Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.C[Si](Cl)(C)C.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.N>N1C=CC=CC=1.O>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@H:15]3[C@H:14]([O:18][C:17]([CH3:19])([CH3:20])[O:16]3)[C@@H:13]([CH2:21][OH:22])[O:12]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (0.400 g, 1.30 mmol) was dried by co-evaporation with pyridine, then suspended in dry pyridine (6.5 mL). TMSCl (0.330 mL, 2.60 mmol) was added and the mixture was stirred for 15 min. 4-Bromobenzoylchloride (0.342 g, 1.56 mmol) was added to the mixture and stirred for 2 h. The solution was cooled to 0° C. and 1 mL of H2O was added. After 5 min a 29% NH3 aq solution (0.847 mL) was added and the reaction mixture was stirred for 30 min while warming to r.t. The mixture was then concentrated and the residue was diluted with H2O (40 mL). The product was extracted with EtOAc (60 mL) and concentrated. The crude material was purified by flash chromatography (65 to 100% EtOAc/hexanes) to afford the title compound (0.305 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>CN(C)C=O>[ClH:1].[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:9]1[N:10]=[C:11]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[C:12]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:13]1
Reactant: CCCCOC(=O)c1nnn(-c2ccc(Cl)cc2)c1N
Reactant: CN(C)CCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nn(CCN(C)C)nc1Nc1ccc(Cl)cc1
Product: Cl

Procedure:
A mixture consisting of 6.0 gm (0.02 mol) of n-butyl 1-(4-chlorophenyl)-5-amino-1H-1,2,3-triazole-4-carboxylate, 100 ml of absolute dimethylformamide and 4.3 gm (0.04 mol) of 1-chloro-2-dimethylamino-ethane was reacted as in Example 1, the reaction mixture was evaporated, the residue was dissolved in 2N hydrochloric acid and water, and the solution was extracted with ether at stepwisely increasing pH values. After evaporation of those ether phases shown to be pure by thin-layer chromatography, the residue was dissolved in a little isopropanol, the solution was acidified with ethereal hydrochloric acid, and the hydrochloride was precipitated with ethyl acetate. After recrystallization from ethanol, 0.8 gm of the desired compound, corresponding to 9.9% of theory, was obtained with a melting point of 171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(Cl)Cl>[C:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH2:1])[CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CC(N)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminoquinoline (6.04 g, 41.89 mmol) and Et3N (5.85 mL, 41.89 mmol) were dissolved in CH2Cl2 (75 mL). Acetic anhydride (3.95 mL, 41.89 mmol) was added and reaction stirred at ambient temperature for 18 hours. The reaction mixture was poured into H2O and filtered. The filtered solid was dried in vacuo to yield the above-titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.ON1C2C=CC=CC=2N=N1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28]>C(O)C>[C:27]([C:26]1[CH:29]=[C:22]([NH:21][C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])[CH:23]=[CH:24][C:25]=1[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:28]
Reactant: N#Cc1cc(N)ccc1N1CCCCC1
Reactant: Cc1c(C(=O)O)cnn1C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Cc1c(C(=O)Nc2ccc(N3CCCCC3)c(C#N)c2)cnn1C
Temperature: 78 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
1-Hydroxybenzotriazole 1,5-dimethylpyrazole-4-carboxylate (1.2 g) and 5-amino-2-piperidinobenzonitrile (0.9 g) were added to ethanol (20 ml) and the mixture was stirred at 78° C. for 3 h. After evaporation of the solvent, aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.7 g), melting point: 217–218° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:18]2[CH:21]=[C:14]([Br:13])[CH:15]=[CH:16][C:17]=2[F:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-bromo-2-fluoro-benzaldehyde (2.03 g, 10 mmol) in ethanol (20 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-bromo-2-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.76 g, 79%) as a white solid: LC/MS m/e calcd for C16H13BrFNO2 M+: 350.2, observed: 350.1, 352.1.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[CH2:13][CH:12]2[CH3:19])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.Br[CH2:32][C:33](Br)=[O:34].[OH2:36]>C1C=CC=CC=1>[CH:1]([N:4]1[C:33](=[O:34])[CH2:32][O:20][CH:6]([C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH2:13][CH:12]3[CH3:19])=[O:36])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)NCC(O)COc1ccc2c(c1)C(C)CC2=O
Reactant: O
