Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:19]1[O:23][C:22](=[S:24])[N:21]=[N:20]1)[CH:3]([NH:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:25][NH:26][C:27]([CH3:31])([CH3:30])[CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:25][N:26]1[C:27]([CH3:31])([CH3:30])[CH2:28][S:24][C:22]1=[N:21][NH:20][C:19](=[O:23])[CH:2]([OH:1])[CH:3]([NH:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O=C(NC(C1CCOCC1)C(O)C1N=NC(=S)O1)C1CCCCC1
Reactant: CNC(C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=NNC(=O)C(O)C(NC(=O)C2CCCCC2)C2CCOCC2)SCC1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of 1:5-(1-hydroxy-2-cyclohexylcarbonylamino-2-tetrahydropyran-4-ylethyl)-2-thioxo-1,3,4-oxadiazoline (prepared in step 1 of example 8; 281 mg) in N,N-dimethylformamide (2 ml) were added N-methyl-N-(1,1-dimethyl-2-chloroethyl)amine (125 mg) and potassium carbonate (328 mg) and the mixture was stirred for 3 hours at 70° C. The reaction mixture was poured into brine and was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give N′-(3,4,4-trimethyl-1,3-thiazolidin-2-ylidene)-[3-cyclohexylcarbonylamino-3-(tetrah ydropyran-4-yl)-2-hydroxypropanohydrazide] (279 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCOCC1>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2N)NC(=O)CO3)c1=O
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2NC(=O)CCl)NC(=O)CO3)c1=O
Yield: 72.9 %

Procedure:
3-[5-Amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (400 mg, 1.07 mmol) was dissolved in anhydrous dioxane and chloroacetyl chloride (135.6 mg, 1.20 mmol) was added. Solution was heated to reflux for 2 hr and solvent removed in vacuo. The residue was washed with ether to afford the title compound (351.9 mg, 0.78 mmol).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].O>CS(C)=O>[CH2:30]([C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.0 g, 12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10° C. To this solution, 60% sodium hydride (600 mg, 15 mmol) was added, and the resulting mixture was stirred for 1 hour at room temperature. 6-Bromo-1-hexene (2.5 ml, 18.75 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to give diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.86 g, Yield 77%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.CN(OC)[C:14]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:17]1)=[O:15].Cl>O1CCCC1>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:14]([C@H:16]1[CH2:17][N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:19](=[O:21])[CH2:20]1)=[O:15]
Reactant: CON(C)C(=O)C1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Brc1nccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2nccs2)CC1=O
Reaction time: 0.17 h
Yield: 36 %

Procedure:
In an atmosphere of nitrogen and at −78° C., n-butyl lithium (20.4 ml, 30.0=mol, 1.47 M hexane solution) was added dropwise to a tetrahydrofuran solution (200 ml) of 2-bromothiazole (4.92 g, 30.0 mmol) spending 10 minutes, and the mixture was stirred at the same temperature for 1 hour. To this was added dropwise a tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide (6.91 g, 25.0 mmol) spending 10 minutes, and the mixture was stirred at −78° C. for 30 minutes and then under ice-cooling for 1 hour. The reaction solution was mixed with 1 mol/l hydrochloric acid (150 ml) under ice-cooling and extracted with ethyl acetate (100 ml×2), and the resulting organic layer was washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.70 g (36%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH2:20])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH:20][C:30](=[O:32])[CH3:31])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ncc(N2CCc3nc(N)sc3C2)nc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3nc(NC(C)=O)sc3C2)nc1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.2 %

Procedure:
As shown in step 9-vi of Scheme 9, to a solution of Compound 1032 (65.4 mg, 0.223 mmol) in DCM (2 mL) was added DIEA (200 μL, 1.148 mmol) and acetic anhydride (200 μL, 2.12 mmol). The reaction solution was stirred at room temperature for 150 min and the crude produce purified by medium pressure silica gel chromatography (10 to 80% EtOAc in Hexanes) to give N-(4,5,6,7-tetrahydro-5-(5,6-dimethoxypyrazin-2-yl)thiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 14, 36.8 mg) as an off white solid, which was salted as its mono-mesylate salt to yield a beige solid: ESMS (M+H) 336.12; 1H NMR (300.0 MHz, DMSO-d6) δ 7.31 (s, 1H), 4.55 (s, 2H), 3.91 (m, 3H), 3.83 (m, 5H), 2.73 (t, J=5.4 Hz, 2H), 2.39 (d, J=0.6 Hz, 3H) and 2.12 (s, 3H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C@H:61]1([C:68](O)=[O:69])[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]1>CN(C=O)C.O.C(#N)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:68]([C@H:61]2[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]2)=[O:69])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: O=C(O)[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (234 mg, 0.61 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (200 mg, 0.51 mmol), DIEA (0.175 mL, 1.02 mmol) and trans-cyclobutane-1,3-dicarboxylic acid (111 mg, 0.77 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (32.1 mg, 0.062 mmol, 12.13%) as a white solid.
Reaction SMILES: Br[CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:21]([CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3])=[N+:22]=[N-:23]
Reactant: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 72.1 %

