Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:40]=[CH:39][C:28]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[C:27]([N+:41]([O-])=O)[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pt](=O)=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[CH:12]([C:25]3[CH:26]=[C:27]([NH2:41])[C:28]([NH:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:39][CH:40]=3)[CH2:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of the product from Example 179D (2.74 g, 4.72 mmol) in EtOH (25 mL) and THF (25 mL) was added platinum(IV) oxide (0.5 g, 2.2 mmol). The resulting mixture was stirred at rt under 1 atm H2 overnight. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-45% EtOAc in hexane to give the title compound (1.74 g, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3](C(N)=O)[C:2]=1[C:10]([NH2:12])=[O:11].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C[N:31](C)[CH:32]=[O:33]>>[NH:31]1[C:3]2[N:4]=[CH:5][CH:6]=[N:1][C:2]=2[C:10](=[O:11])[NH:12][C:32]1=[O:33]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nccnc1C(N)=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c(=O)c2nccnc2[nH]1
Reaction time: 0.25 h

Procedure:
A 50 ml. flask was charged with 0.90 g. pyrazine-2,3-dicarboxamide dissolved in 16 ml. dimethylformamide. A 2.4 g. portion of lead tetra-acetate was added to the solution and the reaction mixture was stirred at 40° for 15 minutes. The reaction mixture was cooled, 30 g. of ice was added and after 1 hour the mixture was filtered. Crystallization of the residue from water gave, after drying in vacuo, a yield of 0.64 g. of pyrazino[2,3-d]pyrimidine-2,4(1H,3H)-dione, melting point 364°-365°, which represented 71 percent of theory. The structure was confirmed by infra-red spectroscopy.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH2:1][CH2:2][CH3:3])[N:16]=1
Reactant: CCCO
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of propan-1-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-60% EtOAc/hexanes gradient elution to yield the title compound (3.8 g, 68%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, J=8.2 Hz, 1 H), 7.69 (br. s., 1 H), 7.06 (d, J=8.2 Hz, 1 H), 5.86 (br. s., 1H), 4.48 (t, J=6.6 Hz, 2 H), 1.99-1.79 (m, 2 H), 1.07 (t, J=7.4 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60]>>[CH2:22]([O:21][N:16]1[C:15]([CH3:30])([CH3:31])[CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:54])([CH3:55])[CH2:38]3)[N:3]=[C:2]([NH:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[N:7]=2)[CH2:18][C:17]1([CH3:20])[CH3:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCC(=O)O
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(NCCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(O)(=O)C>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a suspension of diethyl carbonate (47.4 mL, 391 mmol) and sodium hydride (55 wt % paraffin oil, 23.7 g, 543 mmol) in THF was added 4′-fluoroacetophenone (26.4 mL, 271 mmol) at 60° C. The reaction mixture was heated under reflux for 1 hr, cooled to room temperature, and poured into acetic acid (33.6 ml, 586 mmol) and ice water (1 L). The reaction mixture was extracted with diethyl ether (2×500 mL), the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 3-(4-fluorophenyl)-3-oxopropanoate (45.7 g, 100%, keto form: enol for m=5:1) as a yellow oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[OH:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][CH:12]=1>ClCCl>[O:6]=[C:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:13][CH:12]=1
Reactant: CC(O)CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(=O)CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.3 %