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC1CCc2ccc(OC(=O)C3CN(C(C)C)C(=O)CO3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
To a mixture of 2.77 g. of 3-isopropylamino-1-(3-methyl-1-oxo-5-indanyloxy)-2-propanol, 50 ml. of methylene chloride, and 1.2 g. of triethylamine was added dropwise 2.1 g. of bromoacetyl bromide with stirring under ice-cooling and the mixture was stirred for 18 hours at room temperature. Thereafter, methylene chloride was distilled off and after adding to the residue formed 50 ml. of benzene and 50 ml. of water to form a solution, the benzene layer formed was recovered, washed with 20 ml. of aqueous 5% hydrochloric acid solution and then twice each with 30 ml. of water, dried over anhydrous magnesium sulfate. Then, benzene was distilled off from the reaction mixture and after adding to the residue a solution of 0.3 g. of metallic sodium in 50 ml. of methanol, the mixture was refluxed for 3 hours. Methanol was distilled off and then to the residue were added 50 ml. of benzene and 30 ml. of water. The benzene layer formed was recovered from the mixture, washed twice with 20 ml. of aqueous 5% hydrochloric acid solution and then 20 ml. of water, and dried over anhydrous magnesium sulfate. Then, benzene was distilled off and 2 ml. of acetone was added to the residue to form precipitates, which were recovered by filtration. Thus, 2.3 g. (yield 73.6%) of 4-isopropyl-2-(3-methyl-1-oxo-5-indanyloxymethyl)-5-oxomorpholine was obtained. By recrystallizing the product from acetone, the faint yellow crystals of the product melting 150°-152° C. were obtained.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][NH:16][C:17](=O)[CH2:18][C:19]1([NH:33][CH3:34])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1>C1(C)C=CC=CC=1.C1COCC1>[CH3:34][NH:33][C:19]1([CH2:18][CH2:17][NH:16][CH3:15])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1
Reactant: CNC(=O)CC1(NC)CCN2CCc3ccccc3C2C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNCCC1(NC)CCN2CCc3ccccc3C2C1

Procedure:
To a 500 ml round bottomed flask with stirring bar, refluxed condenser, dropping funnel and argon inlet was added a solution of sodium bis (2-methoxyethoxy)aluminum hydride (20.63 ml of a 3.4M solution in toluene) and 100 ml of dry THF. This solution was heated at reflux and a solution of the acetamide (5.04 g, 17.54 mmol) from Step B in 100 ml of dry THF was added dropwise over 45 minutes. When the addition was complete the mixture was heated at reflux for 2 hours. The reaction mixture was chilled in an ice bath and quenched with 100 ml of saturated aqueous potassium sodium tartrate solution. The resulting mixture was diluted with ethyl acetate (300 ml) and the layers were separated. The organic phase was washed with an additional 200 ml of tartrate solution and 200 ml of brine. Drying (K2CO3), filtration and removal of the solvent in vacuo left 4.90 g of (2RS,11bSR)-2-methylamino-2-(2-methylaminoethyl)- 1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine as an oil.
Reaction SMILES: [NH2:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]2[C:20]([CH3:23])=[N:21][N:22]=[C:3]12.[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.O>O1CCCC1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]3[C:20]([CH3:23])=[N:21][N:22]=[C:3]3[C:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)=[O:38])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)=[CH:14][CH:13]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)C1(N)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(NC(=O)Nc2cccc(C)c2)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21

Procedure:
In a nitrogen atmosphere, 4-amino-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (373 mg) was dissolved in dry tetrahydrofuran (4 ml) and thereto was added 3-methylphenyl isocyanate (139 μl), followed by reaction at room temperature for 3.5 hours. After the completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of citric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform:methanol=45:1) and crystallized to give 219 mg of N-[6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-(3-methylphenyl)urea as pale yellow needle crystals, mp. 168°-172° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1.CN(C)C=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+:25]>CO>[N:18]1([CH2:2][C:3]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[O:5][N:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Na+:25]
