Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12]([NH2:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[NH3:15].[H][H]>CO.[Pd].O>[NH2:15][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([NH2:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: [H][H]
Reactant: N
Reactant: NC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reaction time: 18 h

Procedure:
26 g of 4-oxoadamantane-1-carboxamide (2) was put into a sealed container and 190 mL of 7N NH3 dissolved in MeOH was added thereto. Then, 1 g of a palladium catalyst (10 wt % Pd/C) was put into the reactor, and the reactor was filled with a nitrogen gas and the reactants were stirred for 18 hours. After the nitrogen gas was completely replaced with a hydrogen gas, the reactants were stirred for 24 hours and then filtered and distilled under a reduced pressure to provide a solid product. This solid product was placed and stirred in 100 mL of water and after the solids were removed therefrom, the remaining solution was distilled under a reduced pressure to provide 20 g of 4-aminoadamantane-1-carboxamide (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:16]=2)[NH:11][N:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(C)CC4)c3)cc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (25 mg, 72 μmol) in anhydrous DMF (1.5 mL) was added PS-DCC resin (Argonaut Technologies) (180 mg, 0.22 mmol, 1.21 mmol·g−1) and N-methylpiperazine (9.6 μl, 86 μmol). The resulting mixture was stirred at 60° C. for 16 h. The resin was filtered off, washing with dichloromethane and ether and the filtrate concentrated. The residue was dissolved in dichloromethane and treated with a PS-trisamine resin (Argonaut Technologies) (20 mg). The resin was again removed by filtration and washed with dichloromethane and ether. The filtrate was concentrated and the resulting crude product was purified by reverse phase mass-triggered HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (1.7 mg, 4.0 μmol, 6% yield). 1H-NMR (500 MHz, d6-DMSO) δ8.87 (d, 1H), 8.37 (d, 1H), 8.24 (t, 1H), 8.02 (dt, 1H), 7.98 (dt, 1H), 7.68 (dd, 1H), 7.64 (t, 1H), 7.47 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.86 (s, 3H). MS: m/z 346 [MH+].
Reaction SMILES: BrBr.[F:3][C:4]([F:17])([F:16])[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:15]=1.[S-:18][C:19]#[N:20].[K+].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>C(O)(=O)C.C(OC(C)C)(C)C.C(O)(C)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[NH:20]=[C:19]1[N:14]2[C:8]3[C:7](=[CH:6][C:5]([C:4]([F:3])([F:16])[F:17])=[CH:15][C:9]=3[CH2:10][CH2:11][CH2:12][CH2:13]2)[S:18]1
Reactant: N#C[S-]
Reactant: FC(F)(F)c1ccc2c(c1)CCCCN2
Agent: BrBr
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: N=c1sc2cc(C(F)(F)F)cc3c2n1CCCC3

Procedure:
The procedure is carried out as in Example 1, but starting with 2.38 g of bromine in 5 ml of acetic acid, 3.2 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine and 5 g of potassium thiocyanate in 35 ml of acetic acid. The brown-yellow oil isolated is chromatographed on a silica gel, eluting with ethyl acetate. A yellow oil is obtained which is dissolved in 15 ml of isopropyl ether to which there is added 1 ml of a 1.94 N solution of methanesulphonic acid in isopropanol. The white precipitate formed is filtered off and then dried under vacuum (70 Pa) at 50° C. 0.7 g of 2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][1]benzazepine methanesulphonate is thus obtained in the form of a white solid melting at 226° C. [analysis C13H15F3N2O3S, % calculated C 42.38, H: 4.1, F: 15.2, N: 7.5, O: 13.3, S: 17.41, % found C: 42.4, H: 3.9, F: 15.2, N: 7.5, S: 17.4].
Reaction SMILES: [CH2:1]=O.[CH:3]([O:6][C:7](=[O:31])[CH:8]([NH2:30])[CH:9]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH2:10][O:11][CH3:12])([CH3:5])[CH3:4]>O.Cl>[CH:3]([O:6][C:7]([CH:8]1[CH:9]([CH2:10][O:11][CH3:12])[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[NH:15][C:14]=2[CH2:1][NH:30]1)=[O:31])([CH3:5])[CH3:4]
Reactant: C=O
Reactant: COCC(c1c[nH]c2ccc(OCc3ccccc3)cc12)C(N)C(=O)OC(C)C
Agent: Cl
Solvent: O
Product: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
a suspension of 2.56 g of paraformaldehyde in 8 ml of water and 0.8 ml of concentrated hydrochloric acid is refluxed at 80° C. for 1 hour. One-tenth of the thus-obtained clear solution is added dropwise, after cooling to room temperature, to a solution of 3.8 g (10 mmol) of 2-amino-3-(5-benzyloxyindol-3-yl)-4-methoxybutyric acid isopropyl ester in 500 ml of water and 10 ml of concentrated hydrochloric acid (pH=3). After 1/2 hour of agitation, an estimate of the amount of amino compound still remaining is made by thin-layer chromatography, and a corresponding quantity of formaldehyde solution is added. Thereupon, the mixture is stirred for another hour and then extracted twice by shaking with 50 ml of toluene, respectively. The organic phase is discarded. The aqueous phase is adjusted, after adding 100 ml of toluene, to a pH of 5.3 with 27% strength sodium hydroxide solution. After extraction by shaking, the mixture is additionally extracted by shaking twice with 50 ml of toluene; these 3 organic phases are combined, dried over sodium sulfate, filtered, and concentrated, thus obtaining 3.3 g (85%) of 6-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:22])=[C:6]([S:8]([N:11](COCC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C(F)=CC(F)=C(S(/N=C2/N=CN(COCC)C=C/2)(=O)=O)C=1.[NH2:47][C:48]1[CH:53]=[C:52]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[OH:61])[CH:51]=[CH:50][N:49]=1>>[NH2:47][C:48]1[CH:53]=[C:52]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[O:61][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[C:5]([F:22])[CH:4]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CCOCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Agent: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2Cl)ccn1

