Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[C:34]([F:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[C:34]([F:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1
Reactant: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)c2cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(N)cc3)c2cc1F
Reaction time: 1 h
Yield: 69.1 %

Procedure:
The product of Example 451C (0.23 g, 0.4 mmo) in CH2Cl2 (4.6 mL) was treated with trifluoroacetic acid [TFA] (1.15 mL) dropwise at room temperature then stirred for 1 hour. The reaction mixture was concentrated. The residue was diluted with water, made basic with K2CO3, stirred at room temperature overnight. The pH was adjusted to pH 5-6 with 1N HCl stirred at room temperature for 1 hour, the resulting precipitate was collected by filtration, washed with water and i-Pr2O, and dried at 40° C. in vacuum overnight to give the title compound as yellow crystal (0.13 g, 71%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 3.42-3.60 (m, 1H), 5.64 (br-s, 2H), 6.64 (d, J=8.4 Hz, 2H), 6.84 (d, J=7.7 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.73 (br-d, J=7.7 Hz, 1H), 7.83 (br-s, 1H), 8.58 (s, 1H), 8.65-8.80 (m, 1H), 10.10 (s, 1H), 12.91 (br-s, 1H). MS ESI+m/z: 450 (M+H), ESI− m/z: 448 (M−H).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1>O>[CH2:2]([O:3][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:1]
Reactant: CC[O-]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of NaOEt in dry EtOH (45 mL, 114.90 mmol) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (7.0 g, 38.30 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and ethanol was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give I-g as brown oil in 96% yield. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 4.52 (s, 2H), 3.56 (q, J=7.0 Hz, 2H), 2.57 (d, J=10.1 Hz, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[B:16](OCCCC)([O:22]CCCC)[O:17]CCCC.P(=O)(O)(O)O>CCOCC>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([B:16]([OH:22])[OH:17])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: O=P(O)(O)O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-bromoindole (200 mg, 1.02 mmol) in anhydrous ether (4 mL), at −78° C., is treated dropwise with tert-butyllithium (1.7 M solution in pentane, 2 mL, 3.4 mmol). After stirring for 30 minutes the mixture is treated dropwise with tributyl borate (0.822 mL, 3.06 mmol) and allowed to warm up to room temperature. After stirring overnight the reaction mixture is diluted with ether, and this mixture is added in portions to phosphoric acid (15 mL, 1M), stirred for 30 minutes and extracted three times with ether (20 mL). The combined extracts are extracted three times with sodium hydroxide solution (20 mL, 1N). The combined sodium hydroxide extracts are acidified with phosphoric acid (1 M) to pH=2, extracted with ether. The combined ether extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 1H-indol-6-yl-boronic acid [Intermediate (77)] as a solid, which is used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:19]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:29]=[O:30])[C:23]=2[CH:22]=[CH:21][N:20]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[C:3]=1[CH:29]([C:24]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:28]=2[CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=Cc1cccc2cnccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1c(Br)ccc2c1OCO2)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a solution of 4-bromo-1,2-(methylendioxy)benzene (3.01 g, 15 mmol) in THF (20 mL) at −78° C. was added dropwise lithium diisopropylamide (10.6 mL of 1.5 M in cyclohexane, 16 mmol). The reaction mixture was stirred at −78° C. under argon for 20 minutes. A brown solution was formed. A solution of 5-isoquinolinecarboxaldehyde (1.90 g, 12 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes and warmed to room temperature. Stirring was continued for 30 minutes at room temperature, and then the mixture was quenched with saturated NH4Cl solution. The product was extracted with EtOAc and the solvent was removed under reduced pressure. Chromatography (SiO2 Type-H, 35% EtOAc in Hexanes) of the residue yielded the title compound as a yellow solid (2.8 g, 7.8 mmol, 65% yield): mp 173–175° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-chloroaniline (10.0 g) and triethylamine (16.4 ml) in acetonitrile (80 ml) was added dropwise pivaloyl chloride (14.5 ml) under ice-cooling. The mixture was allowed to warm to room temperature and stirred for 5 hrs. The obtained reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (1500 ml) and water (1500 ml). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and hexane to give N-(4-chlorophenyl)-2,2-dimethylpropionamide (15.0 g) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH2:17][NH2:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:13][NH:15][CH2:16][CH2:17][NH:18][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCNCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNCCNc1cc([N+](=O)[O-])ccc1C#N
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-4-nitrobenzonitrile (13.2 g), N-ethylethylenediamine (16 mL) and potassium carbonate (10 g) in acetonitrile (250 mL) was vigorously stirred for 16 hours resulting in the formation of an orange solid. The mixture was diluted with water and filtered. The precipitate was washed with water and dried to provide 2-(2-methylamino-ethylamino)-4-nitro-benzonitrile (10 g): 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (m, 2H), 5.8 (br, 1H), 3.4 (q, 2H), 3.1 (m, 2H), 2.8 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:4]=[C:3]([CH2:2][C:20]#[N:21])[CH:7]=[N:6]1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole, prepared as in EP 350 237, was treated with potassium cyanide in dimethyl sulphoxide at room temperature for two hours. The mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-ylacetonitrile. In a similar manner to Example 6, this compound was converted to 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole,. (Compound 29a).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Anhydrous K2CO3 (21.9 g, 0.159 mol) and methyl iodide (10.8 mL, 0.178 mol) were added to a solution of 2,5-dichlorophenol (23.5 g, 0.144 mol) in 215 mL acetone. The reaction was allowed to stir at room temperature for 20 hours, then filtered through a celite pad. The filtrate was concentrated to a residue which was taken up in diethylether. The ether solution was washed with 10% NaHSO3, water, several portions of 1M NaOH, and brine, then dried with anhydrous Na2SO4. Upon filtration and concentration, the residue was distilled (8 mm Hg, 110° C.) to yield 23.7 g (93.5%) of a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]/[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)/[C:4]([O:6]CC)=[O:5].Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]/[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)/[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Ethyl Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (580 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1N aqueous solution of sodium hydroxide (3 ml) was added and the mixture was stirred for 3 hours at room temperature. 1N HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (523 mg, yield 96%) as colorless crystals. m.p. 140-142° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 187 mg (60.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1]Cl.[Si:3]([O:10][CH:11]([CH:13]1[CH:16](SC)[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Si:3]([O:10][CH:11]([CH:13]1[CH:16]([Cl:1])[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: ClCl
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C1SCC(=O)S1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C2SCC(=O)S2)C1Cl
Reaction time: 0.5 h

