Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:14][C:15]4[N:20]([CH2:21][CH2:22][C:23]#N)[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[C:33](OC(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)C>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][C:15]4[N:20]([CH2:21][CH:22]([CH3:33])[CH3:23])[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Reactant: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CC(C)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(2-oxo-7-phenyl-1-propyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.078 mmol) was reacted to afford the title compound (34.5 mg). 1H NMR (500 MHz, CH3OD) 7.57 (1H, s), 7.38-7.42 (4H, m), 7.30-32 (3H, m), 7.21-7.2 (2H, m), 4.97 (2H, s), 3.92 (2H, d), 2.73-2.79 (2H, m), 2.54-2.60 (2H, m), 2.22-2.25 (1H, m), 2.13-2.16 (1H, m), 1.95-1.99 (1H, m), 1.0 (6H, d). LCMS (method D) RT: 0.93, M+H+=428.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH3:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:52]=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42](F)[CH:41]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>CS(C)=O.O>[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:41]=[CH:42][C:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[C:51]([NH:7][CH:8]5[CH2:9][C:10]([CH3:18])([CH3:17])[N:11]([CH3:16])[C:12]([CH3:14])([CH3:15])[CH2:13]5)[CH:52]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)OC(C)(C)C)CC1(C)C
Temperature: 90 °C

Procedure:
0.95 g of potassium carbonate and 7.8 ml of 4-amino-1,2,2,6,6-pentamethylpiperidine are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 15 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride and dried over magnesium sulphate. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 0.8 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=3[O:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O1CCOCC1.O=[Mn]=O>[C:1]12([C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=3[O:19][CH:20]([CH3:22])[CH3:21])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)Oc1cc(CO)ccc1C12CC3CC(CC(C3)C1)C2
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(C=O)ccc1C12CC3CC(CC(C3)C1)C2
Reaction time: 6 h
Yield: 73.3 %

Procedure:
A mixture of the product of Step B (0.7 g) and MnO2 (1.5 g) in dioxane (20 ml) was stirred for 6 h at reflux. The mixture was filtered through Celite pad and the filtrate was evaporated to dryness to give the title compound (0.51 g, 73.4%) as creamy solid. 1H-NMR (CDCl3) 1.4 (d, 6H, J=6 Hz); 1.76 (s, 6H); 2.07 (s, 3H); 2.11 (s, 6H); 4.7-4.78 (m, 1H); 7.32-7.42 (m, 3H); 9.91 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[CH:11][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[N:10][N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:26][C:27]1[N:28]([CH3:32])[N:29]=[CH:30][N:31]=1
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)cc1Br
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1Br
Temperature: 60 °C
Yield: 103.8 %

Procedure:
To a solution of 5-bromo-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.29 g, 1.0 mmol) in DMF (4 ml) under nitrogen was added cesium carbonate (0.98 g, 3.0 mmol) followed by 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.25 g, 1.5 mmol). The resulting suspension was heated at 60° C. for 17 h. The mixture was partitioned between ammonium chloride solution (saturated aqueous) and ethyl acetate. The layers were separated and the aqueous phase extracted a second time with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give 5-bromo-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (0.40 g) of adequate purity. δH (400 MHz; CDCl3) 4.04 (3H, s), 5.70 (2H, s), 7.33-7.37 (1H, m), 7.52-7.56 (2H, m), 7.90 (1H, s), 8.06 (1H, s), 8.16-8.19 (2H, m), 8.27 (1H, s); m/z (ES+) 387 (M+H+), 385 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)N
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NC(C)(C)C)nc2ccc([N+](=O)[O-])cc12
Yield: 93.7 %

Procedure:
At 80° C. were stirred 225 mg (0.85 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 696 mg (9.52 mmol) of t-butylamine overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 240 mg (yield: 93.7%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:33])[C:10]([NH:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br>C1COCC1.ClCCl>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45][O:33][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1
Reactant: Oc1cc(-c2ccccc2)cnc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(COc2cc(-c3ccccc3)cnc2N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of 5-phenyl-2-(trityl-amino)-pyridin-3-ol (100 mg, 0.24 mmol) in THF (3 mL) was added Cs2CO3 (79 mg, 0.24 mmol). The mixture was stirred at room temperature for 20 minutes, and then 3-methoxybenzylbromide (0.037 mL, 0.26 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane (5 mL), and filtered to remove the salts. The solvents were evaporated, and the residue was dissolved in 10% trifluoroacetic acid in dichloromethane (2 mL). The reaction was stirred for 2 hr, and evaporated. The residue was dissolved in dichloromethane, washed by sat. NaHCO3, and dried over Na2SO4. After filtration and concentration, the crude product was purified on a silica gel column eluting with methanol-dichloromethane (from 3% to 15% gradient) to provide 3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine as a white solid (43.5 mg, 60% yield).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1>CO.C1COCC1.[Pd]>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1

