Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][OH:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[O:44]=[C:45]1[CH:50]([N:51]2[C:59](=[O:60])[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][C:57]=3O)[C:52]2=[O:62])[CH2:49][CH2:48][C:47](=[O:63])[NH:46]1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:25][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:53]=1[C:52](=[O:62])[N:51]([CH:50]1[CH2:49][CH2:48][C:47](=[O:63])[NH:46][C:45]1=[O:44])[C:59]2=[O:60]
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of polymer-supported triphenylphosphine (1.46 g, 4.4 mmol) and 3,4-dichlorobenzyl alcohol (0.65 g, 3.6 mmol) was stirred in THF (10 mL) at 0° C. Keeping the reaction mixture at 0° C., a solution of diisopropylazodicarboxylate (0.87 mL, 4.4 mmol) in THF (2.1 mL) was added dropwise. 2-(2,6-Dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (1.00 g, 3.60 mmol) was then added as a solid, the reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was evaporated under vacuum and the residue was chromatographed using a methanol-CH2Cl2 gradient, eluting the product at 95:5 CH2Cl2-methanol. This material was dissolved in ethyl acetate (150 mL) and water (100 mL) was added. The organic phase was then washed with 10% dilute aqueous sodium carbonate (2×50 mL) and water (3×50 mL). The solvent was removed under vacuum and the resulting solid was triturated with ether, filtered and dried to provide the title compound as a white solid (0.41 g, 26% yield); mp 245-247° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.50 (99.78%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.45-2.62 (m, 2H), 2.82-2.96 (m, 1H), 5.12 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 5.38 (s, 2H), 7.49-7.51 (m, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.81-7.88 (m, 2H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 68.5, 115.9, 116.8, 120.1, 127.3, 129.0, 130.5, 130.8, 131.2, 133.3, 137.1, 137.5, 155.1, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H14N2O5Cl2+0.3H2O: C, 54.76; H, 3.35; N, 6.39. Found: C, 54.48; H, 3.07; N, 6.29.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16].C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([OH:12])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: Cc1ccc(N)cc1O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Temperature: 120 °C
Yield: 70.3 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with 3-hydroxy-4-methylaniline (150 mg, 1.22 mmol) and diisopropylethylamine (213 μL, 1.22 mmol) in n-butanol (1.3 mL). The mixture is heated to 120° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methyl-phenol (92 mg; 70%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)N[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[S].[CH:28](Cl)(Cl)Cl>>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc([N+](=O)[O-])c1
Agent: [S]
Product: COC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Temperature: 150 °C