Procedure:
A solution of an equimolar amount of chlorine in carbon tetrachloride was added to a solution of p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-(4-oxo-1,3-dithiolan-2-ylidene)acetate (134 mg) in methylene chloride (3 ml), with ice cooling. The solution was stirred at that temperature for 30 minutes and then solvent was distilled off to afford the desired product quantitatively.
Reaction SMILES: [CH:1]1([C:5]2([CH2:9][OH:10])[CH2:8][O:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>ClCCl.N1C=CC=CC=1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][CH2:9][C:5]2([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:8][O:7][CH2:6]2)=[O:17])=[CH:14][CH:13]=1
Reactant: OCC1(C2CCC2)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCC1(C2CCC2)COC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyclobutyl-3-hydroxymethyloxetane (2.84 g, 20 mmol) in dry dichloromethane (40 ml) and pyridine (3 ml) at 0° C. under nitrogen was added a solution of 4-iodobenzoyl chloride (5.33 g, 20 mmol) in dry dichloromethane (10 ml). The solution was stirred overnight at room temperature, washed with water, dried over anhydrous sodium sulphate and evaporated. (3-Cyclobutyloxetan-3-yl)methyl 4-iodobenzoate was obtained as a white solid (7.42 g, 99%) which was not purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)(=[O:18])=[O:17])=[CH:12][C:11]=2[C:27]#[N:28])[CH:5]=[N:6][C:7]=1F.[NH:29]1[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:29]1([C:7]2[N:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)(=[O:18])=[O:17])=[CH:12][C:11]=3[C:27]#[N:28])=[CH:3][C:2]=2[Cl:1])[CH2:32][CH2:31][CH2:30]1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(F)c(Cl)c1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(N2CCC2)c(Cl)c1
Temperature: 50 °C

Procedure:
To a solution of 4-((5-chloro-6-fluoropyridin-3-yl)oxy)-3-cyano-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Example 242, 200 mg, 0.47 mmol) in dimethylsulfoxide (2 mL) was added azetidine (54 mg, 0.94 mmol) followed by potassium carbonate (130 mg, 0.94 mmol) and the reaction was heated to 50° C. for 17 hours. The mixture was filtered and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]34[CH2:22][CH:20]([CH2:21]3)[O:19][C:18](=[O:23])[NH:17]4)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:24].[NH+]1C=CC=CC=1>C1COCC1>[Br:24][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:21][CH:20]([CH2:22]2)[O:19][C:18](=[O:23])[NH:17]3)=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C1NC2(c3ccc(C(=O)Cc4ccccc4)cc3)CC(C2)O1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(4-phenylacetyl-phenyl)-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.34 g) and pyridinium hydrobromide perbromide (2.22 g) in THF (39 mL) was stirred at rt for 2 hours. The mixture was partitioned between EtOAc and water and the organic phase washed successively with dilute aqueous sodium thiosulfate and brine, dried and concentrated to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[N:25]1([C:2]2[C:3]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[NH:18][C:17]5[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=5[N:15]=4)[CH2:12][CH2:13]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)CC3)nc2c1
Reactant: C1COCCN1
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4N4CCOCC4)CC3)nc2c1
Temperature: 130 °C
Yield: 16 %

