Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([C@:10]23[CH2:15][C@H:14]2[CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:25]=[CH:24][C:23](=O)[NH:22][C:21]2=[O:27])[CH2:11]3)=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>COCCOC>[ClH:1].[S:39]=[C:23]1[CH:24]=[CH:25][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:12]2[CH2:13][C@H:14]3[C@:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:29])([F:28])[F:2])=[CH:5][CH:6]=4)([CH2:15]3)[CH2:11]2)[C:21](=[O:27])[NH:22]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1ccn(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]1
Agent: Cl
Solvent: COCCOC
Product: O=c1[nH]c(=S)ccn1CCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Yield: 59.8 %

Procedure:
A solution of 1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione (E5, 110 mg, 0.3 mmol) and Lawesson's reagent (184 mg, 0.5 mmol) in DME (2 mL) was stirred at reflux for 2 hours. The solvent was evaporated under vacuum. The crude was re-dissolved in ethyl acetate and washed with water. The organic phase was dried (Na2SO4) filtered and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound as a yellow oil (80 mg, 63% yield).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[CH3:11][O:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: COc1cnc(Cl)n(C)c1=O
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
To a solution of 750 mg (4.30 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 20 ml THF was added 314 mg (0.430 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(H)dichloride dichloromethane adduct, 1.83 g (8.59 mmol) 4-phenoxyphenylboronic acid, and 4.30 ml (4.30 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 15 min in the microwave, then diluted with 10 ml water, extracted with 50 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.33 g (100% yield) of crude 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:34]1[CH2:40][O:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:35][CH2:34][CH2:40][O:39][CH2:38][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C1CNCCOC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1ccccc1
Yield: 22 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and homomorpholine to give the title compound in 22% yield; NMR Spectrum: 1.75-1.79 (m, 2H), 2.22 (s, 3H), 2.76-2.78 (m, 4H), 2.97 (t, 2H), 3.57-3.59 (m, 2H), 3.62-3.64 (m, 2H), 4.40 (t, 2H), 5.13 (s, 2H), 7.02 (d, 1H), 7.32-7.48 (m, 7H), 8.21 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:36]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:39][CH:38]=[N:37]1
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cccc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M22) (100 mg, 0.17 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (32 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[N:14]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[OH:26])=O>C(O)C.CCOCC>[CH3:1][N:2]1[C:10]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]([CH3:11])([CH3:12])[C:3]21[CH:13]=[N:14][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[O:26]2
Reactant: C=C1N(C)c2ncccc2C1(C)C
Reactant: COc1cc(O)c(N=O)c(OC)c1
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(OC)c2c(c1)OC1(C=N2)N(C)c2ncccc2C1(C)C