Procedure:
2-(1-Bromoethyl)-3-(3,5-difluorophenyl)pyrazolo[1,5-a]pyridine (0.63 g, 1.9 mmol) and sodium azide (0.12 g, 1.9 mmol) were stirred in N,N-dimethylformamide (20 mL) for 1 hour at 20° C. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, concentrated and purified on silica gel with ethyl acetate in hexanes (0-35%) to give the desired compound (0.41 g, 73%). LCMS for C15H12F2N5 (M+H)+: m/z=299.9. 1H NMR (300 MHz, DMSO-d6): δ 8.80 (m, 1H), 7.72 (m, 1H), 7.38 (m, 1H), 7.22 (m, 3H), 7.02 (m, 1H), 4.92 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H](C3C=CC(OC)=CC=3)C)[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(Cl)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
Intermediate 5.64 (41 mg, 0.093 mmol) was dissolved in TFA (1.5 mL) and the resulting solution was heated to 70° C. After stirring 6.5 h, the reaction mixture was cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford crude 6-chloro-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile (5.65) that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H13ClN5O2: 306.1; found: 305.8.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[C:18]([N:19]=[C:20]3[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+]>C1COCC1>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[C:18]([N:19]=[C:20]3[C:25]=1[CH:24]([OH:26])[CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCCOc3ccccc3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCCOc3ccccc3)c21
Reaction time: 0.5 h

Procedure:
In 100 ml of dry THF was dissolved 2.47 g of 3,4-dihydro-9-(3-phenoxypropyl)aminoacridin-1(2H)-one. The mechanically stirred solution was cooled in ice under nitrogen and 3.6 ml of 1M LiAlH4 in THF was added dropwise over 5 minutes. After 0.5 hour the reaction was complete by TLC. The reaction was neutralized with 1 ml of saturated ammonium chloride solution and the inorganic salts were filtered off. The filtrate was evaporated to an oil which solidified when triturated with pentane. The solid was recrystallized from 1:1 dichloromethane/pentane to yield after drying 2.17 g of product, mp 138°-140° C.
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]=[O:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH:36]([OH:37])[C:1]([CH3:4])([CH3:3])[CH3:2])[N:29]=[C:28]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:21]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
2.77 ml of a 2M solution of t-butylmagnesium bromide in tetrabydrofuran were added at -55° C. and under an atmosphere of nitrogen to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-formylimidazole-5-carboxylate [prepared as described in step (a))above] in 26 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature of -55° C. to -50° C. for 30 minutes. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate and with a saturated aqueous solution of ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.87 g of the title compound as an amorphous solid.
Reaction SMILES: O[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14].O.C1(P(Cl)([Cl:24])=O)C=CC=CC=1>>[Cl:24][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1nn(C)c2nc(O)c(C#N)cc12
Solvent: O
Product: Cc1nn(C)c2nc(Cl)c(C#N)cc12
Temperature: 150 °C
Reaction time: 17 h

Procedure:
6-Hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile (2.18 g) was dissolved in phenylphosphonic dichloride, and stirred at 150° C. for 17 hours. The solution was allowed to cool to room temperature and poured into water, then extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and dried over Na2SO4. Evaporation of the solvent gave 6-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>[O-2].[Zn+2]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: N#Cc1cccc(S)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cccc(C#N)c2)SC[C@H]1OC(C)=O
Yield: 30.8 %