Procedure:
A solution of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (1.79 g, 3.29 mmol) in a mixture of MeOH (80 mL) and THF (80 mL) was hydrogenated over 10% Pd on carbon (100 mg). After removal of the hydrogen, the mixture was refluxed in air for additional 2 hrs. The catalyst Pd/C was removed by filtration through celite, and the solvents were removed under vacuum. Recrystallization of the residue from methanol gave tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate: mp (MeOH) 177-179° C.; 1H NMR (CDCl3) δ 8.01 (dd, J=8.4, 0.7 Hz, 1H), 7.58 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 4.22 (m, 2H), 4.05 (s, 3H), 3.99 (m, 2H), 3.94 (m, 2H), 3.81 (m, 4H), 2.94-2.78 (m, 3H), 2.05 (dd, J=13.0, 1.9 Hz, 2H), 1.81 (qd, J=12.7, 4.4 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C26H33F2N7O4: C, 57.2; H, 6.1; N, 18.0. Found: C, 57.4; H, 6.15; N, 18.1%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][NH2:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl[C:23]([O:25][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:24]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([NH:14][NH:15][C:23]([O:25][CH:26]([CH3:27])[CH2:28][CH3:29])=[O:24])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Oc2ccccc2)c1
Reactant: CCC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(C)OC(=O)NNc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.0 g of 3-phenoxyphenyl hydrazine, 100 ml of ethyl acetate and 2.5 ml of pyridine were added and the resultant solution was then stirred at room temperature for 30 minutes. Then, 2.5 ml of sec-butyl chloro-formate was added dropwise to the solution and stirred for 1 hour at room temperature. The solution was then washed twice, each time with 100 ml of water. After each wash, the aqueous fraction was removed from the organic (ethyl acetate) fraction. The resulting ethyl acetate fraction was then dried over anhydrous sodium sulfate, evaporated under reduced pressure, and then purified by column chromatography on silica gel, to produce 1.5 g of 1-methylpropyl 2-(3-phenoxyphenyl)hydrazine carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23]3)[C:17]([NH:27][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
420 mg (purity 92%, 1.04 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 348 mg (61% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1.O[Li].O.C1COCC1>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(N)ccn3)cc2Cc2ccccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
A mixture of ethyl (S)-10,11-dihydro-3-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (2.4 g, 5 mmole), LiOH.H2O (0.3 g, 7 mmole), THF (30 mL), and H2O (10 mL) was stirred at RT for 48 hr, then was concentrated. The residue was diluted with H2O and extracted with Et2O. The Et2O layers were discarded. The aqueous layer was stirred with gentle warming under vacuum to remove residual organic solvents, then was filtered. The resulting aqueous solution was stirred at RT while the pH was slowly and carefully adjusted to 5.5-6.0 with 1.0 N HCl The mixture was stirred for 0.5 hr, then the solid was collected by suction filtration and washed with plenty of H2O. Drying in high vacuum at 60° C. gave the title compound (1.0 g, 42%) as a glassy solid: MS (ES) m/e 417.7 (M+H)+. Anal. Calcd for C25H27N3O3 1.4 HCl (468.554): C, 64.08; H, 6.11; N, 8.97. Found: C, 64.16; H, 6.20; N, 8.71.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:44])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:20]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:19]2)=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:20]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:19]2)=[CH:14][CH:13]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CNC(=O)CN)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of {[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 aqueous solution (20 mL), and the organic layer was removed and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (90:10 CH2Cl2/MeOH) to give 10 mg (20%) of the desired product. 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 8.32 (d, J=5.7 Hz, 2H), 8.02 (s, 1H), 7.53 to 7.30 (m, 6H), 6.96 (d, J=6.6 Hz, 2H), 6.73 (d, J=6.3 Hz, 2H), 6.32 (s, 1H), 4.36 (s, 2H), 3.70 (S, 2H), 1.18 (s, 9H); MS LC-MS [M+H]+=513, RT=2.01 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:16][C:17]1[S:18][C:19]([C:23](O)=[O:24])=[C:20]([CH3:22])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:23]([C:19]2[S:18][C:17]([Br:16])=[N:21][C:20]=2[CH3:22])=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Br)sc1C(=O)NC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
To a stirred mixture of 1-methyl-4-aminopiperidine (125 μL, 114 mg, 1 mmol) and triethylamine (570 μL, 414 mg, 4.1 mmol) in anhydrous tetrahydrofuran (1.0 mL), 2-bromo-4-methyl-thiazole-5-carboxylic acid (266 mg, 1.2 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (232 mg, 1.2 mmol) and 1-hydroxy-benzotriazole (164 mg, 1.2 mmol) were sequentially and the mixture was stirred at room temperature for 22 h. After dilution with dichloromethane (20 mL), the mixture was washed with water (3×10 mL), dried over MgSO4 and concentrated. In this manner the title compound (277 mg, 0.87 mmol, 87%) was obtained as a yellow solid.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[N:63]=[C:62]([C:64]3[CH:71]=[CH:70][C:67]([CH:68]=O)=[CH:66][CH:65]=3)[O:61][N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:58])[CH3:57]>C1COCC1>[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[N:63]=[C:62]([C:64]3[CH:65]=[CH:66][C:67](/[CH:68]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:70][CH:71]=3)[O:61][N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:57])[CH3:58]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
A two-neck round bottom flask was charged with methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (0.235 ml, 1.109 mmol), 18-crown-6 (1465 mg, 5.54 mmol) and THF (15 ml). The mixture was then cooled to −78° C. under an atmosphere of nitrogen. Potassium bis(trimethylsilyl)amide (221 mg, 1.109 mmol) was added and the mixture stirred for a few minutes. 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture stirred at −78° C. for 90 minutes and then left to warm to room temperature overnight. Reaction was quenched by the addition of saturated NH4Cl (aqueous). The mixture was separated and the aqueous layer was extracted with ether (3×10 mL). The combined organics were dried over MgSO4 and concentrated to give an off-white solid. The solid was triturated with MeOH and collected by vacuum filtration and washed with MeOH (3×10 mL). Collected solid was dried overnight in a vacuum oven to give (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylate (325 mg, 73.5%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C:27]([CH3:60])([CH3:59])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]2[C:45]3[N:44]=[C:43]([C:46]4[C:51]([Br:52])=[CH:50][CH:49]=[CH:48][C:47]=4[Br:53])[NH:42][C:41]=3[C:40]3[C:35](=[CH:36][C:37]([O:54][CH2:55][CH:56]4[CH2:58][CH2:57]4)=[CH:38][CH:39]=3)[C:33]=2[CH:34]=1)(C(C)(C)C)(C)C>O>[CH:56]1([CH2:55][O:54][C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[C:41]2[NH:42][C:43]([C:46]4[C:47]([Br:53])=[CH:48][CH:49]=[CH:50][C:51]=4[Br:52])=[N:44][C:45]=2[C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C:27]([CH3:60])([OH:26])[CH3:59])=[CH:34][C:33]3=2)[CH2:57][CH2:58]1
Reactant: CC(C)(Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21

