Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]4[CH3:18])[C:5]4[S:11][CH2:10][CH2:9][CH2:8][C:6]=4[N:7]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1SCCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1SCCC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of 2-chloro-7,8-dihydro-4-((S)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine (150 mg, 0.53 mmol) in DME/H2O (4:1, 10 mL) was added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (175 mg, 0.58 mmol) and Na2CO3 (170 mg, 1.60 mmol) followed by PdCl2(dppf) (15 mg, 0.02 mmol). The resulting mixture was stirred overnight at 70° C. under nitrogen. The solvent was removed under vacuum to give a residue which was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed to give crude material which was purified by preparative TLC (DCM/MeOH=20/1) to give the desired productas a white solid (180 mg, 80%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[N:19]=[CH:18][N:17]=1.C(O)(=O)C>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]3=[O:3])[CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: Fc1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Reactant: Oc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=c1ccccn1-c1ccc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Sodium hydride (0.24 g) was added to a solution of 2-hydroxypyridine (0.95 g) in NMP (10 ml) and the mixture was stirred at ambient temperature for 30 minutes. A mixture of a portion (3 ml) of the resultant solution and 4-(3,4-dichloroanilino)-6-fluoroquinazoline hydrochloride (0.172 g) was heated at 215° C. for 10 hours. The reaction mixture was acidified with glacial acetic acid and evaporated at 90° C. under high vacuum. The residue was chromatographed on silica using a mixture of methylene chloride and methanol, increasing in polarity from pure methylene chloride to a 19:1 mixture of methylene chloride: methanol as eluent. The product so obtained was triturated with a 1:1 mixture of isopropanol and ethyl acetate. The solid was filtered off, washed with ethyl acetate and dried under high vacuum to give 4-(3,4-dichloroanilino)-6-(2-oxo-1,2-dihydropyridin-1-yl)quinazoline (0.099 g); NMR Spectrum: (CD3SOCD3) 6.44 (m, 1H), 6.57 (m, 1H), 7.55-7.66 (m, 1H), 7.68 (d, 1H), 7.75-8.00 (m, 4H), 8.34 (d, 1H), 8.65 (s, 1H), 8.78 (s, 1H), 9.78 (s, 1H);
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]3[N:23]=[C:22]2[CH2:32][CH3:33])=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.O1CCOCC1.[ClH:41]>CO>[ClH:41].[CH2:32]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[N:19][C:14]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:15][CH:16]=2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:33]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cnc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
[5-(2-Ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)pyrimidin-2-yl]phenylcarbamic acid tert-butyl ester (310 mg, 0.676 mmol) obtained in Step 7 was dissolved in methanol (5 mL), and a 4 mol/L hydrogen chloride-1,4-dioxane solution (4 mL) was added to the solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from diethyl ether to obtain Compound 167 (255 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>ClCCCl.O=[Mn]=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Temperature: 75 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide (4 mg, 0.01 mmol) in DCE (2 mL) was added active MnO2 (100 mg, 1.15 mmol). The mixture was stirred at 75° C. for 2 hr and filtered. The filtrate was purified by Pre-TLC (DCM/CH3OH=10/1) to afford 2 mg (50%) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. 1H NMR (400 MHz, CD3OD-d4 and CDCl3-d1) δ 8.62 (d, J=4.4 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.41-7.39 (m, 2H), 7.31-7.26 (m, 3H), 7.11 (d, J=4.4 Hz, 1H), 7.10-7.04 (m, 1H), 7.01-6.97 (m, 4H), 6.90-6.86 (m, 1H).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[OH:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:25]2[CH2:26][C@@H:22]([OH:21])[C@H:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:24]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@H]1O)OCc1ccccc1
Yield: 59.1 %