Reactant: O=C(O)CCc1nc(CCl)no1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C([O-])CCc1nc(CN2CCOCC2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A 25 mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with 3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)propionic acid (1.48 g, 7.77 mmol), dimethylformamide (4 mL) and morpholine (2.0 g, 22.9 mmol). The reaction mixture was then stirred for 4 h at ambient temperature. The resulting suspension was filtered, and the filter cake was washed with ether and dried to afford 2.52 g of the crude product. A portion (1.49 g) of this material was dissolved in methanol (6 mL) and treated with sodium hydroxide (399 mg, 9.98 mmol). After 1 h, the reaction mixture was concentrated to dryness under vacuum, and then triturated with ethyl acetate. The precipitate was filtered and dried under reduced pressure affording a 68% yield of sodium 3-[3-(morpholin-4-ylmethyl)-1,2,4-oxadiazol-5yl]propionate, contaminated with a small amount of sodium acetate, as a white solid. This material was used directly. m.p. 155-161° C. (dec.); 1H NMR (DMSO-d6) δ (ppm) 3.56 (m, 6H), 2.98 (t, 2H,J=7.2 Hz), 2.46 (t, 4H,J=4.3 Hz), 2.36 (t, 2H,J=7.2 Hz): m/z=263 (M−Na).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](=[S:7])[NH2:6])[CH3:2].C([CH:13](Br)[C:14](=O)[C:15]([O-:17])=[O:16])C.[CH2:20](O)[CH3:21]>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5]1[S:7][CH:13]=[C:14]([C:15]([O:17][CH2:20][CH3:21])=[O:16])[N:6]=1)[CH3:2]
Reactant: CCC(Br)C(=O)C(=O)[O-]
Reactant: CCOC(OCC)C(N)=S
Reactant: CCO
Product: CCOC(=O)c1csc(C(OCC)OCC)n1
Yield: 93 %

Procedure:
2,2-Diethoxyethanethioamide (0.654 g, 6.03 mmol; see step (iii) above) and ethylbromopyruvate (Aldrich) (1.28 g, 6.10 mmol) were dissolved in ethanol (10 mL) in the presence of 4 Å molecular sieves (1 g). The mixture was refluxed for 45 min and the solvent removed under reduced pressure. The residue was then dissolved in ethyl acetate (20 mL) and extracted with saturated. NaHCO3 solution (2×20 mL), and brine (2×20 mL). The organic fraction was then dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound (1.452 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:33]2[CH:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccc(Cl)nc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-chloro-5-chloromethylpyridine gave the title compound. ES-MS m/e (%): 524.1(M+H+).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7](C#N)=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.[CH3:13][Li].S(=O)(=O)(O)O.[C:20](=[O:23])([O-])O.[Na+]>O1CCCC1>[O:1]1[C:10]2[C:5](=[N:6][C:7]([C:20](=[O:23])[CH3:13])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c(n1)OCCO2
Reactant: [Li]C
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(n1)OCCO2
Reaction time: 0.08 h
Yield: 47 %

Procedure:
Under an argon atmosphere, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-carbonitrile (16 mg, 99 μmol) was dissolved in tetrahydrofuran (500 μL), added methyllithium (150 μL (1.04 M in THF solution), 148 μmol) under ice-cold conditions, and the mixture was stirred at the same temperature for 5 minutes. The reaction solution was added 1M-sulfuric acid (2.0 mL), and stirred at room temperature for 3 hours. Under ice-cold conditions, the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate (pH=8 was confirmed). The reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (8.3 mg (yield 47%)) was obtained as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[N:5]1([C:11]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([OH:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1.BrC(Br)C>C(#N)C.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:17][C:15]1[CH:16]=[C:11]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH:12]=[CH:13][C:14]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1O
Reactant: BrCCBr
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1OCCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
1,2-Dibromoethane (1.50 mL, 17.4 mmol) was added to 5-Morpholin-4-yl-2-nitro-phenol (0.792 g, 3.53 mmol) and Potassium carbonate (1.71 g, 12.4 mmol) in Acetonitrile (40 mL) and the reaction was stirred under an atmosphere of Nitrogen at room temperature for 72 h (no change by HPLC), then was brought to reflux. After 4d, 1H-NMR indicated that the assumed starting material my LCMS was in actuality the 2:1 phenol-dibromoethane adduct. The reaction was cooled, diluted with ethyl acetate and filtered, conc. onto 5 g Celite. Chromatography (ISCO, 40 g, 0-40% EtOAc:Hex) afforded 4-[3-(2-Bromo-ethoxy)-4-nitro-phenyl]-morpholine (447 mg, 38%) as a colorless oil. 1H-NMR (CDCl3): 7.99 (d, 1H, J=8.8 Hz), 6.48 (m, 1H), 6.36 (d, 1H, J=1.5 Hz), 4.39 (t, 2H, J=6.8 Hz), 3.85 (t, 4H, J=4.8 Hz), 3.71 (t, 2H, J=6.8 Hz), 3.34 (t, 4H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:14][CH:15]([CH3:17])[CH3:16])([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N.O>CO.