Procedure:
Into a three-necked 100 milliliter round bottom flask was charged a solution of 0.8 grams of the thus prepared 1,3,3-trimethyl-2-methylene-1,7-diazaindane in 20 milliliters of absolute ethanol. The solution was heated under a nitrogen pad to 60°-65° C. and 0.84 grams of 2-nitroso-3,5-dimethoxyphenol added to the flask. The reaction mixture was maintained at temperature and refluxing for a total reaction time of about 26 hours. The ethanol was removed on a rotary evaporator and the resulting reaction mixture taken up in ether and filtered. The ether solution sequentially was washed with 100 milliliters of a 10 percent sodium hydroxide solution, and 100 milliliters of a saturated sodium chloride solution and then dried over potassium carbonate. The ether was removed under vacuum. A silica gel column was used to isolate the final product, i.e., 1',3'-Dihydro-1',3',3'-trimethyl-5,7-dimethoxyspiro-[2H-1,4-benzoxazine-2,2'-[2H] pyrrolo[2,3-b]pyridine]. Identification of the product was confirmed by appropriate spectral analysis.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([CH3:17])=[O:16]>CCO.O.[OH-].[Na+]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:11]/[C:4](=[O:3])/[CH:5]=[CH:6]/[C:7]2[CH:10]=[CH:17][C:15]([O:16][C:2]([F:1])([F:12])[F:13])=[CH:14][CH:8]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
A colorless solution of 4-(trifluoromethoxy)-benzaldehyde (0.75 mL, 5.3 mmol) in acetone (0.19 mL, 2.6 mmol), EtOH (5 mL) and H2O (1 mL) was treated with aq. 10% NaOH solution (˜12 drops). The reaction mixture was stirred for 2 h at room temperature and the colorless solution turned into a yellow suspension. The precipitate was filtered, washed with H2O and dried in vacuo to obtain NW254 as a pale yellow solid (275 mg, 25%). mp: 112-115° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.74 (d, 3J=16.1 Hz, 2H, Hvin), 7.67 (d, 3J=8.5 Hz, 4H, HAr), 7.28 (d, 3J=8.2 Hz, 4H, HAr), 7.06 (d, 3J=15.9 Hz, 2H, Hvin.). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.6 (C), 141.8 (CH), 133.3 (C), 129.8 (CH), 126.0 (CH), 121.2 (CH). MS (EI) m/z: 402.1 (M+). Anal. calcd for C19H12F6O3: C, 56.73; H, 3.01. Found: C, 56.44; H, 3.10%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].[H-].[Na+].[CH2:19](I)[CH2:20][CH3:21]>CN(C=O)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 2-bromo-4,6-di-tert-butyl-phenol (18.58 g, 65 mmol) in DMF (200 mL) was added to a stirred slurry of sodium hydride in anhydrous DMF (500 mL) precooled to −7° C. over 15 min. The resulting reaction mixture was stirred at <0° C. for 0.5 h. n-Propyl iodide was added and stirring of the olive green reaction mixture was continued for 18 h. after removal of the ice bath. The reaction was quenched with de-ionized water (2.5 L), 1 M HCl (250 mL) and 5% LiCl solution (250 mL). The resulting mixture was extracted with ethyl acetate (2×250 mL). Sodium chloride (q.s. to saturation) was added to facilitate the separation. The aqueous layer was extracted with hexane (200 mL). The combined organic layers were washed with 5% LiCl (2×200 mL) dried (MgSO4) and filtered. The solvent was removed under vacuum to give a viscous oil which was a 2:1 ration of product to DMF. The residue was dissolved in hexane (100 mL) and the solution was washed with 5% LiCl solution (3×30 mL). The hexane solution was dried (MgSO4), filtered, and the hexane was removed under vacuum to give a light brown oil which crystallized on standing to give a tan solid (21.23 g, 99%). The product may be purified by sublimation at 150° C. at 0.5 torr to give a light yellow solid. NMR (250 Mz, CDCl3): δ 7.32 (d, 1H, J=2.4 Hz), 7.20 (d, 1H, J=2.4), 3.92 (t, 2H, J=6.8), 1.82 (sex, 2H), 1.00 (t, 3H, J=7.4). MS [EI+] 326, 328 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:14]([N+:15]([O-])=O)=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:12]([CH3:22])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:14]1[C:2]([CH3:1])=[C:3]([CH:11]=[C:12]([CH3:22])[C:13]=1[C:18]([O:20][CH3:21])=[O:19])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1N
Yield: 98.1 %

