Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)O
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948: 360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-benzyloxyaniline (999 mg, 5 mmol) and N,N-dimethylaniline (1.209 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL), and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-benzyloxyanilino)quinazoline hydrochloride (1.675 g, 82%) as a mustard yellow solid; mp 246-248° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:36][CH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:36][CH2:37][CH:38]4[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:39]4)[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CC(C)(C)OC(=O)N1CC(CCI)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 155 mmol), tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (68 mg, 219 μmol.41) and Cs2CO3 (203 mg, 622 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (40 g column, 50 μm silica-gel from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (103 mg, 155 μmol, 99.5%) as a white solid. MS (M+Na)+=688; 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.56 (dd, J=8.7, 5.3 Hz, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 6.98-7.16 (m, 2H), 5.75 (s, 2H), 4.46 (t, J=6.4 Hz, 2H), 4.02 (t, J=8.3 Hz, 2H), 3.49-3.72 (m, 5H), 2.49-2.69 (m, 1H), 2.33 (q, J=6.8 Hz, 2H), 1.65 (s, 9H), 1.48 (s, 2H), 1.45 (s, 9H), 0.92-1.03 (m, 2H), 0.00 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+Na]+=688.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][C:11](=[NH:15])OCC.[Cl-:16].[NH4+:17]>CO>[ClH:16].[ClH:16].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][C:11]([NH2:15])=[NH:17]
Reactant: [Cl-]
Reactant: CCOC(=N)CCSCc1ccccn1
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C(N)CCSCc1ccccn1

Procedure:
Ethyl 3-(2-pyridylmethylthio)propionimidate was reacted with an equimolar amount of ammonium chloride in methanol for 2 hours at room temperature and the product was recrystallized from a mixture of ethanol and ether to provide 3-(2-pyridylmethylthio)propionamidine dihydrochloride showing a melting point of 140°-143° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[CH3:21][OH:22].C[O-].[Na+]>O>[CH3:21][O:22][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CO
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C)nc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(SC)nc(Nc2ccc(C)nc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (Preparation Example 303) (51 mg) and methanol (1 mL), sodium methoxide (11 mg) was added under ice cooling and stirred overnight at room temperature. Water was added to the reaction liquid, and the solid was collected by filtration to give 4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (41 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:20](=O)([O-:24])[O:21][CH2:22][CH3:23]>O>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1)[CH2:1][C:20]([O:21][CH2:22][CH3:23])=[O:24]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-trifluoromethylacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in ethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat was generated gradually, the reaction solution was ice-cooled and thereafter stirred at room temperature for 2 hrs. 6N Hydrochloric acid was added thereto to stop the reaction. The mixture was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (71.2 g, 89%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CSC.[F:10][C:11]([F:35])([F:34])[C:12]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:13]=1[CH2:14][N:15]1[CH2:22][CH:21]2[CH2:23][CH:17]([CH2:18][CH:19]([CH2:24][OH:25])[CH2:20]2)[CH2:16]1.[OH-].[Na+]>C1COCC1.C(N(CC)CC)C>[F:35][C:11]([F:10])([F:34])[C:12]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:13]=1[CH2:14][N:15]1[CH2:16][CH:17]2[CH2:23][CH:21]([CH2:20][CH:19]([CH:24]=[O:25])[CH2:18]2)[CH2:22]1
Reactant: OCC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CSC
Product: O=CC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 5.1 %

Procedure:
A solution of oxalyl chloride (1.19 mL) in THF (34.7 mL) was cooled to −78° C., and dimethyl sulfide (1.48 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 20 min, and a solution of {3-[2,4-bis(trifluoromethyl)benzyl]-3-azabicyclo[3.3.1]non-7-yl}methanol (2.65 g) in THF (20 mL) was added dropwise. The mixture was warmed to 0° C., stirred for 30 min, cooled again to −78° C., and triethylamine (4.84 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, poured into 1M aqueous sodium hydroxide solution, 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 (0.135 g).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(Cl)c3)cn2)CC1
Temperature: 95 °C

