added to the reaction solution, and after 2 h the mixture was concentrated and the residue was purified by column chromatography (silica gel, toluene/acetonitrile 2:1→1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:46])[CH2:36][N:37](C)[C:38](=O)OC(C)(C)C)[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12.Cl>CC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:46])[CH2:36][NH:37][CH3:38])[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCN(C(=O)CN(C)C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Agent: Cl
Solvent: CC(C)=O
Product: CNCC(=O)N1CCC(n2nc(-c3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)c3c(N)ncnc32)CC1
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
The crude tert-butyl N-{2-[4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-2-oxoethyl}-N-methylcarbamate (75 mg, 0.119 mmol) was dissolved in acetone (5 mL) then aqueous hydrochloric acid (6N, 1 mL) was slowly added. The reaction mixture was heated at 45° C. for 2.5 hours then concentrated under reduced pressure. The remaining residue was triturated with dichloromethane (25 mL) to yield a light yellow solid. Purification by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300 A, 15 μm, 40×100 mm column) afforded N-[4-(4-amino-1-{1-[2-(methylamino)acetyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea as a white solid (40 mg, 0.075 mmol). HPLC-RT: 12.22 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=532.1.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[F:11][C:12]1[CH:13]=[C:14]([NH:18]N)[CH:15]=[CH:16][CH:17]=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]2[C:7]3[CH2:8][NH:3][CH2:4][CH2:5][C:6]=3[NH:18][C:14]=2[CH:13]=1
Reactant: O=C1CCNCC1
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc2c3c([nH]c2c1)CCNC3
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Piperidone hydrochloride monohydrate (4.55 g) and 3-fluorophenylhydrazine hydrochloride (4.85 g) were added to ethanol (80 ml) and the mixture was heated under reflux for one hour. Hydrogen chloride gas was bubbled into the mixture and refluxing was recommenced for another 1.5 hours. The solution was cooled to 0° C., the hydrochloride was filtered off, washed with ethanol, dissolved in boiling water, decolourised with activated charcoal and filtered. 2M Sodium hydroxide solution was added to the warm solution until it was neutral when tested with pH paper. The pale cream solid was filtered off, washed with water and dried. Recrystallisation from acetonitrile gave a white solid which was a mixture of 7-fluoro and 9-fluoro-isomers in a ratio of 86:14 respectively (HPLC).
Reaction SMILES: [CH3:1][O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][N:8]=1.CI>CN(C)C=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:1])=[CH:9][N:8]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CO
Product: COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
28% Sodium methoxide-methanol (2.0 mL) was added dropwise to the above-obtained 2-chloro-5-hydroxypyridine (1.30 g) and methyl iodide (1.25 mL) in N,N-dimethylformamide (26 mL), followed by stirring at room temperature for 1.5 hours. The reaction mixture was partitioned by use of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (hexane-ethyl acetate), to thereby give 2-chloro-5-methoxypyridine as a solid (1.40 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[C:15]([OH:23])[C:14]=1[CH2:24][CH2:25][CH3:26].Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:33][OH:34])[CH2:20][CH3:21])=[C:15]([OH:23])[C:14]=1[CH2:24][CH2:25][CH3:26]
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc(C(=O)CC)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc(C(CC)=NO)c1O

Procedure:
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-propionylphenoxy)propylthio)phenylacetate (Step B; 25.655 grams) in dry methanol (260 mL) was treated with hydroxylamine hydrochloride (3.833 grams). Anhydrous sodium acetate (4.524 grams) was added and the mixture refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 7 buffer. The organic phase was washed once with water and dried over magnesium sulfate, filtered and evaporated to an oil. The title compound was used without further purification.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:28])[CH2:8][C:9](=[O:27])[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:12][CH2:11]1)C.C1COCC1.O>CO>[O:27]=[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:12][CH2:11]1)[CH2:8][C:7]([OH:28])=[O:6]
Reactant: CCOC(=O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