[Ni]>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][C:9]([CH2:12][NH2:13])([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC(C)C)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N1CCC(CN)(CC(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a heavy wall flask was placed 1-(ethylsulfonyl)-4-isobutylpiperidine-4-carbonitrile (4, 1.4 g, 5.42 mmol) 2N ammonia in methanol (50 ml). To this was added commercially available Raney nickel slurry in water (1.393 g, 16.26 mmol). This was then agitated under hydrogen atmosphere (45 psi) at room temp for 12 hours. The catalyst was filtered off using celite and washed with MeOH (200 ml). The organics were concentrated in vacuo to give 1-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methanamine (5) as a clear oil. MS 263 (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.OC(C(O)(C)C)(C)C.[B:25]([O:34][CH:35]([CH3:37])[CH3:36])([O:30][CH:31]([CH3:33])[CH3:32])OC(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:25]2[O:30][C:31]([CH3:32])([CH3:33])[C:35]([CH3:36])([CH3:37])[O:34]2)=[CH:10][CH:9]=[N:8]1
Reactant: c1cnn(C2CCCCO2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a 500 ml flask was added 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 14.1.A and 100 ml of THF. The solution was cooled to −78° C. at which time butyllithium (52 ml, 83 mmole, 1.6M in hexanes) and pinacol (9.8 g, 83 mmole) were added. The reaction was stirred for 5 minutes at −78 C and then triisopropyl borate (19 g, 103 mmole) was added. The reaction was slowly warmed to room temperature over 90 minutes and then stirred at room temperature for an additional 16 hours at which time the reaction was quenched with NH4Cl aq. (pH ˜7-8), extracted with EtOAc, and purified by silica gel chromatography to give 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14.1.B (7.2 g, 38% yield).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([NH:24][C:25]([NH:27][C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:31]=[C:30]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:29]=2)=[O:26])=[CH:16][CH:15]=1.[N:44]1C=CC=CC=1>>[CH3:1][NH:2][C:3](=[O:4])[NH:44][C:9]1[CH:10]=[C:11]([CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][C:25]([NH:27][C:28]3[N:32]([C:33]4[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=4)[N:31]=[C:30]([C:40]([CH3:42])([CH3:43])[CH3:41])[CH:29]=3)=[O:26])=[CH:16][CH:15]=2)[CH:6]=[CH:7][N:8]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3N)c3ccccc23)cc1
Reactant: CN=C=O
Product: CNC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
Methyl isocyanate (8.5 μl, 0.14 mmol) was added to a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) in pyridine (1.0 mL). The reaction mixture was stirred for 2 hr at RT and a further portion of methyl isocyanate (8.5 μl, 0.14 mmol) was added and stirring continued for 72 hr at RT. The solvent was removed in vacuo and the crude product was purified by column chromatography (4 g, 10-25% MeOH in DCM, gradient elution). The crude product fractions were combined and triturated with DCM (20 mL). The solid was filtered off to afford 1-(4-((3-methylureidopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Example 15) (8 mg, 14%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.68 (3H, d), 5.27 (2H, s), 6.35 (1H, s), 6.53 (1H, m), 6.98 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.65-7.52 (4H, m), 7.92 (1H, d), 8.16 (1H, s), 8.28 (2H, m), 8.61 (1H, s), 8.82 (1H, s), 8.88 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34]C(C)(C)[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].Cl.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]([OH:32])[CH2:35][OH:34])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(CC(O)CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of compound 105 (535 mg, 1.16 mmol) in THF (6.0 mL) was added aqueous HCl (1M, 6 mL)) and the mixture was stirred for 24 h at RT. The reaction mixture was poured into a mixture of EtOAc/saturated NaHCO3. The aqueous phase was washed with more EtOAc. The collected organic phases were washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 2:98 to 10:90 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.3, 145.0, 139.8, 135.7, 133.7, 133.7, 131.6, 128.4, 127.1, 126.6, 126.5 (dd), 124.9, 124.2 (dd), 122.3, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 70.3, 63.2, 53.0, 19.4