Procedure:
A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (2.50 g, 7.28 mmol), benzyl (3R,4R)-4-hydroxypyrrolidin-3-ylcarbamate (2.41 g, 10.2 mmol) and K2CO3 (1.51 g, 10.9 mmol) in THF (40 mL) was stirred at 56° C. for 12 hours. Water (20 mL) and ethyl acetate (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20:1 ethyl acetate/MeOH) to give benzyl (3R,4R)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-4-hydroxypyrrolidin-3-ylcarbamate (1.85 g, 59.2%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:15](=[O:24])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
m-Toluidine (5 g, 46.64 mmol) and pyridine (3.77 mL, 46.64 mmol) were dissolved in dry dichloromethane (25 mL). To the reaction mixture, cinnamoyl chloride (7.72 g, 46.64 mmol) was added and stirred for 3 h at 0° C. The reaction mixture was extracted with dichloromethane washing with water and 2N HCl. The solvent was removed and the crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:37]1COC[CH2:38]1.C(O)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:37]([O:25][C:24](=[O:26])/[CH:23]=[CH:22]/[C:21]1[CH:20]=[CH:19][C:18]([C:13]2[NH:12][C:11]3[N:10]([CH2:29][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[C:9](=[O:36])[N:8]([CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:16](=[O:17])[C:15]=3[N:14]=2)=[CH:28][CH:27]=1)[CH3:38]
Reactant: C1CCOC1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reaction time: 3.75 h
Yield: 72 %

Procedure:
N,N'-Carbonyldiimidazole (Lancaster Synthesis, 908 mg, 5.6 mmol) was added to a pale yellow slurry of (E)-4-[1,3 bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (d) example 1, 1.962 g, 4.0 mmol) in anhydrous DMF (15 mL)-THF (15 mL) under nitrogen. The slurry was stirred for 3.75 h, during which time it became bright yellow as a gas evolved. Absolute ethanol (460 mL, 8 mmol) was then added, followed by DBU (Aldrich, 837 mL, 5.6 mmol). Addition of the base produced a deep red reaction mixture and caused almost complete dissolution of the acyl imidazole. After stirring for 18 h, the reaction mixture was treated with an additional equivalent of absolute ethanol (230 mL, 4 mmol). The orange solution was stirred for 2.5 h before volatiles were removed at 1Torr. The resulting brown mixture was chromatographed on silica gel, eluting with a gradient from 0-6% methanol in dichloromethane. The title compound eluted in 0-1% methanol in dichloromethane as an off-white solid (1.643 g, 79%). Recrystallization from dichloromethane-hexanes provided a white powder (1.501 g, 72%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]2CC[C:10]=12>C(Cl)Cl>[C:9]1([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:11][CH:10]=1
Reactant: Nc1cccc2c1CC2
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: O=C(O)/C=C\C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.80 g (28.55 mmole) of maleic anhydride was dissolved completely in about 60 ml of methylene chloride. To this solution was added the freshly prepared 4-aminobenzocyclobutene (3.35 g., 28.11 mmole). Immmediately, bright yellow precipitates formed quantitatively. The reaction was quite exothermic as evidenced by the self-refluxing of methylene chloride. Additional 30 ml of methylene chloride was added to moderate the reaction temperature. Finally, the resultant bright yellow heterogeneous mixture was stirred overnight at room temperature. The reaction mixture was filtered and the yellow solid product collected was washed with methylene chloride (3 ×25 ml) and air-dried. Yield: 5.03 g (82.4%). Anal Calc. for C12H11NO3 : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.66; H, 5.27; N, 6.34.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:23][OH:24])=[C:19]([CH2:21][OH:22])[CH:20]=3)=[CH:10][CH:9]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[OH:22][CH2:21][C:19]1[CH:20]=[C:15]([CH:16]=[CH:17][C:18]=1[CH2:23][OH:24])[O:14][CH2:13][C:11]1[S:12][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][CH:10]=1
Reactant: CCC1(c2ccc(COc3ccc(CO)c(CO)c3)s2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(COc2ccc(CO)c(CO)c2)s1