Procedure:
TBAF (1 M in THF, 10 mL) was added to a flask containing 6-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-9-(cyclopropylmethoxy)-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole (0.223 g, 0.31 mmol) from Step 7 above, at room temperature. The resulting solution was heated at reflux for 36 h, after which water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, the organic layer dried over MgSO4, filtered and concentrated. The crude product was used directly in the next reaction (Step 9 below).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].C(N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C([Br:43])C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([Br:43])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(Br)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(Br)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-6-bromo-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-bromo-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 238). MS (ESI, pos. ion) m/z 461, 463 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].[CH3:36][NH2:37].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:37][CH3:36])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Yield: 75 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (436 mg, 0.866 mmol) and 2.00N methylamine in THF (1.93 mL, 3.85 mmol) were combined to provide 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (141 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6): δ 2.89 (s, 3 H), 3.53-3.61 (m, 3 H), 7.24-7.31 (m, 3 H), 7.49-7.51 (m, 2 H), 7.65-7.75 (br. m, 1 H), 7.79 (m, 1 H), 8.03 (s, 1 H), 8.37-8.39 (m, 1 H), 8.65-8.73 (m, 2 H), 9.40 (s, 1H); MS (ESI) m/z: 487.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCN(C(C)C)C(C)C>CC(O)C>[C:12]([N:19]1[CH2:20][CH2:21][N:22]([C:6]2[N:7]=[CH:2][C:3]3[CH2:10][C:9](=[O:11])[NH:8][C:4]=3[N:5]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc3c(n2)NC(=O)C3)CC1
Reaction time: 14 h

Procedure:
A solution of 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (prepared according to the literature: Li Sun et al. Bioorg. and Med. Chem. Lett. 2002, 12, 2153-2157; 690 mg, 3.7 mmol), Boc-piperazine (630 mg, 3.7 mmol), and DIEA (0.96 mL, 5.5 mmol) in 20 mL IPA was heated to reflux and stirred 14 hours, after which the reaction mixture was concentrated. The crude was purified on silica gel (1:2 DCM:EtOAc to 1:4 DCM:EtOAc gradient) to give 4-Boc-piperazin-1-yl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one, which was used in the next step.