Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[O:45](S(C(F)(F)F)(=O)=O)[S:46]([C:49]([F:52])([F:51])[F:50])(=O)=[O:47]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[S:46]([O:20][CH2:19][C@H:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:47])=[O:45]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2,3-bis(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH2:19][NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:5][C:6]([O:8][CH3:9])=[O:7].FC(F)(F)C(O)=O.COC(=O)[C@@H](CC1C=CC(OC)=CC=1CNCC(F)(F)F)CC(OC)=O>C1(C)C=CC=CC=1.CC#N>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C@H:4]1[C:3](=[O:2])[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:19][C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[CH2:10]1
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Agent: COC(=O)C[C@H](Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A toluene solution S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester (950 mL, 212 mmol) was placed in a 2 L round bottom flask and concentrated under rotary evaporation to a volume of 460 mL (to remove residual water). Toluene (450 mL) was added and the mixture was transferred to a 3 neck 2 L flask. The flask was fitted with reflux condenser, thermometer, nitrogen inlet/outlet, and stir bar. The mixture was de-gassed under a flow of nitrogen gas. The mixture was heated to 50° C. and trifluoroacetic acid (200 mmol, 22.8 g) was added over a 5 min period. The mixture was heated to reflux. After 2.5 h, HPLC analysis (Waters Cosmosil 4.6×150 mm, 60% CH3CN/40% 0.1% TFA, 220 nm, 0.5 mL/min) showed less than 0.2% (area %) of (S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester remaining. The mixture was cooled to 25° C. and was washed with 1×400 ml NaHCO3 solution (satd.), and 1×400 mL water. The solvent was removed by vacuum distillation. The residue was treated with hexane (800 ml) and was heated to reflux with rapid stirring. This resulted in a solution with some oily residue. Toluene (20 mL) was added and a clear solution was obtained. The mixture was allowed to cool to 25° C. with rapid stirring over a 1 hour period. The mixture was then cooled to 0-5° C. for 1 hour. The resulting solid was isolated by filtration, washed with hexane (70 mL) and air dried to provide the product as an off-white solid (64.4 g, 88%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]([CH3:38])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:23])[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11](OC)=[O:12])[CH:7]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]([CH3:38])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:23])[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11]([NH:42][CH:39]2[CH2:41][CH2:40]2)=[O:12])[CH:7]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252h, 10.50 g) dissolved in THF (100 mL) was treated with cyclopropylamine (7.61 mL). Isopropylmagnesium chloride (45.2 mL of a 2.0M solution in THF) was added dropwise over 10 min under nitrogen. The resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (×3). The organic was dried (MgSO4), filtered and evaporated. The crude product was triturated with diethyl ether and filtered to afford the subtitle compound (9.86 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:23][CH2:22]1
Reactant: NCCC1CCOCC1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCC2CCOCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (0.3 g) and 2-(tetrahydropyran-4-yl)ethylamine (1.15 g) is stirred under nitrogen at 140° for 6 hours. The mixture is concentrated to dryness at reduced pressure, the residue is dissolved in ethanol, the solution is treated with propylene oxide (2 ml) and stirred overnight. It is concentrated to dryness and chromatographed through a 25×180 mm column of silica gel, with methylene chloride and ammonia-saturated methanol (9:1) as eluent. The fractions containing the desired product are combined and concentrated at reduced pressure. The residue is dissolved in absolute ethanol and treated with ethanolic hydrogen chloride to form the hydrochloride salt of 2-[2-(tetrahydropyran-4-yl)ethyl-amino]adenosine; [alpha]D25 -13.6° (DMSO); m.p. 120°-130° dec.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[CH:20]12[O:25][CH:24]1[CH2:23][O:22][CH2:21]2.B(F)(F)F.[OH-].[Na+]>C1COCC1.CCCCCC.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:24]2[CH2:23][O:22][CH2:21][C@@H:20]2[OH:25])=[CH:14][CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C1OCC2OC12
Agent: FB(F)F
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O[C@H]1COC[C@@H]1c1ccc(F)cc1
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
1.6M BuLi/hexane (399 mL, 0.64 mol, 1.10 eq) was added to a solution of 1-bromo-4-fluorobenzene (70 mL, 0.64 mol, 1.10 eq) in absolute THF (400 mL) in a stream of argon at −90° C. for 1 h. The mixture was stirred at −90° C. for 30 min, cooled to −100° C., and 3,6-dioxabicyclo[3.1.0]hexane (50 g, 0.58 mol, 1 eq) was added. The mixture was stirred at −100° C. for 15 min, and borontrifluoride diethyletherate (81 mL, 0.64 mol, 1.10 eq) was added at the same temperature for 1 h so that the temperature was no higher than −80° C. The reaction mixture was heated to 0° C. for 3 h and diluted with hexane (300 mL) and water (300 mL). 10N sodium hydroxide (50 mL) was added, and the layers were separated. The aqueous layer was extracted with ether. The organic layer was washed with the saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The mixture was subjected to chromatography on silica (1 L, carbon tetrachloride→25, 50, 75, 100% chloroform) to give title compound as a yellow oil (42 g, 0.23 mol, 39.7%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: C#Cc1cnc2cnccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 3-Ethynylimidazo[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of Cul, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:27])[C:13](=[O:18])[N:12]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)OCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c2c(ncn2Cc2ccccc2)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
2,2-Dimethylpropionic Acid [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.66 g) was dissolved in N,N-dimethylformamide (30 ml), potassium carbonate (1.6 g) and iodomethane (1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was removed by distillation. The residue was triturated with toluene to give 2.16 g of the title compound.
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]2[CH2:14][C:13](=[O:15])[CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)C>[C:16]1([CH:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:11]2[CH2:14][C:13]([CH3:1])([OH:15])[CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Mg]I
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl magnesium iodide (3M in diethyl ether, 1.4 mL, 4.2 mmol) was added dropwise to an ice-cold solution of 1-(diphenylmethyl)-3-azetidinone (1 g, 4.20 mmol) in diethyl ether (25 mL) and the mixture was stirred for 1 hour at 0° C. The crude reaction mixture was then purified directly by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford the title compound the title compound as a pale yellow oil in 68% yield, 730 mg. 1H NMR (CDCl3, 400 MHz) δ: 1.54 (s, 3H), 3.02 (m, 2H), 3.22 (m, 2H), 4.39 (s, 1H), 7.20 (m, 4H), 7.26 (m, 4H), 7.41 (m, 2H); LRMS ESI+ m/z 254 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:9][C@H:10]1[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)[S:5]([CH3:8])(=[O:7])=[O:6])[CH3:3].[ClH:30]>CCOC(C)=O>[ClH:30].[ClH:30].[CH3:3][CH:2]([N:4]([CH2:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1)[S:5]([CH3:8])(=[O:6])=[O:7])[CH3:1]
Reactant: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)N(C[C@H]1CNCCN1)S(C)(=O)=O
Temperature: 70 °C
Yield: 96.2 %