Procedure:
A mixture of methyl 1,6-dihydro-4-methyl-6-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.5 g) and sulfur powder (0.046 g) was heated at 150° C. for 1 hour. After cooling, the mixture was dissolved in chloroform and filtered. The filtrate was evaporated under reduced pressure to give a crystal of methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyridinecarboxylate (0.2 g).
Reaction SMILES: Cl[C:2]1N=C(C2C(C3C=C(NC(=O)C4C=C(F)C=CC=4F)C=CC=3)=NN3C=CC=CC=23)C=CN=1.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:43]2[N:48]=[C:47]([C:49]3[C:50]([C:58]4[CH:59]=[C:60]([NH:64][C:65](=[O:74])[C:66]5[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=5[F:73])[CH:61]=[CH:62][CH:63]=4)=[N:51][N:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=34)[CH:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.CCOC(C)=O>[F:73][C:67]1[CH:68]=[CH:69][CH:70]=[C:71]([F:72])[C:66]=1[C:65]([NH:64][C:60]1[CH:61]=[CH:62][CH:63]=[C:58]([C:50]2[C:49]([C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH3:2])[CH:37]=4)[N:48]=3)=[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][N:52]3[N:51]=2)[CH:59]=1)=[O:74]
Reactant: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 72.8 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,5-difluorobenzamide (100 mg, 0.22 mmol) (prepared according to a procedure similar to that described in Example 43, Step A) and N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (59 mg, 0.27 mmol) (prepared as described in Example 180) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was heated to 180° C. in a microwave for 15 min. The reaction mixture was diluted with 25 mL EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and purified by flash chromatography to give the title compound (90 mg, 64% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.64 (s, 1H), 9.99 (t, J=5.7 Hz, 1H), 9.63 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.42-7.55 (m, 5H), 7.35 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.14 (t, J=6.8 Hz, 4H), 6.85 (d, J=7.3 Hz, 1H), 6.54 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H). MS (ESI) m/z=645 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([Br:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[OH:30])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[SiH](Cl)Cl>O1CCOCC1>[C:31]1([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([Br:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[OH:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1-c1c(O)ccc2cc(Br)ccc12
Agent: Cl[SiH](Cl)Cl
Solvent: C1COCCO1
Product: Oc1ccc2cc(Br)ccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
An optically active binaphthol (VII) as a starting material is reacted by a method described in the literature (M. Vondenhof and J. Mattay, Tetrahedron Lett., 1990, Vol. 31, pp . 985-988; L. Kurz, G. Lee, D. Morgans, Jr., M. J. Waldyke, and T. Ward, Tetrahedron Lett., 1990, Vol. 31, pp. 6321-6324) and by a method described in the literature (Y. Uozumi, A. Tanahashi, S. -Y. Lee, and T. Hayashi, J. Org. Chem., 1993, Vol. 58, pp. 1945-1948). That is, the binaphthol (VII) is reacted with trifluoromethanesulfonic anhydride (Tf2O) using pyridine in methylene chloride to convert compound (VII) to 2,2′-bis(trifluoromethanesulfonyl-oxy)-1,1′-binaphthyl (VIII), which is reacted with diphenylphosphine oxide (Ph2PHO) in the presence of a catalytic amount of a palladium-phosphine complex, whereby 2′-diphenylphosphinyl-2-trifluoromethanesulfonyloxy-1,1′-binaphthyl (IX) can be synthesized. Compound (IX) is hydrolyzed with lithium hydroxide (LiOH) to obtain 2′-diphenylphosphinyl-2-hydroxy-1,1′-binaphthyl (XVIII), which is brominated in dioxane to obtain 2′-diphenylphosphinyl-2-hydroxy-6-bromo-1,1′-binaphthyl (XIX). Compound (XIX) is reduced with trichlorosilane (HSiCl3) to obtain 2′-diphenylphosphino-2-hydroxy-6-bromo-1,1′-binaphthyl (XX), which is reacted with 2-vinyl-5,5-dimethyl-1,3-dioxa-2-borinane using a palladium catalyst by a method described in the literature (Y. Miyaura and A. Suzuki, J. C. S. Chem. Commun., 1979, p. 866) to obtain 2′-diphenylphosphino-2-hydroxy-6-vinyl-1,1′-binaphthyl (XXI).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][N+:23]([CH3:26])([O-:27])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1cccc(Nc2ncnc3cnc(NC4CCN(C)CC4)nc23)c1
Product: Cc1cccc(Nc2ncnc3cnc(NC4CC[N+](C)([O-])CC4)nc23)c1

Procedure:
Prepared from compound 62 of Example 1 by reaction with hydrogen peroxide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1.[C:29](=[O:31])=[O:30]>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([C:25]([Br:28])=[CH:24][N:23]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ncc1Br
Temperature: -30 °C

Procedure:
A 20-L 4-necked round-bottom flask purged and maintained under a N2 atmosphere was charged with a solution of diisopropylamine (582 g, 5.76 mol, 1.05 equiv) in THF (4.2 L), followed by the dropwise addition over 30 min of n-BuLi (2.4 M, 2.4 L, 1.05 equiv) with stirring at −30° C. The resulting solution was stirred at −30° C. for 30 min then cooled to −80° C. To the LDA solution was added dropwise over 1 h with stirring a solution of 2,5-dibromopyridine (1.3 Kg, 5.49 mol, 1.00 equiv) in THF (5.2 L). The resulting solution was stirred at −70° C. for 30 min. To the mixture was added CO2 (dry ice) (1267 g, 28.80 mol, 5.00 equiv) in several batches at −70° C. The resulting solution was stirred at −70° C. for 30 min, quenched by the addition of 5 L of water at −70° C., concentrated in vacuo and extracted with 3×4 L of EtOAc. The pH value of the aqueous layer was adjusted to 3-4 with HCl (12 mol/L). The precipitate was collected by filtration to afford 2,5-dibromoisonicotinic acid (A-2) white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-(dimethylamino)acetic acid (0.0018 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(dimethylamino)-1-ethanone (0.031 g, 0.00007 mol).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=1)([O-:7])=[O:6].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:17]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:16]=2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1ccc([N+](=O)[O-])cc1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Yield: 53.3 %

Procedure:
4-Nitrophenyl-guanidine nitrate (20 g, 0.08 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (11.75 g, 0.06 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(4-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (9.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N)C1C=CC=CC=1.[NH2:18][C:19]1[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:21]2[S:20][C:19]([NH2:18])=[N:23][C:22]=2[CH3:24])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: NCc1ccc(Cl)cc1
Solvent: NCc1ccccc1
Product: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 15 %