Procedure:
If the procedure described in Preparation IV is followed starting from 10.3 g (74.1.10-3 mol) of 3-mercaptobenzonitrile, 28.94 g (81.5.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.05 g (74.3.10-3 mol) of zinc oxide (ZnO), 9.6 g (yield: 31%) of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
4-Methoxyacetophenone (1.4 g) and sodium hydroxide (0.2 g) were suspended in 15 Ml of methanol pre-chilled at −10° C. The solution was kept for 1 hr under 0° C. with stirring. Benzaldehyde (1 g) was added thereto, and refluxed for 10 hr at room temperature with stirring. After neutralization with 5% hydrochloric acid solution, the product was extracted with 100 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and evaporated under vacuum. The resulting 1.3 g of white powder was purified through silica gel column chromatography (5×3 cm, Merk), which is eluted with n-hexane:ethylacetate (v/v, 1:7). The purified compound was identified as follows:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16](=[O:26])[CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[CH:7]2[CH2:12]C(O)=O.BrC1C=CC=C2C=1CCN(C(=O)CNC(OC(C)(C)C)=O)C2CC(OC)=O.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:20])[CH:12]=[C:7]12
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(Br)cccc2C1CC(=O)O
Agent: COC(=O)CC1c2cccc(Br)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid. To a stirred solution of methyl 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (113 g, 257 mmol) in EtOH (1000 mL), 4N aqueous NaOH (74.5 mL, 298 mmol) was added and the solution was stirred at RT for 2 h. The white precipitate was filtered off and the white solid was washed with a small amount of EtOH (1×) and diethyl ether (2×). The sodium salt was partitioned between 0.5N aqueous HCl and DCM, the organic layer was separated and washed with 0.5N aqueous HCl (1×) and brine (1×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as white foam (110 g). UPLC-MS: MS 427.2/429.2 (M+H+); UPLC rt 0.98 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:47])[C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([NH:30][CH2:29][CH2:28][C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)=[O:47])=[CH:33][CH:34]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: CC1(C)OB(c2ccc(C(=O)NCCc3ccncc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nc3scnc23)cc1OC
Yield: 31.5 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol) and N-(2-(pyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 0.4 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (64 mg, 0.6 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with EtOAc) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (50 mg, 31%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 10.15 (s, 1H), 9.37 (s, 1H), 8.68 (t, 1H, J=5.3 Hz), 8.46-8.42 (m, 4H), 7.94-7.91 (m, 2H), 7.81 (d, 1H, J=2.7 Hz), 7.52-7.47 (m, 1H), 7.27-7.26 (m, 2H), 7.00 (d, 1H, J=8.7 Hz), 4.02 (s, 3H), 4.00 (s, 3H), 3.58-3.52 (m, 2H), 2.89 (t, 2H, J=7.0 Hz). LC-MS: 513 [M+H]+, 511 [M−H]−, tR=1.32 min. HPLC: 97.72% at 214 nm, 96.31% at 254 nm, tR=4.19 min.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4ON3C4C=CC=CC=4N=N3)[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:48]([NH2:52])[CH:49]([CH3:51])[CH3:50]>CS(C)=O>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:52][CH2:48][CH:49]([CH3:51])[CH3:50])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(On4nnc5ccccc54)ncnc31)O[C@@H]2c1nc(C(C)(C)C)no1
Reactant: CC(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)CNc1ncnc2c1ncn2[C@@H]1O[C@H](c2nc(C(C)(C)C)no2)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-(1H-1,2,3-benzotriazol-1-yloxy)9H-purine (50 mg) in dimethylsulfoxide (0.4 ml) was added diisopropylethylamine (0.1 ml) and isobutylamine (0.038 ml). The mixture was stirred at 20° C. for 16 h under nitrogen. The mixture was then evaporated to dryness in vacuo to give a residue that was purified by automated preparative HPLC to afford the title compound (14 mg) as a white compound.
Reaction SMILES: N1([NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.N[C:42]1[CH:51]=[C:50]2[C:45]([C:46]([CH3:53])=[CH:47][C:48](=[O:52])[O:49]2)=[CH:44][CH:43]=1>>[CH3:53][C:46]1[C:45]2[C:50](=[CH:51][C:42]([NH:7][C:8]([C:10]3[CH:40]=[CH:39][C:13]4[N:14]([CH:33]5[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]5)[C:15]([C:17]5[CH:18]=[C:19]6[C:24](=[CH:25][CH:26]=5)[N:23]=[C:22]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:21]=[N:20]6)=[N:16][C:12]=4[CH:11]=3)=[O:9])=[CH:43][CH:44]=2)[O:49][C:48](=[O:52])[CH:47]=1
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: Cc1cc(=O)oc2cc(NC(=O)c3ccc4c(c3)nc(-c3ccc5nc(-c6ccccc6)cnc5c3)n4C3CCCCC3)ccc12
Yield: 27 %

Procedure:
The general procedure described for Compound 574 was used with 7-Amino-4-methyl-chromen-2-one (17.5 mg), producing 8 mg of the title compound (27% yield). MS: 606.29 (M+H+) HPLC Procedure A, retention time=19.22 min.