Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>CO.O>[CH2:12]([N:11]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[C:8]=2[N:9]=[CH:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2ncn(CC(C)C)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc3c2ncn3CC(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
3-isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid methyl ester 207 mg, 0.64 mmol) was suspended in a mixture of methanol (10 mL) and water (2 mL). To this suspension was added LiOH (46 mg, 1.92 mmol). The mixture was stirred overnight at room temperature, then made acidic by addition of 1N aqueous HCl, and concentrated to dryness under reduced pressure. The residue was re-dissolved in methanol, filtered to remove insolubles, and the filtrate was concentrated under reduced pressure to provide 165 mg (84%) of 3-isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1.[CH3:16][C:17]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][NH2:19].Cl>>[ClH:1].[CH3:14][CH:13]([S:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:19][CH2:18][C:17]([CH3:24])([CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:8]=1)[CH3:15]
Reactant: CCCCC(C)(C)CN
Reactant: CC(C)Sc1ccc(OCCCCl)cc1
Agent: Cl
Product: CCCCC(C)(C)CNCCCOc1ccc(SC(C)C)cc1

Procedure:
Reaction of 1-chloro-3-[4-(1-methylethylthio)phenoxy]propane with 2,2-dimethylhex-1-ylamine according to the procedure of Example 2(b) and conversion of the base to the hydrochloride provides N-[3-[4-[(1-methylethyl)thio]phenoxy]propyl]-2,2-dimethylhex-1-ylamine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13](C(OCC)=O)[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][S:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)ns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ncsn2)cc1
Temperature: 85 °C

Procedure:
Ethyl cianoformate was added to a dodecane suspension of 5-(4-nitrophenyl)-1,3,4-oxathiazol-2-on, and the mixture was refluxed under heating for 3 hours. After cooling the reaction mixture to room temperature, the precipitation was separated by filtration and washed with hexane. The crude product obtained was purified by silica gel column chromatography to obtain ethyl 3-(4-nitrophenyl)-1,2,4-thiadiazole-5-carboxylate (pale yellow solid). The ethanol suspension of this product was added with water and sodium hydroxide and heated at 85° C. for 40 minutes while stirring. After cooling to room temperature, the mixture was added with 1M hydrochloric acid to make it acidic. The resulting mixture was heated for one hour while stirring on an oil bath at 95° C. The mixture was then cooled to room temperature and added with chloroform and an aqueous sodium hydrogencarbonate to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 3-(4-nitrophenyl)-1,2,4-thiadiazol (pale yellow solid). The ethanol suspension of this product was added with water and 1M hydrochloric acid, heated to 80° C. and added with reduced iron. The reaction mixture was further heated at 80° C. for 50 minutes while stirring and then filtered through Celite. After evaporation of the ethanol in the resulting filtrate under reduced pressure, chloroform and an aqueous sodium hydrogencarbonate were added to the residue to separate an organic layer, which was then washed and dried. The solvent was evaporated under reduced pressure to obtain 4-(1,2,4-thiadiazol-3-yl)aniline (pale yellow solid). Electron Impact-MS (M)+: 177.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)[nH]c2n1

Procedure:
To a solution of 7-chloro-1H-[1,8]naphthyridin-2-one (prepared as described in J. Org. Chem. (1990), 55, 4744; 5.36 g, 29.68 mmol) in MeOH (98 mL) was added NaOMe (25 wt % in MeOH, 161 mL). The resulting solution was stirred at reflux for 15 h. The solvent was removed in vacuo. Water (100 mL) and EA (80 mL) were added. The phases were separated and the aq. layer was extracted with EA (8×80 mL). The combined org. layers were washed with brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The title compound was obtained as a beige solid (5.22 g, 100% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7](=[CH2:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[N:3]1>[Pd].CO>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:18])[C:8]([OH:10])=[O:9])=[N:3]1
Reactant: C=C(C(=O)OCc1ccccc1)c1ccn(C)n1
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)O)c1ccn(C)n1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To 0.10 mg (0.093 mmol) of 10% palladium on carbon was added a solution of (0.23 g, 0.93 mmol) of benzyl 2-(1-methyl-1H-pyrazol-3-yl)acrylate prepared in step C above in 6 mL of methanol. The resulting suspension was stirred under an atmosphere of hydrogen (1 atmosphere) overnight. The residue was filtered through a pad of Celite® and the pad was washed cold methanol. The combined filtrates were evaporated under reduced pressure to give yield the title compound as an off-white gum (0.11 g, 76%). LC-MS: m/z (ES) 155 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[F:11].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:2][C:3]2[C:4]([F:11])=[CH:5][CH:6]=[C:7]([F:10])[C:8]=2[F:9])[CH:18]=1
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: Cc1ccnc(O)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2c(F)ccc(F)c2F)c1
Yield: 15.5 %

