Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:24])(=O)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH2:42])=[O:41])(=[O:34])=[O:33].[H-].[Na+]>C1COCC1.O>[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH:42][C:13](=[O:24])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1)=[O:41])(=[O:34])=[O:33]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NC(=O)c2ccc3c(c2)OCO3)c1Br
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
Carbonyldiimidazole (21 3 mg. 1.31 mmol) was added to a solution of piperonylic acid (181.5 mg., 1.09 mmol) in dry THF (10 ml). The resulting mixture was stirred for 15 minutes. N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide (Example 89) (400 mg, 1.09 mmol) and NaH (175 mg, 60% in mineral oil, 4.37 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours. Water was added to destroy the excess NaH. The solvent was then evaporated and the residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4), the solid filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]aminocarbonyl}thiophene-3-sulfonamide (20 mg, 3.6% yield) as a yellowish powder (m.p. 90°-93° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.[SH2:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:8])=[S:17]
Reactant: S
Reactant: COCCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCC(O)=S
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A solution of 2-methoxyethoxyacetyl chloride (700 mg.; 4.59 mmoles) in methylene chloride (10 ml.; dried over molecular sieves) was added dropwise at 0°-5° to a stirred solution of triethylamine (0.7 ml.; 508 mg.; 5.04 mmoles) in methylene chloride (20 ml.) which had been saturated at 0°-5° with H2S (ca. 30 min.). The light yellow mixture was stirred at 0°-5° for 30 min. and then at room temperature for 30 min. The mixture was washed with 1 N HCl (10 ml.×2) and then brine. The CH2Cl2 layer was dried (Na2SO4) and evaporated yielding 2-methoxyethoxythioacetic acid (480 mg.; 3.20 mmoles; yield 69.7%) as a light yellow liquid: nmr (CDCl3): δppm 3.42 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 -- ), 4.10 (2H, s, --OCCH2O), 5.0 (1H, br, --COSH); ir (neat): 2550 cm-1 (γS--H), 1770 (γc=o, thio acid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrimidin-2-yloxy)biphenyl-3-carboxylic acid (20 mg, 0.065 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (30 mg, 0.143 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([CH2:28][S:29]([CH3:31])=O)=[O:27].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[C:28]([S:29][CH3:31])[S:26]([CH3:25])=[O:27])=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)CS(C)=O
Reactant: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=C(SC)S(C)=O

Procedure:
3.43 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde was dissolved in 30 ml of tetrahydrofuran. To the resulting solution were added 2.42 ml of methyl methylsulfinylmethyl sulfoxide and 2 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and the resulting mixture was heated under reflux for 3 hours. After concentrating the reaction mixture, water was added thereto followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 4.58 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:41]3[CH2:42][CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:40]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: c1ccc2c(c1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCc3ccccc3C2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (97 mg), 1,2,3,4-tetrahydroisoquinoline (67 μl), HOBt (19 mg) and triethylamine (104 μl) were dissolved in 1,2-dichloroethane (5 ml), WSC.HCl (107 mg) was added, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (102 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1([C:12]2[N:16]([CH2:17][C:18]3[CH:26]=[CH:25]C(C(O)=O)=[CH:20][CH:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[N:7]1([C:12]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:1]([C:2]([Cl:4])=[O:3])=[CH:25][CH:26]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1

Procedure:
Oxalyl chloride (4 mL) was added to a suspension of 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid (0.28 g, 0.872 mmol) in chloroform (50 mL). The mixture was heated at reflux for 1 hour and then concentrated under vacuum. The residue was diluted with toluene, concentrated under vacuum and then dried under vacuum at ambient temperature over the weekend to provide crude 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.Cl.CC1CC[C@@H](C(C)=C)CC=1.N(Cl)=[O:23].CN(C)C=O>C(O)(C)C.N([O-])=O.[Na+]>[CH3:1][C:2]1[C:7](=[O:23])[CH2:6][C@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: O=NCl
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC=C(C)C(=O)C1

