Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:26][O:27]CC4C=CC=CC=4)=[O:25])=[CH:20][CH:19]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>[Pd].CO.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH:26][OH:27])=[O:25])=[CH:22][CH:23]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 4-{[(benzyloxy)amino]carbonyl]phenyl 1-(4-methoxyphenyl) cyclohexanecarboxylate (22a) (0.072 g, 0.16 mmol) and 5% palladium on activated carbon (0.054 g) in methanol (1 ml) was hydrogenated at room temperature until the starting material disappeared (ca. 45 minutes). The black suspension was filtered, the catalyst was washed with methanol (3×1 ml), and the filtrate was evaporated to give a white solid. The solid was suspended in diethyl ether (3 ml) and the mixture was intensively stirred overnight. The solid was filtered, washed with diethyl ether (1 ml), and dried in vacuum to give the title compound (0.037 g, 64%) as white crystals, m.p. 127-129° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.18-1.90 (8H, m); 2.36-2.65 (2H, m, overlapped with a signal of DMSO); 3.76 (3H, s); 6.97 (2H, d, J=8.6 Hz); 7.01 (2H, d, J=8.8 Hz); 7.40 (2H, d, J=8.8 Hz); 7.77 (2H, d, J=8.6 Hz); 9.07 (1H, br s); 11.23 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 2.2% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 230 nm; sample concentration 0.3 mg/ml; flow rate 1.0 ml/min). Anal. Calcd for C21H23NO5*0.3H2O, %: C, 67.29; H, 6.35,; N, 3.74. Found, %: C, 67.29; H, 6.23; N, 3.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:21]1[NH:15][C:16](=[O:17])[NH:18][C:19]1=[O:20]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1OC
Yield: 83.3 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (2.497 g.) and hydantoin (1.276 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.17 g., 1.5 molar ratio) was added, followed by magnetic stirring and heating (90°-92°, bath temperature) for 4 hours. Usual workup gave the title compound as a yellow solid (2.950 g.), m.p. 266°-268°. Crystallization from dioxane (80% recovery) gave m.p. 268°-270°.
Reaction SMILES: [CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7]([C:8]2[NH:12][CH:11]=[CH:10][N:9]=2)=[O:31])=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1
Reactant: COCCNc1cc(C)c(OC)c(C)c1CSc1ncc[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCNc1cc(C)c(OC)c(C)c1CS(=O)c1ncc[nH]1
Yield: 37.3 %

Procedure:
2.00 g (6.2 mmol) of 2-[4,6-dimethyl-5-methoxy-2-(2-methoxyethylamino)benzylthio]imidazole was dissolved in a mixture of 20 ml of chloroform and 2 ml of methanol. To the resulting solution was added 1.27 g of 85 % m-chloroperbenzoic acid under chilling with NaCl-ice for a period of 20 min. After the reaction was completed, chloroform and 5 % aqueous sodium carbonate were added. The organic portion was collected and washed twice with 20 ml of 0.05 N aqueous sodium hydroxide. The resulting mixture was then subject to extraction with 30 ml of 1 N aqueous sodium hydroxide. The aqueous portion was collected and washed with chloroform. To the washed solution was added 45 ml of 1 N aqueous ammonium chloride. The deposited oily product was extracted with dichloromethane. The dichloromethane portion was collected and dried over anhydrous sodium sulfate. Dichloromethane was distilled off and then the residue was crystallized from ether/hexane to give 0.78 g of the desired compound as a pale brown crystalline powder. (Yield: 37 %)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccccn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 90 °C

Procedure:
{3-[2-((4S,5R)-4-Methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.1 g, 0.18 mmol), 2-bromopyridine (0.042 g, 0.26 mmol), potassium carbonate (0.061 g, 0.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.02 mmol) were combined in 2:1 DME:H2O (4 mL) and degassed with N2 for 10 minutes. The reaction was then heated to 90° C. for 3.5 hours. The mixture was neutralized to pH 6 with 10% aqueous HCl and extracted with EtOAc. The crude material was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:34]([NH:33][CH2:31][CH3:32])=[O:35])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3)nc2N2CCOC[C@@H]2C)C1
Reaction time: 5 h
Yield: 33.4 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 15) (102 mg, 0.25 mmol) in DCM (3 mL) at room temperature (20° C.) was added ethyl isocyanate (32 uL, 0.27 mmol). The reaction mixture was stirred for 5 h. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford an orange solid (40 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:21]2[CH2:22][CH2:23][C@@H:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:24])[F:25])[CH2:20]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1[C@@H]1CCNC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1cccc(Br)n1)N1CC[C@@H](c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
After 6-bromopicolinic acid (430 mg, 2.13 mmol) was suspended in acetonitrile (25 ml), (S)-3-(2-(trifluoromethyl)phenyl)pyrrolidine (503 mg, 2.34 mmol), N,N-diisopropylethylamine (0.56 ml, 3.20 mmol), and HBTU (969 mg, 2.56 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 765 mg of white solid (90%).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(=O)O)cc1
Yield: 88 %

Procedure:
Next, 1.40 g (2.22 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[4-(benzyloxycarbonyl)phenyl(methyl)phosphono]butanoate was dissolved in 28 mL of a solvent mixture of acetic acid and water at 2:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced at room temperature for 2.2 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated, and the residue was freeze-dried from water to obtain 2-amino-4-[4-carboxyphenyl(methyl)phosphono]butanoic acid (0.62 g, yield 89%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (256 mg, 0.85 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1272 mg, 3.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (485 mg, 1.03 mmol) in Chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[O:10][CH:11]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2nc(CO)co2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2nc(COS(C)(=O)=O)co2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[O:9]=[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]1[CH2:27][C:28]([F:31])([F:30])[F:29].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl>[OH:7][CH:16]1[N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]([F:31])([F:29])[F:30])[C:10]1=[O:9]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(O)N=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 0.25 h