Procedure:
A mixture of 8.32 g (36.96 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 4.84 g (44.35 mmol) of 2-hydroxy-4-methylpyridine [CAS No.: 13466-41-6] was dissolved in 227 ml of THF. The solution was admixed with 12.23 g (44.35 mmol) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and washed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by means of silica gel chromatography (eluent:cyclohexane/dichloromethane gradient: 10/0 to 1/1). 1.45 g of the title compound were obtained (15% of theory).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][C:21]=2[F:22])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=2[F:22])[NH2:23])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cc([N+](=O)[O-])ccc2F)c1
Agent: [Pd]
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cc(N)ccc2F)c1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of 5.92 g 3-(3-t-butyldimethylsilyloxymethylphenyl)-4-fluoronitrobenzene in 200 ml 50% ethyl acetate/hexanes was hydrogenated over 5 g of 5% palladium on carbon at 50 p.s.i. for 15 minutes. The reaction mixture was filtered and evaporated to yield the crude product (5.43 g, 100% yield) which was used directly without further purification. On purification, the compound is characterized by the following data: NMR (CDCl3, 250 MHz): 7.45 (m, 4H), 6.98 (dd, 1H), 6.75 (dd, 1H), 6.62 (8 line multiplet, 1H), 4.8 (s, 2H), 3.6 (br s, 2H), 0.95 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:21]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
In a pressure sealed vial, 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 107, mg, 0.19 mmol), 3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (WO2010079443, 50 mg, 0.17 mmol) and potassium carbonate (70 mg, 0.51 mmol) were stirred at 90° C. in dimethyl sulfoxide for 18 hours. The mixture was cooled down to room temperature and treated with 2M hydrochloric acid (5 mL). The mixture was stirred for 1 hour and the resulting precipitate was filtered and purified by preparative HPLC to afford the title compound (17 mg, 18%) as a white solid.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH:18]=[O:19])=[CH:8][CH:7]=1.[NH4+].[Cl-]>CCOCC.O>[OH:19][CH:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[S:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=1)[CH3:1]
Reactant: COc1ccc(Sc2sccc2C=O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Sc2sccc2C(C)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a stirred solution of methylmagnesium bromide (20.7 ml, 0.06 mol of 2.9M solution in ether) in anhydrous ether (50 ml) cooled to -5° C. was added 2-(4-methoxyphenylthio)thiophene 3-carboxaldehyde (10.0 g, 0.04 mol) in anhydrous ether (40 ml) over a 1/2 hour period under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours and was decomposed by adding a solution of NH4Cl (5.3 g, 0.1 mol) in water (50 ml) over a 20 minute period at 0° to 15° C. The ether layer was separated, washed with 3NHCl, saturated, NaHCO3 and water. It was dried, filtered and concentrated in vacuo at room temperature to obtain an amber oil. The product was purified by silica gel column chromatography using 50/50 hexane-ethyl acetate. This procedure gave 8.8 g of amber oil. Yield was 83%.
Reaction SMILES: Cl[C:2]1[C:3]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=O)=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[C:3]2[C:2](=[N:7][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:5][N:4]=2)[NH:28][N:27]=1
Reactant: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(Oc2cnc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Yield: 42.1 %

Procedure:
To a solution of [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (0.73 g, 1.9 mmol, 1.0 eq) in ethanol was added hydrazine hydrate (0.19 mL, 3.8 mmol, 2.0 eq). The resulting mixture was refluxed under nitrogen for 0.5 hours. The reaction mixture was cooled and filtered to give 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-b]pyrazine (0.285 g, 0.8 mmol, 42% yield) as a solid. MP=240.5-241.5° C. Mass spec., M+1=359.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][N:6]([CH3:7])[C:2]=3[NH:1][S:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OC)nn2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.9 %