Procedure:
The title compound was prepared by analogy with the method used for Example 813 below using 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide, 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide and 5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide, (Preparation 719) used as a mixture of three regioisomers and 2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 721).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]([CH3:19])[CH2:16][CH2:17]O>CCOCC>[Br:2][CH2:17][CH2:16][CH:15]([C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[O:6][CH3:5])[CH3:19]
Reactant: BrP(Br)Br
Reactant: COc1ccc(OC)c(C(C)CCO)c1
Solvent: CCOCC
Product: COc1ccc(OC)c(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(2,5-dimethoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[N:26][CH3:27]>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[CH3:27][NH:26][CH:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Reactant: CN=Cc1cccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1cccs1
Temperature: -6 °C
Reaction time: 2.3 h
Yield: 36.7 %

Procedure:
A stirred, chilled (-10° C.) solution of 19.3 g of N-[(2-methyl)phenyl]-2,2-dimethylpropanamide in 150 ml of tetrahydrofuran was treated over 43 min with 140 ml of a 1.6M solution of n-butyllithium in hexane, while maintaining the temperature at or below 0° C. Stirring for 2.3 hours with cooling afforded a suspension. The stirred, cooled (-6° C.) suspension was treated over 13 min with a solution of 15.02 g of N-(2-thienylmethylene)methanamine in 30 ml of toluene. The reaction mixture was stirred with cooling (1° C.) for 1.5 hours, quenched by the addition of 120 ml of water and concentrated. The concentrate was extracted with dichloromethane (2×200 ml), and the combined extract was dried over anhydrous sodium sulfate, filtered, and evaporated to an oil. Preliminary purification of the oil was achieved by preparative high pressure liquid chromatography (hereinafter "HPLC") separations utilizing a Water's Model 500A High Pressure Liquid Chromatograph (silica gel; eluting with 10% methanol in ethyl acetate). The appropriate fractions from each separation were combined and concentrated to an oil. The purification procedure was repeated utilizing 5% methanol in ethyl acetate as the eluent to yield 11.71 g of N-[2-[2-methylamino-2-(2-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide as a solid, mp 78.5°-82° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1c2cnn1CC
Reaction time: 12 h

Procedure:
5.7 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol) are dissolved in 50 ml of dry alcohol. After addition of 1.5 g of n-butylamine, the mixture is heated at reflux temperature with stirring for 12 hours. The solvent is removed and the crystalline residue is treated with water. The N-butyl-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3e]pyrimidin-5-amine is filtered off and recrystallized from ethyl acetate, yield 5 g (77%); m.p. 160°-162°.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]3[C:20](=[O:33])[C:21]([CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:22]([OH:25])[C:23]([OH:24])=[C:16]3[C:15]2=[O:34])=[CH:11][CH:10]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][C:21]2[C:20](=[O:33])[N:17]3[CH2:18][CH2:19][N:14]([CH2:13][C:12]4[CH:11]=[CH:10][C:9]([F:8])=[CH:36][CH:35]=4)[C:15](=[O:34])[C:16]3=[C:23]([OH:24])[C:22]=2[OH:25])[CH2:32][CH2:31]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1c2c(O)c(O)c(CC3CCNCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(Cc2c(O)c(O)c3n(c2=O)CCN(Cc2ccc(F)cc2)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione mono TFA salt (50 mg, 0.125 mmol) in anhydrous methylene chloride (2 mL), pyridine (12 μL, 0.149 mmol) and acetic anhydride (14 μL, 0.149 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue was purified by prep HPLC (Gilson semi preparative HPLC system using a Waters Nova Pak column [10×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.10% TPA)/acetonitrile (0.10% TFA) gradient at 35 mL/min]. Collection and lyophilization of appropriate fractions provided he title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](OCC)=[O:26])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].OC1C=C([NH:37]C2N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC3C=CC=CC=3OC)N=2)C=CC=1.[CH2:61]([OH:63])C>[Pd]>[OH:24][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:61](=[O:63])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:37])=[O:26])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCO
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(O)c3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl 5-amino-2-(3-hydroxyphenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(3-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (227 mg, 0.534 mmol) was dissolved in ethanol (15 mL) and 10% palladium on carbon (56.8 mg, 0.053 mmol) was added. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was then filtered through Celite, solvent was removed under reduced pressure and purified by column chromatography (2% methanol in methylene chloride). A second chromatographic purification was necessary (50% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (186.8 mg, 0.472 mmol, 89% yield). MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3](O)=[O:4].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.C(O)C>C1(C)C(C)=CC=CC=1>[NH2:1][CH:2]1[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:3]1=[O:4]
Reactant: Nc1ccccc1CCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1C
Product: NC1CCc2ccccc2NC1=O