LiOH.H2O (93 mg, 2.2 mmol) was added to a solution of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester (400 mg, 1.1 mmol) in a mixture of methanol (2 mL), THF (5 mL) and H2O (2 mL). The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated and the residue was diluted with water, washed with diethyl ether and acidified with concentrated HCl. The residue was extracted with ethyl acetate and concentrated to afford 230 mg (62%) of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid. LCMS: 331.09 (M+1)+, 90.2%, 1H NMR: (CDCl3): δ 7.0 (t, 2H), 3.7 (s, 4H), 3.5 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])O)[C:5]([F:27])=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O.O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:21][C:20](=[O:26])[NH:19]2)[C:5]([F:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1cc(F)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (253 mg, 0.283 mmol) was dissolved in trifluoroacetic acid (10% in dichloromethane, 10 mL) and stirred at room temperature overnight. In the morning, the reaction was concentrated and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The crude aminoalcohol was eluted with 2M ammonia in methanol and concentrated to give 53 mg as a solid. The crude solid was dissolved in tetrahydrofuran (5 mL), cooled to 0° C., and treated with carbonyldiimidazole (45.9 mg, 0.283 mmol). After 5 min, the ice bath was removed, and stirring continued for 1 h. The reaction was quenched by addition of 2M ammonia in methanol. The reaction was concentrated and purified by column chromatography (25%→50% EtOAc/Hex) to give 20 mg (9.5%). Mass spec.: 373.1 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@@H:17](Br)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[N-:29]=[N+:30]=[N-:31].[Na+].C(O)(=O)C.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([N:29]=[N+:30]=[N-:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](Br)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 87.5 %

Procedure:
A solution of 36 (0.10 g, 0.22 mmol), sodium azide (0.05 g, 0.77 mmol) and glacial acetic acid in DMF (3 mL) was stirred at room temperature for 4 h. H2O (30 mL) was added and the mixture was extracted with EtOAc (20 mL). The EtOAc solution was washed with H2O (2×20 mL) and saturated NaCl (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 30% EtOAc/n-hexanes) to afford 0.08 g (86%) of 38 as a white solid, mp 200-203° C. (EtOAc/n-hexanes); 1H NMR (CDCl3): δ 1.13 (3H, s); 1.48 (3H, s); 1.68 (5H, m); 2.14 (31H, m); 2.34 (1H, ddd, J=3.6, 7.2, 27); 2.60 (1H, dd, J=5.1, 13.2); 2.72 (1H, dd, J=3.3, 13.2); 3.74 (3H, s); 3.92 (1H, dd, J=7.5, 12.6), 5.56 (1H, dd, J=5.1, 11.7); 6.39 (1H, dd, J=0.9, 1.8); 7.41 (1H, dd, J=1.2, 2.1); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Al]>ClCCl>[CH2:10]([NH:17][C:18](=[O:19])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=NCc1ccccc1
Reactant: OC1C=CCCCCC1
Agent: O=C(NCc1ccccc1)OC1/C=C/CCCCC1
Agent: OC1/C=C/CCCCC1
Agent: [Al]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)OC1C=CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-cyclooct-2-enol 31 (minor isomer 100 mg, 0.792 mmol) in dichloromethane (6 mL) were added benzyl isocyanate (101 μL, 110 mg, 0.826 mmol, 1.04 eq) and a drop of triethylamine. The flask was covered with aluminum foil and the solution was stirred under a nitrogen atmosphere at room temperature overnight. Evaporation of the reaction mixture gave mainly starting material. Benzyl isocyanate (200 μL, 220 mg, 1.65 mmol, 2.08 eq) and a drop of triethylamine in dichloromethane (6 mL) were added and the solution was stirred overnight at room temperature, at 50° C. for 1 hr and at 25-30° C. over the weekend. The volatiles were removed by bulb-to-bulb distillation (50° C., 2 hr). The residue was purified by column chromatography to give carbamate 32 (43 mg, 0.166 mmol, 20.9%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:27]([NH2:29])=[O:28].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.[Cl-].[Na+].O>[CH3:30][O:1][C:2]1[N:6]=[CH:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)c1c(O)ncn1Cc1ccc(NC(=O)c2cccc3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ncn(Cc2ccc(NC(=O)c3cccc4ccccc34)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
200 mg (0.517 mmol) of 5-hydroxy-3-{4-[(naphthalene-1-carbonyl)amino]benzyl}-3H-imidazole-4-carboxamide are dissolved in 5 ml of dry DMF in a round-bottomed flask under argon. 285 mg (2.07 mmol; 4 eq.) of potassium carbonate are then added. After one hour at room temperature, 440 mg (3.1 mmol; 6 eq.) of methyl iodide are added. After stirring for 24 hours at room temperature, the reaction medium is poured into brine and a precipitate appears. After stirring for 20 minutes, the precipitate is filtered off and then washed with water. After drying, 72 mg of a white solid are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[NH:26][C:38](=[O:39])[NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4[nH]c(=O)[nH]c4cc3-c3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.046 g, 0.094 mmol) was dissolved in 1 ml DCM and 1,1′-carbonyldiimidazole (0.017 g, 0.104 mmol) was added. After 8 h additional 1,1′-carbonyldiimidazole (0.017 g, 0.104 mmol) was added. After stirring overnight the reaction was diluted with saturated aqueous Na2CO3. The mixture was extracted 3× with DCM then 1× with iso-BuOH. Purification by flash column chromatography (95:5 to 90:10 DCM/MeOH) afforded 5-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4-5). 1H NMR (CDCl3) δ 7.69 (m, 1H), 7.55 (m, 1H), 7.27-7.16 (m, 9H), 7.08 (m, 2H), 6.76 (s, 1H), 4.12 (m, 1H), 3.34 (s, 2H), 2.96 (d, 2H), 2.61 (s, 3H), 2.52 (m, 2H), 2.27 (m, 2H), 1.79 (d, 2H, J=10.0 Hz). MS m/z (M+H)=515.16.