Procedure:
1-tert-Butyl 4-methyl 2,5-dimethyl-3-nitroterephthalate (0.5 g, 1.62 mmol) was dissolved in tetrahydrofuran (4 mL). 10 wt % Palladium on carbon (Degussa type, 50 mg) was added to the solution and the mixture was treated with hydrogen at ambient temperature for 3 h. 10 wt % Palladium on carbon (Degussa type, 50 mg) was added to the solution, and the mixture was treated with hydrogen at ambient temperature for a further 2 h. 10 wt % Palladium on carbon (Degussa type, 100 mg) was added to the solution, and the mixture was treated with hydrogen at ambient temperature for a further 5 h. The mixture was filtered and the filtrate was concentrated to afford 1-tert-butyl 4-methyl 3-amino-2,5-dimethylterephthalate (0.444 g, 1.59 mmol, 98% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.78 (s, 1H), 5.20 (br s, 2H), 3.90 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 1.59 (s, 9H); MS (EI) for C15H21NO4: 280 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[CH2:24]([S:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1)(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from Intermediate 4 and ethane sulfonyl chloride using the method of Example 4; mass spectrum (API): Found 421 (MH−), C20H26N2O4S2 requires 422; 1H-NMR (400 MHz, CDCl3): 1.42 (9H, m), 2.98 (2H, m), 3.18 (3H, m), 3.37 (2H, m), 4.36 (2H, m), 7.21 (2H, m), 7.29 (1H, m), 7.39 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12](SC)[NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:10])=[O:9].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[N:25][OH:26])(=[O:10])=[O:9]
Reactant: CSC(=NS(=O)(=O)c1ccccc1Cl)Nc1nc(C)cc(C)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=NO)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 0.5 g of methyl N'-(2-chlorophenylsulfonyl)-N-(4,6-dimethylpyrimdin-2-yl)carbamimidothioate in 10 ml of tetrahydrofuran was added 0.3 g of hydroxylamine hydrochloride and 0.3 g of sodium acetate. The mixture was stirred at room temperature for 2 hours, whereupon the product was precipitated with ice-water, filtered, washed with water, and dried by suction to afford 0.3 g of the title compound, m.p. 165°-167°. NMR(CDCl3 /DMSO-d6) δ2.6 (s, 6), 6.8 (s, 1), 7.4 (m, 3), 8.2 (m, 1), 10.2 (br, 1), 12.0 (br, 1). m/e: 355 (M+).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]1=[O:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:3]1=[O:25])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2C(=O)N(N)C[C@H]2c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)C[C@H]2c2ccc(OC)cc2)cc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(R)-(4-methoxyphenyl)-2-imidazolidinone (247 g, 0.72 mol) in dichloromethane (2.35 L) and pyridine (174 mL, 2.15 mol) is cooled in an ice bath to 18° C. Methanesulfonyl chloride (73 mL, 0.94 mol) is added dropwise. The reaction is stirred cold for 2.5 hours then washed with 0.5 N HCl (2×1.5 L), brine (2×1.5 L) and dried (Na2SO4). The solvent is then removed in vacuo to afford a mixture of the desired product (75%) and unreacted starting material (25%) which is separated by liquid chromatography. [α]20D −39.83 (c 0.89, CHCl3) 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.81, 2H, ArH), 7.02 (d, J=8.51, 2H, ArH), 6.91 (d, J=8.81, 2H, ArH), 6.80 (d, J=8.81, 2H, ArH), 4.41 (m, 1H), 3.92 (m, 1H), 3.82 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.60-3.72 (m, 1H), 3.30 (m, 1H), 3.03 (s, 3H, CH3), 2.87-2.98 (m, 1H), 2.53-2.79 (m, 3H). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[C:4](=[O:17])[C:3]=1[C:18]#[N:19].[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:20][C:7]1[C:2]([Cl:1])=[C:3]([C:18]#[N:19])[C:4](=[O:17])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C#N)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(F)c1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-1-(2-cyano-6-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (4.0 g) in N,N-dimethylformamide (40 mL) was added N-bromosuccinimide (3.90 g) at room temperature. The reaction mixture was heated at 50° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:6][CH2:5]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC=O
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2cc(N3CCOCC3)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine (14 mg, 0.0363 mmol) produced in Example (81e), butyraldehyde (0.0097 mL, 0.109 mmol) and tetrahydrofuran (0.5 mL) was added sodium triacetoxyborohydride (23 mg, 0.109 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled of by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4-[3-(4-butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][N:25]=1)([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]([C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:26][N:25]=1)([CH3:23])[CH3:22]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CC(C)c1ncc(CN)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C(C)C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (80 mg, 0.28 mmol) and (2-isopropylpyrimidin-5-yl)methanamine (60 mg, 0.40 mmol) (prepared similarly according to the method for Intermediate 13) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.3 mL, 2 mmol) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A mixture of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (5.3 g, 20.89 mmol), methyl iodide (1.6 mL, 25.70 mmol) and K2CO3 (4.0 g, 28.94 mmol) in THF (100 mL) were stirred at r.t. for 18 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound (4.84 g, 87%). LCMS (method H): RT 2.74 min [M+H]+ 268.2
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:36][CH2:35][CH:30]1[N:29]([CH3:28])[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:27]=[CH:26][C:9]3[N:10]=[C:11]([NH:14][CH:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][C:22]=5[O:24][CH3:25])[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31]1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: CN1CCNCC1CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)C(CO)C4)cc3CO1)CC2
Yield: 67 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (150 mg, 0.39 mmol), commercially available rac-(1-methyl-piperazin-2-yl)-methanol (CAS no. 141108-61-4) (76 mg, 0.58 mmol) and diisopropylethyl amine (198 ul, 1.17 mmol) in acetonitrile (5 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (125 mg, 67%), MS (ISP) m/e=480.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].CCO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(C#Cc3ccccc3)ccc2c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ncc2cc(CCc3ccccc3)ccc2c1O
Reaction time: 48 h
Yield: 569.4 %

Procedure:
A mixture of 4-hydroxy-7-phenylethynyl-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.20 mmol), 10% Pd/C (200 mg), EtOH (10 mL) and EtOAc (20 mL) was stirred under H2 atmosphere for 48 h. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (0-40% EtOAc/hexanes) to give 350 mg of the title compound. MS: (+) m/z 308.26 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19].O>N1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.7 %

Procedure:
To a solution of 2-phenyl-1H-indol-6-amine (54 mg, 0.26 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (30 μL, 0.29 mmol). The resulting mixture was stirred at room temperature for 2 days. When water was added, a precipitate was formed. This solid was recrystallised from hot ethyl acetate to afford 15 mg (21%) of the title compound (LCMS RT=6.27 min, MH+ 279.0)