Procedure:
Pyrididium chlorochromate (7.32 g, 34.00 mmol) was added to a mixture of benzyl 4-[4-(4-hydroxypentyl)phenyl]butylcarbamate (138) (6.27 g, 17.00 mmol) and 4 Å molecular sieves in dichloromethane (250 mL) in three portions and stirred at rt for 6 h. The reaction mixture was then filtered through diatomaceous earth and the filtrate was concentrated to a black oil. Purification by column chromatography (silica, 30:70 ethyl acetate/hexanes) afforded ketone 140 (6.58 g, >99% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.50-1.56 (m, 2H), 1.60-1.66 (m, 2H), 1.85-1.90 (m, 2H), 2.11 (s, 3H), 2.42 (t, 2H), 2.56-2.60 (m, 4H), 3.19-3.23 (m, 2H), 4.70 (br s, 1H), 5.08 (s, 2H), 7.07 (s, 4H), 7.29-7.36 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4 g, 13.6 mmol) in absolute ethanol (30 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified by 1N HCl, and concentrated. The residue was taken into chloroform and washed with 1N HCl, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10]>C1COCC1.[Cu]I>[Cl:6][C:7]1[C:8]([C:9](=[O:10])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=[CH:14][N:15]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: [Li]C(C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cccnc1Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of copper(I) iodide (1.18 g, 6.2 mmol) in 5 mL of THF was cooled to -40° C. and then tert-butyllithium (8.85 mL, 1.4M, 12.4 mmol) was added. The mixture was stirred for 1 hour and 2-chloronicotinic acid chloride (2 g, 11.3 mmol) was added dropwise. The mixture was stirred at -40° C. for 1.5 hours and then allowed to warm to room temperature. The mixture was quenched with water and then diluted with ethyl acetate. The mixture was filtered, washed with water (2×10 mL) and brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with hexanes/ethyl acetate (85:15) to give 1-(2-chloro-3-pyridyl)-2,2-dimethylpropan-1-one (1.735 g, 8.8 mmol) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:18](OC(C)(C)C)=O.Cl.O1CCOCC1.[NH2:32][C:33]1[N:38]=[C:37]([Cl:39])[CH:36]=C(Cl)[N:34]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CCOCC>[Cl:39][C:37]1[N:38]=[C:33]([NH2:34])[N:32]=[C:18]([N:3]2[CH:2]([CH3:1])[CH2:11][C:10]3[C:5](=[CH:6][C:7]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)=[CH:8][CH:9]=3)[CH2:4]2)[CH:36]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
tert-butyl 3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.320 g, 0.977 mmol) in ethyl acetate (1 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.00 mL, 4.00 mmol) at r.t. for 1 h. The mixture was diluted with ether (5 mL), and was centrifugalized. The solvents were decanted. The residue was dried in-vacuo, and dissolved in tert-butanol (10 mL). To the solution was added 2-amino-4,6-dichloropyrimidine (0.246 g, 1.50 mmol) and N,N-diisopropylethylamine (522 uL, 3.00 mmol). The mixture was heated and stirred at 120° C. overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to give the desired product (303 mg, 87.6%). LCMS (M+H)+: m/z=355.1/357.1.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.C(OCC)(=O)C>CC(C)=O.[O-2].[O-2].[Mn+4]>[SH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(S)c(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(S)c(C=O)c2c1

Procedure:
Manganese dioxide (1.38 g, 15.89 mmol) is added at room temperature to a stirred solution of (3-mercapto-6-methoxy-quinoline-4-yl)-methanol and its corresponding dimer (500 mg) in acetone (30 mL) and the resulting suspension is heated under reflux for 8 hours. The reaction mixture is then filtered through decalite and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford 3-mercapto-6-methoxy-quinoline-4-carbaldehyde and its corresponding dimer as a yellow solid (64 mg, 13% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH2:14](O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[C:2]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)[O:1][CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC2(CC1)OCCO2
Yield: 106.2 %

Procedure:
A mixture of ethyl hexahydro-4-oxoazepine-1-carboxylate (0.585 mol), 1,2-ethane-diol (0.585 mol) and p-toluenesulfonic acid (0.0058 mol) in toluene (800 ml) was stirred and refluxed overnight, using a water separator (10.5 ml was separated). The solvent was evaporated, yielding 142.5 g of ethyl 1,4-dioxa-8-azaspiro[4.6]undecane-8-carboxylate (intermediate 4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].[F-].[K+].O>CN(C=O)C>[CH3:19][C:13]1([CH3:20])[C:14](=[O:15])[NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
At room temperature, a solution of 2-amino-4-nitro-phenol (82.5 g, 0.54 mol) in DMF (660 ml) is treated with ethyl 2-bromoisobutyrate (160 ml, 1.07 mol) and KF (124.7 g, 2.15 mol), stirred at the same temperature for 1 h, warmed to 60° C., and stirred for 48 h. After pouring the mixture into H2O (3500 ml), the resulting precipitate is collected by filtration, and washed with H2O and Et2O for several times respectively to give 2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (84.8 g, 71%) as yellow solid. Rf (hexane/EtOAc 2:1) 0.42. 1H-NMR (400 MHz, DMSO-d6) 1.48 (s), 7.16 (d, J=9.0), 6.42 (d, J=0.4), 8.00 (dd, J=9.0, 0.4). 13C-NMR (100 MHz, DMSO-d6) 167.7 (s), 147.5 (s), 142.0 (s), 128.0 (s), 119.2 (d), 117.3 (d), 110.3 (d), 78.9 (s), 23.7 (2q).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].N[C:29]1C(C(OCC)=O)=NC(NC2C=CC=C(O)C=2)=NC=1NC1C=CC=CC=1OC.N>CO>[OH:24][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([N:1]=[CH:29][N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:27])=[O:26])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccccc1Nc1nc(Nc2cccc(O)c2)nc(C(N)=O)c1N
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2ccccc2OC)c1N
Agent: N
Solvent: CO
Product: COc1ccccc1-n1cnc2c(C(N)=O)nc(Nc3cccc(O)c3)nc21
Temperature: -78 °C
Yield: 87 %