Procedure:
A solution of 6-Chloro-N-(3-chloro-4-iodo-phenyl)-nicotinamide (100 mg, 0.26 mmol), ethyl isonipecotate (60 mg, 0.38 mmol), diisopropyl ethyl amine (0.14 mL, 0.77 mmol) and a catalytic amount of DMAP in dioxane, in a sealed tube was heated at 85° C. for 19 h. Followed addition of another portion of ethyl isonipecotate (60 mg, 0.38 mmol) and the mixture was heated at 95° C. for 24 h. The mixture was then cooled, the solvent was evaporated and the residue was purified with a silica gel column and 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C20H21N3O3ClI [M+H]+: 514.0389. Found: 514.0387.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[CH3:15][NH:16][CH3:17].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([N:16]([CH3:17])[CH3:15])[N:3]=[C:4]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:5]=1
Reactant: FC(F)(F)CNc1nc(Cl)nc(Cl)n1
Reactant: CNC
Solvent: CC(C)=O
Solvent: O
Product: CN(C)c1nc(Cl)nc(NCC(F)(F)F)n1
Yield: 93 %

Procedure:
14.8 g (0.06 mol) of 2,4-dichloro-6-(2,2,2-trifluoroethylamino)-s-triazine (prepared as described in Example 3) were dissolved in 100 ml of acetone, and 12 ml of an approximately 45% strength aqueous dimethylamine solution were added dropwise at room temperature. The temperature was kept below 30° C. by cooling with water. The reaction product was precipitated by further addition of water. 14 g (=93% of theory) of 2-chloro-4-dimethylamino-6-(2,2,2-trifluoroethylamino)-s-triazine were obtained; melting point 181° to 184° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:48])([S:44](F)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]>CN(C)C=O>[F:38][C:39]([F:48])([S:44]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.0 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (23.5 mmol, 1.0 equivalent) in 100 mL of N,N-dimethylformamide was added 6.5 g of 325-mesh potassium carbonate (47 mmol, 2.0 equivalents). 1,1,2,2,2-pentafluoroethanesulfonyl fluoride (4 g, 20 mmol, 0.85 equivalents) was bubbled sub-surface into the reaction mixture over 3 hours, and the mixture was stirred for 0.5 hours. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 5 mL of N,N-dimethylformamide. The solution was diluted with 24 mL of water and 150 mL of ethyl acetate and the resultant solution was washed four times with 50 mL portions of 10 wt % aqueous sodium chloride, followed by 25 mL of saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant solid was purified by chromatography over silica gel with gradient elution (40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes). The desired product was dissolved in 10 mL of ethyl acetate and 200 mL of heptanes was added over 60 minutes. The product crystallized and was isolated by filtration. The wet cake was washed with 40 mL of heptanes and dried in vacuo with heating at 50° C. The title compound was isolated as a white solid (9.4 g, 67% yield). 1H NMR (600 MHz, CDCl3) δ ppm 8.60 (d, J=0.5 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (d; J=2.5 Hz, 1H), 7.42 (dd, J=9.0, 2.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27-7.26 (m, 2H), 5.82 (dd, J=8.0, 2.3 Hz, 1H), 3.30 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ ppm 162.6 (C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.23 (C), 132.18 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 61.0 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, CDCl3) δ ppm −79.1 (3F), −113.4 (2F). LC-MS m/z 599.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5](=[O:12])[N:4]1[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:28][C@@H:29]([C:31]1[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(O)(C)C>[C:23]([O:28][C@@H:29]([C:31]1[N:32]=[C:33]([N:8]2[CH2:9][CH2:10][C:11]3[N:3]([CH3:2])[N:4]([C:13]4[CH:22]=[N:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[C:5](=[O:12])[C:6]=3[CH2:7]2)[CH:34]=[CH:35][N:36]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C, 175 mg, 0.55 mmol) and (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 μL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanol/chloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ9.70 (s, 1H), 8.29 (d, 1H), 8.15 (dd, 1H), 8.03 (m, 1H), 7.82-7.70 (c, 2H), 6.48 (d, 1H) 5.72 (q, 1H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 474 (MH+).
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:26][C:25]=2[N:24]=[C:23]([SH:34])[N:22]=1.CCN(CC)CC.C(OCC)(=O)C>CN(C=O)C>[N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:26][C:25]=2[N:24]=[C:23]([S:34][CH:2]([CH2:19][CH3:20])[C:3]([N:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:4])[N:22]=1
Reactant: CCC(Br)C(=O)N1c2ccccc2Sc2ccccc21
Reactant: Sc1nnc2c(n1)[nH]c1ccccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(Sc1nnc2c(n1)[nH]c1ccccc12)C(=O)N1c2ccccc2Sc2ccccc21
Temperature: 0 °C