Procedure:
A 150-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-(((1-methylethyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.617 g, 1.42 mmol), HCl (4.0 M in 1,4-dioxane, 2.80 mL, 11.2 mmol) and EtOAc (20 mL). The mixture was heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature and the resulting white solid was collected by filtration. The solid was washed with EtOAc and to obtain N-(1-methylethyl)-N-((2R)-2-piperazinylmethyl)methanesulfonamide dihydrochloride (0.421 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16]C)=[C:6]([NH2:18])[N:5]=[C:4]([SH:19])[N:3]=1.[OH-].[K+].Cl.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>O.C(O)C.CO>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([NH2:18])[N:5]=[C:4]([S:19][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:3]=1
Reactant: ClCCN1CCNCC1
Reactant: CCOc1ccccc1Cc1c(N)nc(S)nc1N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: COc1ccccc1Cc1c(N)nc(SCCN2CCNCC2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
2.99 g (9.5 mmoles) of 4,6-diamino-2-mercapto-5-(2-ethoxy-benzyl)pyrimidine are suspended in a solution of 3.37 g (60 mmoles) of potassium hydroxide in 60 ml of water, and, to the suspension obtained, a solution of 2.22 g (10 mmoles) of 1-(2-chloroethyl)piperazine dihydrochloride in 10 ml of water are added, drop by drop, at 25° C. The reaction mixture is stirred at room temperature for 2 hours, then 50 ml of water and 100 ml of methyl alcohol are added. The mixture is heated to boiling point, filtered while hot, and the filtrate is allowed to crystallize at 0° C. The substance obtained is purified by chromatography over a column filled with 130 g of Kieselgel 60 using a mixture of methyl alcohol and toluene in a ratio of 2:3. The crystalline product obtained is recrystallized from a mixture of 20 ml of methyl alcohol and 20 ml of water to obtain 2.20 g of substance that is the dihydrate of the base. This compound is dissolved in 40 ml of ethyl alcohol under heating, and the solution obtained is added to a solution of 0.64 g of fumaric acid in 15 ml of ethyl alcohol. After crystallization at room temperature, 2.56 g (53%) of the title product are obtained. M.p.: 187-189° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]#[CH:26]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:26][C:25]#[CH:24])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(CC)sc12
Temperature: 65 °C

Procedure:
To a stirred solution (pale orange) of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (0.24 g, 1.0 mmol) was dissolved in anhydrous DMF (5 mL) was added cesium carbonate (3.0 eq., 1.0 g, 3.0 mmol) and 1.1 eq. of an 80% solution of propargyl bromide in toluene (0.16 g). The mixture was heated to 65° C. and maintained overnight. The reaction was quenched by slowly adding the reaction mixture to 10 volumes of water (50 mL). The resulting solid was collected by vacuum filtration, rinsed with acetonitrile and air dried, to provide 0.22 g of 2-ethyl-7-[(prop-2-ynyl)oxy]thiazolo[4,5-c]quinolin-4-amine as a pale-peach colored crystalline solid. MS (ACPI) m/z=284 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH3:2]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Yield: 88.4 %