Procedure:
5-Amino-2-(3-hydroxyphenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carbox-amide. In a sealed tube, ethyl 5-amino-2-(3-hydroxyphenylamino)-6-(2-methoxyphenyl-amino)pyrimidine-4-carboxylate (See example 36.B) (76.4 mg, 0.193 mmol) was dissolved in anhydrous methanol (5 mL) and was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 h the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting material was purified by column chromatography (100% ethyl acetate) to provide the title compound (61.5 mg, 0.168 mmol, 87% yield). MS (ESI) m/z 367.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:11][CH:12]=[C:13]([C:15]([N:17]2[CH2:22][C:21]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[O:20][CH2:19][CH2:18]2)=[O:16])[N:14]=1)[CH3:9]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:11][CH:12]=[C:13]([C:15]([N:17]2[CH2:22][C:21]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:20][CH2:19][CH2:18]2)=[O:16])[N:14]=1)[CH3:9]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Example 26, step a] (24 g) in dichloromethane (100 mL) and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (50 mL) and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), TFA (50 mL) was added and the mixture was stirred for 4 hours. The mixture was diluted with toluene (50 mL), concentrated in vacuo, the residue triturated with ether and the precipitated solid collected by filtration and dried to afford the subtitled compound as a white solid. Yield 28 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClCCl.C(N(CC)CC)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoic acid (0.560 g, 2.17 mmol, Example 3, Step 1), triethylamine (0.620 ml), and diethylamine (0.230 ml) in dichloromethane (5 ml) at room temperature was added bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.560 g). After 3 hours, HCl 1M (10 ml) was added and the product was extracted with dichloromethane (10 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 50% giving 0.44 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C(N(CC)CC)C>ClC(Cl)Cl.CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:28][C:29]1[CH:34]=[C:33]([NH:27][C:4]2[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:10]=3)[N:5]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccnc(F)c4)n3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 0.277 mmol, 1. eq.), 78.0 mg of (2-fluoropyridin-4-yl)boronic acid (0.553 mmol, 2 eq.) and 205 mg of copper (II) acetate were suspended in 4 ml of trichloromethane. 154 μl of triethylamine (1.11 mmol, 4 eq.) and 16.9 mg of N,N-dimethylpyridin-4-amine (138 mmol, 0.5 eq.) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered off over Celite 545 and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 13 mg (0.03 mmol, 10.9%) of the analytically pure target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(CCO)cc1
Product: Nc1ccc(CCO)cc1C1=CCCCC1

Procedure:
The title compound was prepared by Suzuki coupling of 2-(4-amino-phenyl)-ethanol (prepared in the previous step) and 1-cyclohexen-1-yl-boronic acid according to the procedure of Example 44, step (b). Mass spectrum (ESI, m/z): Calcd. for C14H19NO, 218.1 (M+H), found 218.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH2:13][CH2:14]O)[N:12]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[C:16](=[O:17])[O:18][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Mix 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (81.2 g, 286.2 mmol) with p-TsOH monohydrate (32.0 g, 168.2 mmol) and toluene (1200 mL). Heat the slurry to reflux during which time the solids dissolve. Stir the resulting tan solution mechanically for 2 h, using a Dean-Stark trap to collect water (21 mL). Cool the solution to room temperature and add saturated aqueous NaHCO3 (1700 mL) and EtOAc (1700 mL). Separate the organic solution, then extract the aqueous layer with EtOAc (2×1700 mL). Combine the organic solutions, wash with brine (1700 mL), and concentrate in vacuo to give a solid. Mix the solid with CH2Cl2 (500 mL) and concentrate in vacuo and repeat two times to give 60.1 g (79%) of the title compound. ES/MS m/z (35Cl) 266.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-dichloropyrazine (470 mg, 3155 μmol) was combined with 4-aminophenol (344 mg, 3155 μmol) and cesium carbonate (1233 mg, 3786 μmol) in DMSO (5 ml) and heated to 70 C. After 3 hours, the mixture was cooled to room temperature, transferred to a separatory funnel rinsing with ethyl acetate and water, the layers were separated and the aqueous was extracted with ethyl acetate (3×). The combined organics were rinsed with brine, dried over sodium sulfate, filtered and concentrated to yield a brown solid which was carried forward without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:38]
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and methoxy-acetyl chloride the title compound is obtained as colorless solid.