Procedure:
2-bromo-1-(10H-phenothiazin-10-yl)butan-1-one (3.675 g, 25 mmol) and 5H-[1,2,4]triazino[5,6-b]indole-3-thiol (2.125 g, 25 mmol) were dissolved in 50 ml anhydrous DMF and cooled to 0° C. 11.1 ml Et3N (250 mmol) was dropped to the above mixture. After stirring for 1.5h, TLC indicated that the reaction was completed and stopped. 300 ml ethyl acetate was added to the reaction mixture. The organic phase was washed by saturated NH4Cl for five times. It was dried by anhydrous Na2SO4 and filtered. The organic phase was concentrated to about 15 ml and the pale solid was formed. The amorphous solid was collected and washed by a few ethyl acetate. 1H NMR (500 MHz, DMSO-d6) δ; 12.63 (br, 1H), 8.34 (d, J=7.5?, 1H), 7.89-7.96 (m, 1H), 7.56-7.73 (m, 4H), 7.37-7.47 (m, 5H), 7.29-7.22 (m, 1H), 5.27 (t, J=7.0, 1H), 1.86 (br, 1H), 1.74 (br, 1H), 0.85 (br, 3H). 13C NMR (125 MHz, DMSO-d6) δ 170.0, 146.8, 141.7, 140.9, 138.5, 138.3, 131.4, 128.6, 128.2, 128.0, 127.7, 127.4, 123.0, 122.0, 118.0, 113.2, 31.1, 25.9, 11.8. HRMS was calculated for C25H19N5OS2 469.1031 and found 469.1047.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C:21]([O:23]CC1C=CC=CC=1)=O)[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:20][C:21]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:39])=[O:23])[C:9]([N:11]1[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
A solution of 1.03 g (2.52 mmole) of 3-[2(R)-benzyl-3-(benzyloxycarbonyl)propionyl]-4(S)-isopropyl-2-oxazolidinone (prepared as described in Preparation 13) in 20 ml of ethanol was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 100 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The residue was dissolved in 50 ml of anhydrous tetrahydrofuran, and 0.39 ml (3.02 mmole) of N-benzyl-N-methylamine, 0.46 ml of 95% diethyl cyanophosphonate and 0.42 ml of triethylamine were added, in that order, to the solution, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure column chromatography through silica gel using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 1.04 g (yield 98%) of the title compound as white crystals, melting at 60°-62° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:34][C:35]([NH2:37])=[O:36].[I-].[Na+]>C(#N)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]([N:27]5[CH2:32][CH2:31][N:30]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:29][CH2:28]5)[CH:24]=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCNCC5)c4)nc23)cc1
Reactant: NC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCN(CC(N)=O)CC5)c4)nc23)cc1
Temperature: 70 °C