Procedure:
The title compound (2.45 g, 88%) was synthesized by the reaction of N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.33 g, 4 mmol) and 2-[4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.51 g, 4 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 10.99 (s, 0.6H,), 10.98 (s, 0.4H), 8.30˜7.80 (m, 5H), 7.50˜7.25 (m, 10H), 6.94 (t, 1H), 6.79 (s, 1H), 4.79 (s, 1.2H), 4.61 (s, 0.8H), 4.33 (s, 0.8H), 4.15 (q, 0.8H), 4.05 (q, 1.2H), 4.01 (s, 1.2H), 3.52 (t, 1.2H), 3.36 (t, 0.8H), 3.24 (q, 1.2H), 3.02 (q, 0.8H), 1.23 (t, 1.2H), 1.15 (t, 1.8H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:17][CH2:18][CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 80 °C
Yield: 16 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g), 2-methoxyethyl-p-toluenesulfonate (3.8 g), potassium iodide (0.5 g) and potassium carbonate (1.3 g) in DMF (18 ml) was heated at 80° C. for 16 hours and evaporated in vacuo. The residue was extracted with ethyl acetate after an addition of water and the extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was triturated with ethyl acetate, collected by filtration, and recrystallized from aqueous ethanol to give 6-[4-(2-methoxyethylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.41 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:11]1[CH:12]=[C:8]([NH2:7])[CH:9]=[N:10]1
Reactant: CC(C)(C)OC(=O)Nc1cnn(-c2ccccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cnn(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of (1-pyridin-2-yl-1H-pyrazol-4-yl)-carbamic acid tert-butyl ester (185 mg, 0.72 mmol) in dioxane (1.85 ml) was treated with 4M HCl in dioxane (1.85 ml) and the resulting suspension was stirred at ambient temperature for 2 hours. The reaction mixture was adjusted to basic pH with sodium hydroxide (20 ml, 0.5M aqueous solution) and extracted with dichloromethane. The combined organic phases were dried and the solvent was evaporated to yield the product as light brown solid (110 mg, 96%) which was used without any further purification. MS: M=161.3 (M+H)+
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[N:25]([CH3:31])[C:26]1([CH3:30])[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:28]1[CH2:27][C:26]([N:25]([CH3:31])[C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)([CH3:30])[CH2:29]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N(C)C4(C)CNC4)cc3N21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(C)(N(C)c2cc3c(cc2-c2ccccc2F)OCC2=NNC(=O)[C@@H](C)N23)C1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 17.7 %

Procedure:
(R)-7-(2-fluoro-phenyl)-4-methyl-6-[methyl-(3-methyl-azetidin-3-yl)-amino]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.125 g, 0.30 mmol) was dissolved in DCM (1 mL) and DIPEA (98 μl, 0.561 mmol) was added. The reaction mixture was stirred at room temperature for 6 min then acetyl chloride (59.8 μl, 0.841 mmol) was added. The reaction mixture was stirred at rt for 10 min and concentrated in vacuo. The residue was purified by basic prep-HPLC (Table 3, Method 32) to give (R)-6-[(1-acetyl-3-methyl-azetidin-3-yl)-methyl-amino]-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.024 g, 18%). 1H NMR (CD3OD, 400 MHz) δ 7.36-7.33 (m, 2H), 7.25-7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.95-6.92 (m, 2H), 4.80 (m, 1H), 4.68-4.62 (m, 2H), 4.09-4.05 (m, 1H), 3.85-3.73 (m, 2H), 3.55-3.50 (m, 1H), 2.58 (m, 3H), 1.79 (s, 3H), 1.50 (m, 3H), 1.44 (m, 3H). LC/MS (Table 1, Method 4), Rt=2.300 min., MS m/z: 452 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([NH:20][CH2:21][CH:22](O)[CH2:23][CH3:24])[CH:16]=[CH:17][C:18]=1[Cl:19].O>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]2[N:20]([C:15]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=3)[CH2:21][CH:22]([CH2:23][CH3:24])[O:7]2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CCC(O)CNc1ccc(Cl)c(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1CN(c2ccc(Cl)c(C(F)(F)F)c2)C(c2cccc(C#N)c2)O1

Procedure:
Meta-cyanobenzaldehyde (2.1 g, 0.016 mole) was added to 4.3 g of 1-(3-trifluoromethyl-4-chlorophenylamino)-2-butanol in 50 ml of toluene and 2-3 drops of methane sulfonic acid was added. The mixture was refluxed under a modified Dean-Stark apparatus until no more water came off and the mixture was stripped on a rotary evaporator. Yield was 6 g of product, nD30 1.5774. It was characterized by IR and NMR.