Procedure:
Synthesis of the exemplary Formula VI terpene compound L-Carvone (2-cyclohexen-1-one, 2-methyl-5-(1-methylethenyl)-(R); Millenium Chemicals) from D-limonene is described in Ikan, Natural Products—A Laboratory Guide pp. 151-155 (Academic Press, 1969), incorporated herein by reference. Briefly, a solution of D-limonene in isopropanol is cooled to below 10° C. Solutions of HCl in isopropanol and concentrated aqueous sodium nitrite are added dropwise to the D-limonene solution to generate limonene nitrosochloride. The limonene nitrosochloride and dimethylformamide is refluxed with isopropanol. After cooling, crystallization is induced and the precipitate filtered and washed with water. The resulting L-carvoxime is refluxed with 0.5 M oxalic acid and the mixture is steam distilled. The distillate is extracted with ether, dried over anhydrous magnesium sulfate, and the excess ether evaporated to leave L-carvone.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][C@H:39]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a suspension of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]urea from Example 95B (0.45 g, 1 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.225 g, 1.2 mmol), and Ph3P (0.393 g, 1.5 mmol) in THF (10 mL) was added di t-butyl azodicarboxylate (0.345 g, 1.5 mmol). After it was stirred at room temperature overnight, it was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 70-90% EtOAc/hexane as eluants to afford (S)-tert-butyl 3-(4-{3-[3-(5-tert-Butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate as solid (0.609 g, 98%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.8 (s, 1H), 8.61 (s, 1H), 7.67 (m, 1H), 7.50 (m, 2H), 7.34 (t, 1H), 7.31 (m, 1H), 6.96 (d, 1H), 6.13 (s, 1H), 5.12 (m, 1H), 4.06 (s, 3H), 3.61-3.80 (m, 4H), 2.34 (m, 2H), 1.47 (s, 9H), 1.31 (s, 9H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 70 °C
Yield: 55.8 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-amino-7-trifluoromethylquinoline (250 mg) were dissolved in dichlorormethane (5 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/6) to give 5-methyl-3-phenyl-N-(7-trifluoromethyl-4-quinolinyl)-4-isoxazolecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.91 (s, 3H), 7.33-7.69 (m, 9H), 8.39 (s, 1H, NH), 8.99 (d, J=5.1 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-63.26; LCMS: ret. time: 34.04 min.; purity: 98.90%; MS (m/e): 398.77 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O.O>CN1CCCC1=O>[C:12]1([N:18]2[C:6](=[O:8])[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:11][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
42.5 g of 4-chloroanthranilic acid were dissolved in 250 ml of N-methylpyrrolidone and 29.5 g of phenyl isocyanate were added dropwise at room temperature in 30 minutes. The mixture was further stirred for 5 hours at 80° C. and then 24.5 g of concentrated sulphuric acid were added dropwise in the course of 1 hour. The mixture was then further stirred at 80° C. for 3 hours, then cooled to room temperature, 500 ml of water were added, the product precipitated out was filtered off by suction, washed with water and dried in a vacuum drying cabinet. In this manner 57.4 g (85% of theory) of pure 3-phenyl-7-chloro-quinazoline-2,4-dione were obtained having a melting point of above 300° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.Cl.[CH:16]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.C(N(CC)CC)C>C(#N)C>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:22]2[CH:16]3[CH2:21][CH2:20][CH:19]2[CH2:18][CH2:17]3)=[N:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(Br)nc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (300 mg, 1.107 mmol), 7-azabicyclo[2.2.1]heptane hydrochloride (177.4 mg, 1.328 mmol) and triethylamine (224.0 mg, 308.5 μL, 2.214 mmol) in acetonitrile (3 mL) was heated at 80° C. overnight. The reaction was cooled to room temperature and quenched with water. The resulting precipitate was filtered, washed with water and dried under vacuum to provide 7-[5-nitro-6-(trifluoromethyl)-2-pyridyl]-7-azabicyclo[2.2.1]heptane (300 mg, 94% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.27 (d, J=9.2 Hz, 1H), 7.20 (d, J=9.3 Hz, 1H), 4.71 (s, 2H), 1.71 (d, J=7.7 Hz, 4H), 1.55 (d, J=6.9 Hz, 4H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of cyanuric chloride (2 g, 10.84 mmol) in DCM (40 ml) at 0-5° C. was added dropwise a solution of N-methyl aniline (1.16 ml, 10.84 mmol) and DIPEA (2.08 ml, 12.26 mmol) in DCM (30 ml). The resulting mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was diluted with DCM (40 ml) the solution was then extracted with 2M aq. HCl (2×40 mL) and saturated brine (30 mL) and dried further over anhydrous sodium sulfate. The organic phase was evaporated to dryness to furnish the title compound as an off white solid (2.726 g, 99%). Method C HPLC-MS: MH+ requires m/z=255. Found: m/z=255, Rt=1.48 min (100%). 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 7.29 (1H, d), 7.15-7.21 (3H, m), 3.48 (3H, s).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([N:33]([CH2:50][P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]=2[C:44]#[C:45][Si](C)(C)C)(=[O:32])=[O:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([N:33]([CH2:50][P:51](=[O:58])([O:52][CH2:53][CH3:54])[O:55][CH2:56][CH3:57])[C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]=2[C:44]#[CH:45])(=[O:31])=[O:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: CCOP(=O)(CN(c1c(C#C[Si](C)(C)C)ccc2ccccc12)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2ccccc2c1N(CP(=O)(OCC)OCC)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
115 mg tetrabutylammonium fluoridetrihydrate are added to 155 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(2-trimethylsilanylethynyl-naphthalen-1-yl)-amino]-methyl}-phosphonate in 4 ml of tetrahydrofuran at ambient temperature. The reaction mixture is stirred for 15 minutes at ambient temperature, then it is mixed with water and extracted with ethyl acetate. The combined extracts are dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (50:50) as eluant.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)(OC(C)(C)C)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:38].Cl.Cl.CCOCC.CO>CCOCC>[ClH:38].[ClH:38].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: CCOCC
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2)c1
Yield: 99 %