Procedure:
Alternatively, a solution of 2-amino-4-(2-nitrophenyl)butyric acid hydrochloride (2.5 g) in water (200 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% Pd-C (0.5 g) as catalyst. After uptake of hydrogen ceased, the catalyst was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in water (50 ml) and the pH adjusted to 7 by the addition of 10% sodium hydroxide. The solid was filtered off, washed with water, and dried to give 2-amino-4-(2-aminophenyl)butyric acid. A solution of the 2-amino-4-(2-aminophenyl)butyric acid (1.0 g), hexamethyldisilazane (5.4 g), and chlorotrimethylsilane (0.1 g) in xylene (125 ml) was refluxed for 65 hours. The reaction mixture was cooled, poured into ethanol (200 ml) and evaporated under reduced pressure. Water (100 ml) was added, and the solution extracted with dichloromethane (2×125 ml). The combined dichloromethane solutions were washed with water (50 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as above.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of 100 mg (0.43 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.45 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 117 mg (0.43 mmol) 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 160 mg (79%) of the title compound as white powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([S:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:16]2[CH:15]=[N:14]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:36]([C:33]1[CH:32]=[N:31][C:30]([N:26]2[CH2:25][CH2:24][CH:23]([S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]4[N:13]([C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=5[F:2])[N:14]=[CH:15][C:16]=34)[CH2:28][CH2:27]2)=[N:35][CH:34]=1)[CH3:37]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCc1cnc(N2CCC(Sc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
A mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (250 mg, 0.56 mmol), 2-chloro-5-ethyl-pyrimidine (680 μL, 5.6 mmol), and triethylamine (315 μL, 2.24 mmol) in isopropanol (4 mL) was heated under microwave irradiation for 15 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A237 as a white solid (100 mg, 35%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (t, 3H), 1.82-1.94 (m, 2H), 2.28-2.37 (m, 2H), 2.53 (q, 2H), 3.06 (s, 3H), 3.55-3.64 (m, 2H), 4.41-4.55 (m, 3H), 7.82 (m, 3H), 8.24 (s, 1H), 8.37 (s, 2H), 8.74 (s, 1H). Exact mass calculated for C23H24FN7O2S2 513.61, found 514.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC(C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc(COc2ccc3nc(Cl)ccc3c2)cc1
Yield: 22 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxy-quinoline (0.6 g, 3.0 mmol) in acetone (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 4-fluorobenzylbromide (0.76 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(4-fluoro-benzyloxy)-quinoline as a white solid (0.19 g, 20%), MS 288.8 [(M+H)+].
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc2[nH]cnc2c1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2[nH]cnc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 4.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-benzimidazol-5-ylcarbamate (313 mg, 1.01 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.212 ml, 1.22 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 1 day. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 20.2 mg (5.0%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19]C(Cl)Cl>>[ClH:19].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Agent: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Product: Cl
Reaction time: 1 h

Procedure:
To a stirred and cooled (0° C.) solution of 8.7 parts of N-[(4-fluorophenyl)methyl]-4-nitro-3-pyridinamine, 1-oxide and 150 parts of trichloromethane was added dropwise a solution of 10.2 parts of phosphor trichloride in 75 parts of trichloromethane. Upon completion, the mixture was allowed to reach room temperature and stirring was continued for one hour at reflux temperature. The reaction mixture was cooled and the solvent was evaporated. The residue was stirred in trichloromethane. The product was filtered off and dried, yielding 9 parts of N-[(4-fluorophenyl)methyl]-4-nitro-3-pyridinamine monohydrochloride (intermediate 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[S:5][CH:6]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cc(Cl)cs1
Product: ClCc1coc(-c2cc(Cl)cs2)n1
Yield: 48 %

Procedure:
In substantially the same manner as in Reference Example 47, 4-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4-chloro-2-thienyl)oxazole. The yield was 48%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 72-73° C.