Procedure:
Following the procedure as described in Preparation 1, making variation only as required to use 4-chlorobenzylamine to replace benzylamine to react with 2-amino-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid in 15% yield; 1H NMR (CD3OD, 300 MHz) δ 7.26-7.32 (m, 4H), 4.41 (s, 2H), 2.38 (s, 3H). MS (ES+) m/z 282.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (20.4 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.57 g (24.5 mmol) piperazine 1-carboxylic acid tert-butyl ester using 10.4 mL (61.3 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure yielding 7.5 g (94%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[CH:25]12[CH2:31][CH2:30][CH:29]1[CH2:28][N:27]([C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH2:26]2>>[CH:29]12[CH2:30][CH2:31][CH:25]1[CH2:26][N:27]([C:32]1[N:37]=[CH:36][C:35]([NH:38][C:12]([C:10]3[N:9]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:23])([F:1])[F:24])[CH:4]=[C:5]4[CH:11]=3)=[O:14])=[CH:34][CH:33]=1)[CH2:28]2
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC3CCC3C2)nc1
Product: O=C(Nc1ccc(N2CC3CCC3C2)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 67.3 %

Procedure:
According to a method similar to that described in Stage 12.3, starting from 0.12 g (0.35 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 1.3, and 0.075 g (0.38 mmol) of 6-(3-azabicyclo[3.2.0]hept-3-yl)-3-aminopyridine, prepared in the preceding stage, we obtain 0.12 g of the expected product.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]Br.Cl.Cl.[CH3:12][NH:13][NH:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH3:12][N:13]1[CH2:2][C:3]2[N:4]=[CH:5][S:6][C:7]=2[CH2:8][N:14]1[CH3:15]
Reactant: CNNC
Reactant: BrCc1ncsc1CBr
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1Cc2ncsc2CN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice cooling, 4,5-bis(bromomethyl)thiazole (600 mg) and 1,2-dimethylhydrazine dihydrochloride (294 mg) were suspended in ethanol (20 ml). Triethylamine (1.23 ml) was added in one portion to the reaction mixture, followed by stirring at room temperature for 30 minutes and then, at 50° C. for 30 minutes. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (5% methanol—methylene chloride), whereby the title compound (90 mg, 24%) was obtained.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[NH2:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:2]([O:3][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[NH2:4])[CH3:1]
Reactant: CCO
Reactant: Nc1ncccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccnc1N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
EtOH (500 mL) was added to 2-amino-nicotinic acid (25 g), followed by H2SO4 (25 mL, conc), and the mixture stirred at 75° C. overnight. The reaction mixture was then redissolved in H2O, neutralized with Na2CO3 (aq), and the resulting precipitate filtered and dried to provide 2-amino-nicotinic acid ethyl ester, which was used without further purification.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[N:21]([CH2:24][CH2:25][NH2:26])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2.Cl.[OH-].[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])[N:21]([CH2:24][CH2:25][NH:26][C:2](=[O:1])[NH2:3])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCN)c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Sodium cyanate (6.0 g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0 g, 0.046 mol) in water (600 ml) and 1N HCl (92 ml) at 80° C. After stirring for 2 h at 80° C. the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3×200 ml) and the combined extract was dried (MgSO4) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2Cl/MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9 g, 54%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:22][OH:23])([CH2:18][CH2:19][CH:20]=[CH2:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:18]([C:12]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:22][O:23][C:26]([CH3:28])([CH3:27])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:19][CH:20]=[CH2:21]
Reactant: COC(C)(C)OC
Reactant: C=CCCC(CO)(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCCC1(C(=O)OCC)COC(C)(C)N1C(=O)OCc1ccccc1
Yield: 57 %

Procedure:
A solution of the ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate 4 (820 mg, 2.55 mmol) in toluene (10 mL) was treated with 2,2-dimethoxy propane (2 mL) and 4-toluenesulfonic acid (100 mg). The mixture was heated under reflux for 1 h, cooled, concentrated and purified using a combiflash system (12 g silica gel column, eluting with 5-50% of ethyl acetate in heptanes) to give 3-benzyl 4-ethyl 4-(but-3-enyl)-2,2-dimethyloxazolidine-3,4-dicarboxylate (530 mg, 57%). 1H NMR (CDCl3) δ 7.36 (m, 5H), 5.75 (m, 1H), 4.51 (m, 4H), 4.06 (m, 4H) 2.08 (m, 4H), 1.65 (2 s, 6H), 1.13 (t, J=7.1 Hz, 3H). MS found for C20H27NO5 m/z [332 (M+1)].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH2:33][CH3:34]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][C:7](=[O:9])[CH3:8])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.[Br:16]Br>C(O)COCCO>[Br:16][CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:4](=[O:10])[C:3]2[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]1=[O:15]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Solvent: OCCOCCO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Commercially available phthalimidoacetone (2.0 g, 9.8522 mmol), under a nitrogen atmosphere, was taken up in diethylene glycol (13 mL) and cooled to 0° C. in an ice bath. Bromine (0.51 mL, 9.9242 mmol) was added dropwise. The reaction was shielded from light, allowed to reach ambient temperature, and stirred overnight. LCMS: (M+H)+=282.0.