Procedure:
A mixture of 2-[1-(3-chloro-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (150 mg, 0.68 mmol) and morpholine (3 mL) in pyridine was heated at 130° C. under microwave for 45 min. Then it was concentrated to give the crude product which was purified by column chromatography and followed by preparative HPLC to afford pure product 2-[1-(3-morpholin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (30 mg, 16%). [M+1] 390. IC50 (uM) 1.996.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH3:20].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 3.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 1.8 g of 1-bromopropane, 2.5 g of sodium bicarbonate and 30 ml of dimethylformamide was stirred and heated at 60° for 2 hr. After stirring at ambient temperature for 14 hr, the reaction was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate yielded 2.3 g (63%) of product. This material was combined with a sample from another experiment and recrystallized from ethyl acetate to yield the analytical sample, mp 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]2[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=2[CH:73]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:26])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:63]=[CH:64][C:65]5[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=5[CH:73]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.65 g, 3.95 mmol) and Et3N (1.6 g, 15.8 mmol) in MeCN (35 ml) was stirred at rt for 5 min and then HATU (3 g, 7.9 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (906 mg, 4.74 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and preparative HPLC to provide the product (500 mg, yield 21%). 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.92 (s, 1H), 7.82 (s, 1H), 7.61 (m, 5H), 7.40 (m, 3H), 4.49 (d, 2H), 4.37 (d, 2H), 2.39 (s, 3H), 1.44 (s, 6H) ppm; HPLC purity: 97.4% at 220 nm and 98.1% at 254 nm; MS: m/z=591.3 (M+H, ESI+).
Reaction SMILES: C([O:4][CH2:5][CH:6]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=O)C.[OH-].[K+]>CO.O>[N:19]1([CH:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][OH:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)OCC(COc1cccc2ccccc12)N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCC(COc1cccc2ccccc12)N1CCCCC1

Procedure:
A suspension of 2-piperidino-3-(1-naphthyloxy)-1-propanol acetate (6.4 g), 15% KOH in methanol (10 ml), methanol (10 ml) and water (20 ml) is heated at reflux for one hour. The reaction mixture is concentrated to dryness. The residue is taken up in diethyl ether. The ether extract is washed with water and concentrated to give the title compound as an oil, γmaxEtOH 319 nm (ε=1780), 350 nm (ε=3330), 288 nm (ε=6340), 230 nm (ε=30,600), 212 nm (ε=44,180).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]([CH3:14])[C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]([CH3:14])[C:8]([CH2:12][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cn1c(CCl)nc2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(CN2CCCC2)nc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
The mixture of 7-bromo-2-(chloromethyl)-3-methylquinazolin-4(3H)-one (125 mg, 0.43 mmol), pyrrolidine (65 mg, 0.91 mmol), K2CO3 (244 mg, 1.768 mmol) and DMF (10 mL) was stirred at room temperature for 30 min. Then water was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, filtered and evaporated to give 100 mg of the desired product. MS (ESI): 322, 324 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[NH:4][N:3]=1.Br[CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:24][CH2:25][Cl:26])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)c2c(N)n[nH]c2n(Cc2ccccc2)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(N)n(CCCl)nc2n(Cc2ccccc2)c1=O
Yield: 60.2 %

Procedure:
A mixture of 3-amino-7-benzyl-5-propylpyrazolo[3,4 -d]pyrimidine-4,6(5H,7H)-dione (11 g), 1-bromo-2-chloroethane (8.0 g) and potassium carbonate (7.0 g) was stirred in DMF (120 ml) at 50°-60° C. for 12 hours. The reaction mixture was concentrated to dryness, then the concentrate was extracted with chloroform/water. The chloroform layer was washed with water, dried and concentrated. The resultant brown syrup was purified by flash chromatography (silica gel 100 g, chloroform). The resultant syrup was crystallized from isopropylether to afford colorless needles (8.0 g, 60%), m.p. 126° to 128° C.