Procedure:
The product of step 159a (0.23 g, 0.70 mmol) was deprotected and isolated as the free base in 99% yield according to the procedure of Example 20b, followed by conversion to the dihydrochloride with excess HCl/Et2O. [α]D23 +12.46 (c 0.1, MeOH); 1H NMR (D2O, 300 MHz) δ2.65-2.75 (m, 2H), 3.66 (s, 3H), 4.08-4.19 (m, 2H), 4.43 (s, 2H), 4.53-4.69 (m, 2H), 4.90 (m, 1H), 8.22 (s, 1H), 8.44 (s, 1H), 8.63 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 252 (M+H)+. Anal. Calcd for C12H17N3O·2.5 HCl·1.5 H2O·0.4 Et2O: C, 40.93; H, 6.69; N, 10.53. Found: C, 40.96; H, 6.63; N, 10.46.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:36]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:45][C:36]([CH3:38])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Yield: 73.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-acetoxybenzoic acid (7.92 g, 44.0 mmol) was dissolved in DMF (45 mL), and the solution was treated with EDCI (12.7 g, 66.0 mmol), HOBT monohydrate (3.37 g, 22.0 mmol) and cumylamine (14.2 mL, 96.8 mmol), followed by purification by slurry using diisopropylether to obtain 3-acetoxy-N-(1-methyl-1-phenylethyl)benzamide (9.57 g, yield 73%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4].C1(=O)[NH:30]C(=O)C2=CC=CC=C12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:30][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NCC(=O)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
7.1 g of 2-(2-chloroacetamidopropyl)-4-phenyl-1(2H)-isoquinolone, 3.7 g of phthalimide and 3.7 g of potassium carbonate were added to 50 ml of dimethylformamide, and the mixture was stirred at 80° C. for 5 hours. The resulting reaction mixture was poured into water and the precipitated crystals were collected by filtration, washed with water and dried in air. The resulting crystals and 2 g of hydrazine hydrate were added to 100 ml of ethanol and the mixture was heated at reflux for 3 hours. After allowing the mixture to cool, 5 ml of concentrated hydrochloric acid was added to the resulting reaction mixture and the mixture was stirred for 5 hours. The solvent was then distilled off, and water was added to the residue, followed by thoroughly stirring. The mixture was filtered and the filtrate was rendered neutral with a 10% aqueous solution of sodium hydroxide. The precipitated was extracted with dichloromethane, and the extract was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 2.3 g (34% yield) of 2-(2-aminoacetamidopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 141° C. as colorless needles.
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH3:26])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:27][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:27])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:26])[CH3:25]
Reactant: CC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc2n1C(C)C
Yield: 47 %

Procedure:
To a solution of 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (30 mg, 0.072 mmol) and Pd(dppf)Cl2, (3 mg, 5% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (210 μl, 1.0 M in heptane solution) in a sealed tube. The mixture was heated to about 65′C. MeOH was added drop wise and the solvents removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography on silica gel to obtain 5-(9-isopropyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.40 (s, 2H), 4.81 (m, 1H), 3.89 (m, 4H), 3.82 (s, 4H), 3.71 (s, 3H), 1.73 (d, 6H). m/z: 355.16 [MH]+.