Procedure:
N-Bromosuccinimide (0.335 g, 1.88 mmol) was added to a solution of 2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (H. G. Selnick et al., J. Med. Chem., 1997, 40, 3865-3868) (0.500 g, 1.57 mmol) in carbon tetrachloride (20 mL) at room temperature. After 15 min, trifluoroacetic acid (1.0 mL) was added, and the reaction refluxed for 5 h. The reaction was cooled and concentrated. The residue was dissolved in 5% aqueous sodium acetate (15 mL) and acetone (10 mL) and stirred overnight. The reaction was concentrated and worked up, and the crude product purified by chromatography (silica gel, 0-30% ethyl acetate in hexane gradient elution), providing the title compound. MS 335 (M+1) 1H NMR (500 MHz, CDCl3) □ 7.92-7.30 (9H, m), 5.21 (dq, J=15, 8 Hz, 1H), 5.07 (d, J=10 Hz, 0.5H), 4.51 (d, J=10 Hz, 0.5H), 4.22 (t, dq, J=15, 8 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH2:12]=[C:13]([CH2:16][CH2:17][C:18]#[N:19])[C:14]#[N:15].C(O)C>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]#[N:19])[C:14]#[N:15]
Reactant: C=C(C#N)CCC#N
Reactant: Sc1ccc2ccccc2c1
Solvent: CO
Solvent: CCO
Product: N#CCCC(C#N)CSc1ccc2ccccc2c1

Procedure:
A mixture of 2-naphthalenethiol (10.0 g), 2-methyleneglutaronitrile (6.8 ml), ethanol (150 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 2 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 15.6 g of 2-(2-naphthylthiomethyl)glutaronitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1>O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)ccn1
Solvent: O
Product: Cc1cc(N2CCCCC2)ccn1

Procedure:
Piperidine (31.7 ml) and 4 -chloro-2 -picoline (13.65 g) were heated together in a bomb at 170 ° for 4.5 hours. After cooling, the mixture was taken up in water and extracted with ether. After drying (K2CO3) and stripping, the residue was distilled to give 4 -piperidino-2 -picoline, 15.45 g, b.p. 105°-10 ° (0.1 mm).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[C:22](=[O:24])=[O:23].Cl>C1COCC1.O>[OH:21][C:11]1([C:7]2[S:6][CH:10]=[C:9]([C:22]([OH:24])=[O:23])[N:8]=2)[CH2:12][CH2:13][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:19][CH2:20]1
Reactant: O=C=O
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of n-butyllithium (17.1 mL of 1.6 M solution in hexane, 27.35 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 12.43 mmol) in THF (50 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, dry ice (10 g, 227 mmol) was added to the lithiated compound solution and stirred for 2 h at −78° C. Water was added and the solution was warmed to room temperature. The mixture was then treated with 1N HCl to pH 3 to 4 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated and chromatographed EtOAc to 1% AcOH/EAOAc) to give 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS (EI) calcd: (M+H)+=286.1; found: 286.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)Cc3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added phenyl acetyl chloride (0.22 mL, 1.7 mmol) and N,N-diisopropyl ethylamine (0.57 mL, 3.5 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-phenyl-acetamide as a light yellow solid (254 mg, 40% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.70 min (98.5%); mp, 275-277° C.; 1HNMR (DMSO-d6)2.11-2.18 (m, 1H, CHH), 2.58-2.86 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, CH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.21-7.71 (m, 8H, Ar), 8.35 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.27, 30.58, 41.69, 42.41, 56.48, 117.69, 124.70, 125.56, 126.34, 128.20, 129.03, 133.80, 136.30, 140.74, 148.44, 154.79, 160.91, 169.48, 170.23, 172.58. LCMS MH=419; Anal Calcd For C23H22N4O4+0.2H2O: C, 65.45; H, 5.35; N, 13.27. Found: C, 65.32; H, 5.04; N, 13.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (200 mg, 0.42 mmol) and 3-chlorobenzylamine (238 mg, 1.7 mmol) was heated at 130° C., with stirring for 2 hours. The oil obtained was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 38 mg, 16.4%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13]>C(O)(=O)C>[NH:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13])[C:1]([CH3:2])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)cc1NC(C)=O
Yield: 89.4 %

Procedure:
Acetic anhydride (1.89 mL, 20 mmol) was added to a suspension of 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) in acetic acid (10 mL), and the mixture was heated with reflux for 6 hours. After cooling, the precipitated solid was filtered to obtain 2.12 g of the desired product as a colorless solid (yield 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:9]
Reactant: NCCCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: O=C(NCCCCO)C(F)(F)F
Yield: 104.8 %

Procedure:
A solution (100 ml) of 4-aminobutanol (2.50 g, 28.05 mmol) and trifluoroacetic acid ethyl ester (19.92 g, 140.26 mmol) in ethanol was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-trifluoroacetamidobutanol (11) (5.44 g, q.) as a colorless syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>CN(C=O)C.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cc(Br)ccc1Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Br)ccc1Cl)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (425 mmol) in DMF (400 mL) was added imidazle (58 g, 850 mmol), 4-(dimethylamino)pyridine (2.6 g, 21 mmol), and triisopropylsilyl chloride (136 mL, 638 mmol). The resulting solution was stirred at ambient temperature for 15 h, diluted with a saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water then brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to yield the titled compound 32 (152 g, 403 mmol, 95%) as a colorless oil.