Procedure:
To a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and 4-dimethylaminopyridine (50 mg) in pyridine (4 ml) at room temperature was added 4-methoxybenzenesulfonyl chloride (145 mg), the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue quenched with citric acid (10%, 10 ml) and then extracted with ethyl acetate (2×10 ml). The organic fractions were combined and washed with saturated aqueous sodium chloride solution (50 ml) the organic fraction was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (259 mg) was purified by preparative HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an amorphous white solid (10 mg).
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)C1C=CC=CC=1.C([Li])CCC.[C:24]([O:29][CH2:30][C@@H:31]1[O:33]C1)(=[O:28])CCC>C1COCC1>[F:17][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][CH:30]([CH2:31][OH:33])[O:29][C:24]2=[O:28])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC(CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of amine 102 (39.2 g, 160.0 mmol) in anhydrous THF (300 mL) was cooled to −78° C. in a dry-ice/acetone bath before a solution of n-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) was dropwise added under N2. The resulting reaction mixture was subsequently stirred at −78° C. for 1 h before a solution of (R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at −78° C. under N2. The resulting reaction mixture was stirred at −78° C. for 30 min before being gradually warmed to room temperature for 12 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (200 mL), and the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. White crystals precipitated from the concentrated solution when most of the solvent was evaporated. The residue was then treated with 20% EtOAc/hexane (100 mL) and the resulting slurry was stirred at room temperature for 30 min. The solids were collected by filtration and washed with 20% EtOAc/hexane (2×50 mL) to afford the desired (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one 103 (24.4 g, 72.3% yield) as white crystals. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 111, J=12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H), 7.32-7.56 (m, 3H). C10H10FNO3, LCMS (EI) m/e 212 (M++H).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:19][NH:18][C:16]([C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[CH:7]=[C:6]([NH:5][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:39][CH:38]=3)[NH:10][N:9]=2)[CH:22]=[CH:21][CH:20]=1)=[O:17]
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Reactant: CNC(=O)c1cccc(CCc2cc(N)[nH]n2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CNC(=O)c1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(C)CC4)cc3)[nH]n2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
A 2M solution of trimethylaluminium (0.936 mL, 1.87 mmol) in toluene, was added drop-wise to a stirred suspension of 3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.183 g, 0.75 mmol) and methyl 4-(4-methylpiperazin-1-yl)benzoate (0.176 g, 0.75 mmol) in toluene (5 mL) at room temperature. The solution was then stirred at 60° C. for 18 h. The reaction mixture was cooled, poured into methanol (5 ml) and acidified with 2N HCl (15 ml). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford an oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.109 g, 32.6%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH:28]([CH2:29][C:30](O)=[O:31])[CH:24]([CH2:25][CH2:26][CH2:27]1)[CH2:23][CH2:22][CH2:21]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:24]12[CH:28]([CH2:29][C:30]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:31])[CH:20]([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:22][CH2:23]2
Reactant: O=C(O)CC1C2CCCC1CCC2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CCCC1CCC3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.12 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg and stirred at 0° C. for 30 min. 9-bicyclo[3.3.1]nonylacetic acid 97.0 mg and WSC 0.15 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 19 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(bicyclo[3.3.1]nonan-9-yl)acetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 41 mg and refluxed under heating for 1 hour. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([CH3:12])[CH:3]=1.[BrH:13].BrBr.C([O-])([O-])=O.[Na+].[Na+]>>[Br:13][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:12])=[O:11]
Reactant: CCC(=O)c1cnc(Cl)cc1C
Reactant: Br
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)ncc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(6-Chloro-4-methyl-pyridin-3-yl)-propan-1-one (100 mg, 0.545 mmol) is dissolved in hydrobromic acid (48%) (2 ml, 17.68 mmol); to this is then added bromine (0.031 ml, 0.599 mmol) dropwise and the resulting orange solution stirred at RT. After 4 hours, further 0.2 eq (5 ul) of bromine is added and the reaction is left stirring O/N at RT. The reaction mixture is basified by careful addition of 2M Na2CO3 (5 ml) and then extracted into EtOAc (2×25 ml). The combined organic phase is washed with H2O, brine, dried (MgSO4) and evaporated to give a clear oil. The crude material is chromatographed on silica gel (20 g) eluting with (10% EtOAc/iso-hexane) to give the desired compound; MS: m/z 262.1 [M+H]+; 1H NMR (400 MHz, (CDCl3) δ 7.9 (d, 1H), 7.3 (d, 1H), 5.1 (q, 1H), 2.7 (s, 3H), 1.9 (d, 3H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2)=[O:36]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)cc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 2,4-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (3×20 mL) and dried in vacuo to give 1-(2,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.44 g, 96% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.99 min (96.51%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.89-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.78-3.06 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.38-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CH), 7.33 (dd, J=2.5, 9.1 Hz, 1H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.57 (d, J=2.5 Hz, 1H, Ar), 7.62 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.20 (d, J=8.9 Hz, 1H, Ar), 8.26 (s, 1H, NH), 10.99 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.82, 47.13, 51.58, 121.63, 121.92, 122.02, 123.04, 125.33, 126.99, 127.50, 128.39, 130.45, 135.81, 142.48, 144.12, 154.67, 167.90, 170.99, 172.86; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.37; H, 3.84; N, 12.15; Cl, 15.50.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.5 %

Procedure:
To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in 20 mL of abs. EtOH is added 2,4′-dibromoacetophenone (0.7 g, 2.5 mmol) all at once. The reaction mixture is stirred at room temperature for 3 hours and then chilled in ice bath. The precipitate is collected by filtration, washed with cold EtOH (5 ml×2) and dried in vacuum to give 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole as a white fluffy crystaline solid (1.55 g, 93%). mp.158-9° C.