Procedure:
8 g (22.8 mmol) of {5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienylmethoxy]-2-hydroxymethylphenyl}methanol are dissolved in 75 mL of water and 75 mL of acetone. 1 g of para-toluenesulphonic acid is then added and the reaction medium is refluxed for 1 hour. The reaction medium is treated with sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried and concentrated under reduced pressure. A white powder (m.p.=123° C.) is obtained (m=6.9 g; Y=100%).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=1.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45](O)=[O:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:45]([CH:41]4[CH2:42][CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:46])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)C4CCCN(C(=O)OC(C)(C)C)C4)CC3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride (from Example 1, 80 mg, 0.22 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), triethylamine (50 mg, 0.50 mmol, 2.10 equiv), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (60 mg, 0.26 mmol, 1.20 equiv), HATU (250 mg, 0.66 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield tert-butyl 3-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazine-4-carbonyl)piperidine-1-carboxylate as yellow oil. MS: 536 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[F:41][C:42]1([F:54])[O:46][C:45]2[CH:47]=[CH:48][C:49](B(O)O)=[CH:50][C:44]=2[O:43]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=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>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:45]4[O:46][C:42]([F:41])([F:54])[O:43][C:44]=4[CH:50]=3)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
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: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OC(F)(F)O4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 85 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g) in 1,2-dimethoxyethane (80 mL) were added 2,2-difluoro-benzo[1,3]dioxole-5-boronic acid (430 mg), 2 M aq. sodium carbonate solution (3.1 mL) and Pd(PPh3)4 (40 mg) and the resulting mixture was stirred at 85° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (1.0 g, 89% yield). HRMS calcd for C37H44O10F2S [M+H]+ 719.2696, observed 719.2693.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Yield: 100 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (52 mg), PdCl2dppf (10 mg), copper(I) iodide (2 mg), trimethylsilyl acetylene (0.11 mL) and triethylamine (0.2 mL) were heated in DMF (4 mL) at 80° C. for 1 hour under an inert atmosphere. The reaction mixture was concentrated in vacuo, EtOAc (20 mL)/MeOH (0.3 mL)/water (10 mL) added and the aqueous layer removed. The organic layer was dried (MgSO4), filtered, concentrated in vacuo, then purification by flash chromatography on silica eluting with 4% MeOH/DCM gave the title compound as a light brown solid (48 mg, 100%);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.2 g, 0.71 mmol) and 2.0 M aqueous sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-chloro-4-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.100 g, 42%) as a solid. MS calcd. for C22H21ClNO5S [(M−H)−] 446, obsd. 446.4.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[CH2:9][N:10]([CH3:14])[CH2:11]2)=[CH:6][CH:5]=1.Br>>[ClH:1].[CH3:14][N:10]1[CH2:9][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]2[C:12](=[CH:13][C:4]([OH:3])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: COc1ccc2c(c1)CN(C)CC2c1cccc([N+](=O)[O-])c1
Agent: Br
Agent: Cl
Product: CN1Cc2cc(O)ccc2C(c2cccc([N+](=O)[O-])c2)C1

Procedure:
The free base obtained from 4.0 g. of rac.-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline hydrochloride is heated to 150°C. (bath-temperature) for 1.5 hours with 60 ml. of 48% hydrogen bromide solution. After concentration and partitioning between sodium bicarbonate solution and ethyl acetate, acidification with ethanolic hydrogen chloride, crystallization with ether and recrystallization from methanol-ether, there is obtained colorless rac.-1,2,3,4-tetrahydro-2-methyl-4-(3-nitrophenyl)-7-isoquinolinol hydrochloride of melting point 257°-258°C. (dec.).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CN(C=O)C.[Br:22][CH2:23][C:24](Br)=[O:25]>O1CCOCC1>[Br:22][CH2:23][C:24]([NH:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:16][CH:15]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline (14.0 g, 59 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (11.91 g, 5.18 mL, 59 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water. The resulting precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 8.73 g (61%) Of the title compound as a pale yellow crystals, mp 128°-134° C. (decomp), became wet at 89°-93° C.: 1H NMR (DMSO-d6) δ10.35 (s, 1H), 7.52 (d, J=8.8, 2H), 7.26 (d, J=8.8, 2H), 4.43 (s, 2H), 4.04 (s, 2H); 13C NMR (DMSO-d6) δ164.58, 138.00, 137.15, 126.97, 118.94, 62.51, 30.43; MS (El, m/z) 243 (M+).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: NCCN
Product: CC[C@@H]1C(=O)N(C)c2cnc(NCCN)nc2N1C(C)C

Procedure:
Intermediate C (1 mmol, 269 mg) in ethylenediamine (10 mmol, 600 mg, 0.7 mL) was heated at 120° C. in a microwave for 3 h. The reaction was evaporated, taken up in EtOAc and washed 3× with water, then dried with MgSO4 and evaporated to give (R)-2-(2-aminoethylamino)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (compound I-246).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(O)(C)C>[ClH:25].[Cl:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Clc1cc2cnccc2cc1SC1CCNCC1
Yield: 224.6 %

Procedure:
1.98 g of 4-(7-Chloro-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (274) were dissolved in 7 ml dichloromethane and 5 ml 6N HCl in isopropanol. After 18 h at RT the volatiles were evaporated, water was added and lyophilized. 1.85 g of the expected compound were obtained. Rt=0.70 min (Method B). Detected mass: 279.1/281.1 (M+H+).