Procedure:
A suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine (100.0 mg, 0.2229 mmol), 2-chloroacetamide (23.0 mg, 0.246 mmol) and sodium iodide (3.0 mg, 0.020 mmol) in acetonitrile (2 mL) was stirred and heated at 70° C. for 6 hours. The suspension was cooled to room temperature, diluted with water (30 mL). The precipitate was filtered and rinsed with water. The recovered yellow solid was triturated with methanol (5 mL), filtered and placed under high vacuum overnight. 2-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-acetamide and was isolated as a yellow solid (0.075 g, 67%). MP=271-275° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.86 (d, J=6.5 Hz, 1H), 8.43 (d, J=7.5 Hz, 2H), 8.06 (d, J=7.6 Hz, 2H), 7.96 (d, J=7.5 Hz, 1H), 7.53 (s, 1H), 7.26-7.06 (m, 5H), 6.50 (d, J=6.5 Hz, 1H), 3.29 (s, 3H), 3.20-3.15 (m, 4H), 2.93 (s, 2H), 2.64-2.58 (m, 4H). MS=506 (MH)+.
Reaction SMILES: [NH:1]([CH2:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[NH2:2].[Cl:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([CH2:16][CH2:17][C:18](O)=[O:19])=O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[OH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH2:3][N:1]1[C:18](=[O:19])[CH2:17][CH2:16][C:14]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:22][CH:21]=2)=[N:2]1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: CC(C)C(O)CNN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Yield: 92.1 %

Procedure:
A mixture of 9.5 grams (0.085 mol) of 1-hydrazino-3-methyl-2-butanol, 14.4 grams (0.070 mol) of 3-(p-chlorobenzoyl)-propanoic acid and 100 milliliters of toluene are stirred in a flask equipped with a condenser and Dean-Stark water collecting apparatus at reflux for about 2.0 hours during which 2.8 milliliters of water is collected in the Dean-Stark tube. The toluene solution is washed with 50 milliliters of 2 N sodium hydroxide solution, 25 ml. of 2 N hydrochloric acid and then water. The toluene layer is then dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is crystallized from methylene chloride-petroleum ether to yield 19.0 grams of 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)4,5-dihydropyridazine-3(2H)-one, (m.p. 90°-92° C.)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].[F:16][C:17]([F:23])([F:22])[S:18]([OH:21])(=[O:20])=[O:19]>C(CC(C)(C)C)(C)C.C1(C)C=CC=CC=1>[F:16][C:17]([F:23])([F:22])[S:18]([O-:21])(=[O:20])=[O:19].[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:15][CH2:11][CH2:12][CH2:13][S+:14]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: SCCCS
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)CC(C)(C)C
Product: Brc1ccc(C2=[S+]CCCS2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 73.2 %

Procedure:
48.64 g (242 mmol) of 4-bromobenzoic acid, 31.8 ml (314 mmol) of propane-1,3-dithiol and 27.9 ml (314 mmol) of trifluoromethanesulfonic acid are refluxed in 1.61 of a mixture 1/1 isooctane/toluene for 18 hours. The mixture is cooled down and the product is precipitated by addition of 1.51 of TBME to yield 75 g of 2-(4-bromophenyl)-5,6-dihydro-4H-1,3-dithiin-1-ium trifluoromethanesulfonate as yellow crystals.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11](NC(=O)OCC)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:20]1C=CC=CC=1.[CH3:26][O:27][CH2:28][CH:29]1[CH2:33][O:32][C:31](=O)[O:30]1>>[CH2:5]1[CH2:4][CH2:3][CH2:2][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[N:20]2[CH2:33][CH:29]([CH2:28][O:27][CH3:26])[O:30][C:31]2=[O:32])[CH2:7][CH2:6]1
Reactant: CCOC(=O)Nc1ccc(C2CCCCCC2)cc1
Reactant: COCC1COC(=O)O1
Reactant: c1ccncc1
Product: COCC1CN(c2ccccc2C2CCCCCC2)C(=O)O1
Reaction time: 20 h
Yield: 42.2 %

Procedure:
4.18 g (16.0 mmol) of ethyl 4-cycloheptylphenylcarbamate were treated with 1.3 g (16.0 mmol) of pyridine and 18 g (0.136 mol) of (RS)-4-methoxymethyl-1,3-dioxolan-2-one and stirred at 160° bath temperature for 20 hours. After cooling the reaction mixture was chromatographed on 400 g of silica gel 60 with ether. After recrystallization from isopropyl ether there were obtained 2.05 g of (RS)-3-[(4-cycloheptyl)phenyl]-5-methoxymethyl-oxazolidin-2-one as a white crystallizate. M.p.: 70°-72°.